Advance in biopharma_india_ch_14_shah

Endocrine Technology, LLC

Magnetical

CanBiotech

Biospectrum Asia

Serum Institute of India Ltd.

Cadila Pharmaceuticals Ltd.

J. Sagar Associates

Amgen, Inc.

Apothecaries Ltd.

Chiltern International Private Limited

Strategic Manufacturing Worldwide, Inc.

Ad

vAn

CES In � �Biopharm

aceuticalTechnology �in �India

1060757819349

ISBN 978-1-934106-07-5

About Advances Biopharmaceutical Technology in India

The biopharmaceutical industry in India has grown dramatically over the past few years, and sales have exceeded US$1.5 billion. This study describes the Indian

biopharmaceutical industry, its history, its advantages and opportunities, as well as its challenges and risks. Today, the biopharmaceutical industry in India has brought several protein drugs to market and is developing many more. The next several years will be interesting as India takes its place on the global stage. Biopharmaceutical products have a long history in India, and trace their roots back several thousand years through schools of healing practice. The Indian government is currently working towards developing that experience into a sound biotech industry. The country’s objective is to help minimize foreign dependence, especially in high-tech areas. This study describes the industry’s history, and the Indian government policies that have helped enable the manufacture of modern biotech products at affordable prices. We discuss the patent factors and history that have shaped the Indian industry, including the industry’s reliance on production of outside-of-patent products. As the Indian government continues its efforts to create alliances between private industry and research institutes, the next decade should show a significant growth in the Indian biotech industry, and novel biotech drugs may ultimately dominate. India is expected to emerge as a strong player in the production and sale of biotech products in the coming years, as local consumption rises, and as its local biotech industry takes steps to develop a globally competitive local industry that stands on a foundation of basic research.

Authors �from: �M J Biopharm Pvt. Ltd.

Bharat Biotech International Ltd.

neo BioMed Services

beòcarta Ltd.

Chiltern International Pvt. Ltd.

Jim Schnabel, BioPlan Associates, Inc.

John Curling Consulting AB

ProMetic BioTherapeutics, Inc.

Celestial Biologicals Ltd

dow AgroSciences LLC

GAEA Resources Inc.

Finston Consulting, LLC

Chiltern International Private Ltd.

Health Interactions

national Institute of Health

Uniformed Services University of the Health Sciences

national Institute of Science Technology and development Studies

Advances in Biopharmaceutical

Technology in India

January 2008

Editor: Eric S. Langer

BioPlan Associates, Inc.Rockville, MD, USA

SOCIETY FOR INDUSTRIAL MICROBIOLOGYArlington, VA, USA

ii

BioPlan Associates, Inc. 15200 Shady Grove Road, Suite 202

Rockville MD 20850 USA

301-921-9074

www.bioplanassociates.com

and

Society for Industrial Microbiology3929 Old Lee Highway Suite 92A

Fairfax, VA 22030-2421

703-691-3357

Copyright © 2008 by Eric S. Langer

All rights reserved, including the right of reproduction in whole or in part in any form. No

part of this publication may be reproduced, stored in a retrieval system, or transmitted in

any form or by any means, electronic, mechanical, photocopying, recording or otherwise,

without the written permission of the publisher.

For information on special discounts or permissions contact BioPlan Associates, Inc. at

301-921-9074, or [email protected]

Editor: Eric S. Langer

Project Director, Enterprise: Yibing (Eliza) Zhou

Project Director, Scientific: John Morrow

Production: ES Illustration and Design, Inc.

Text and Cover Design: Esperance Shatarah

Cover photos courtesy of Shantha Biotech

ISBN 978-1-934106-07-5

iii

Acknowledgment

This project would not have been possible without the exceptional efforts of the many people involved. In particular, we would like to thank: Yibing (Eliza) Zhou, Project Director, Enterprise John Morrow, Project Director, Scientific ES Illustration and Design, Inc., Production Manager, cover graphics.

We would also especially like to thank our reviewers, whose expertise ensured this volume addressed today’s most important issues: Prof. P.S. Biesen, Director, Madhav Institute of Technology and Science, India Prof. Ananda Chakrabarty, University of Illinois, USA Dr. Thomas E. Colonna, President, Biotech Consultant LLC, USA Dr. John Curling, President, John Curling Consulting, Sweden Dr. Milind Deshpande, Technical Director, Fermentation and Processing, University of Iowa, USA Dr. P.K. Ghosh, President, Biotechnology, Cadila Pharmaceuticals Ltd., India Dr. Vijai Kumar, President & Chief Medical Officer, Excel Life Sciences, Inc., USA Dr. Yennapu Madhavi, Scientist, National Institute of Science Technology and Development Studies, India Dr. John Morrow, President, Newport Biotech, USA Dr. Brandon Price, President. Falconridge Associates, Inc., USA Dr. Gayatri Saberwal, Scientist, Institute of Bioinformatics and Applied Biotechnology (IBAB), India Dr. V.K. Srinivas, General Manager R&D, Bharat Biotech, India Dr. S. Vsisalakshi, Scientist, National Institute of Science Technology and development Studies, India Dr. Scott Wheelwright, President, Strategic Manufacturing Worldwide, Inc., USA

We also extend our sincere appreciation to Shantha Biotech, and Ms. Sravanthi Reddy for her support and use of cover photos and graphics.

Thank you for your efforts, and your recognition of the importance of this study.

Eric S. LangerManaging Editor

iv

Preface

This study was undertaken, managed and coordinated by BioPlan Associates, Inc., a biopharmaceutical management and marketing research consulting firm in Rockville, MD, based on nearly 20 years

experience and knowledge of the market segment. BioPlan surveyed the industry to identify required content, and then selected subject matter experts to author relevant chapters to this study.

The Society for Industrial Microbiology (SIM), in recognizing the importance of applied sciences in biotechnology processes, has lent its name to this endeavor. The Society for Industrial Microbiology is a nonprofit professional association dedicated to the advancement of microbiological sciences, especially as they apply to industrial products, biotechnology, materials, and processes. Founded in 1949, SIM promotes the exchange of scientific information through its meetings and publications, and serves as liaison among the specialized fields of microbiology. Membership in the Society is extended to all scientists in the general field of microbiology.

India is one of the fastest growing economies in the world. The country has invested heavily in advancing its pharmaceutical and biopharmaceutical technologies to improve its healthcare systems, its population’s general health, and its overall economy.

Both scientists and entrepreneurs in India have made important contributions to advancing the field at many levels. This study provides a framework from which both those new to India’s rapid advancements in biotherapeutics and vaccines, and those with long histories can recognize the potential, and plan for the future. The findings of this study support worldwide public health and economic policy.

Each chapter provides unbiased, peer-reviewed perspectives of the current state of the science and technology associated with biopharmaceuticals in India. While no single work can encompass all the advances being made in the field, this study offers a comprehensive assessment of the technological and economic advancements in India.

The intended audiences include decision-makers at biopharmaceutical research organizations, biotherapeutic manufacturers, contract manufacturing organizations, suppliers to the industry, policy-makers, and international entities evaluating this market. We plan to keep this study current by providing regular updates as technologies, and the industry advance.

v

Advances in Biopharmaceutical Technology in India Table of Contents

PART 1: Introduction .............................................................vii

Chapter 1 Prospects for Modern Biotechnology in India ....................................................... 1 Prasanta K. Ghosh, Prasenjeet Ghosh, Soma Ghosh, and Kushal Shodhan

PART 2: State of India’s Life Sciences Industry ......................67

Chapter 2 A Window into India’s Biopharma Sector .............................................................69 Narayan Kulkarni

Chapter 3 Indian Biopharmaceutical System and Policies ................................................109 Yennapu Madhavi, Ph.D.

Chapter 4 Government Support for Biotech and Biopharmaceuticals Industry ..........127 Dr. B.M. Gandhi

Chapter 5 Biopharmaceutical Products in India ..................................................................179 Scott M. Wheelwright, Ph.D., and Hazel Aranha, Ph.D.

Chapter 6 Biogeneric Manufacturing in India ......................................................................203 Ashesh Kumar, Ph.D.

Chapter 7 Biopharmaceutical Market Situation ..................................................................235 Merlin H. Goldman, PhD MBA CEng MIChemE

Chapter 8 The Contract Research Industry in India ............................................................281 Umakanta Sahoo, MBA, Ph.D., and Faiz Kermani, Ph.D.

Chapter 9 Regulatory Landscape for Clinical Trials in India ..............................................313 Romi Singh, Ph.D. and Brijesh Regal

INDIA BRIEF 1 Pre-Clinical and Clinical Trial in India ............................................................................................. 327 V.K.Srinivas, Ph.D

Chapter 10 Life Sciences Education in India ...................................................................................333 Dr Dipti Sawant, Ph.D., MBA, CCRA

vi

PART 3: Scientific Issues in India .........................................383

Chapter 11 Vaccine Industry in India .......................................................................................385 Dr.PrasadS.Kulkarni,M.D.andSureshS.Jadhav,Ph.D.

Chapter 12 Development of Plasma-Derived Biopharmaceuticals in India: Challenges and Opportunities .............................................................................465 JohnM.Curling,ChristopherP.Bryant,TimothyK.Hayes,RanjeetS.Ajmani

Chapter 13 Bioprocess Expression and Production Technologies in India .......................519 DavidMMousdale

INDIA BRIEF 2 Technology Transfer: Impact and Importance for Indian Biotechnology Growth ........ 555 SusanKlingFinston

Chapter 14 Application of Recent Advances in Immunology for Developing Novel Biotherapeutics in India .........................................................................................563 KumarShah,MD

Chapter 15 Early-stage Key R&D Components for Successful Development of Protein Therapeutics ..............................................................................................589 KrishnaM.Madduri,Ph.D.

Chapter 16 Understanding Ayurveda Medicine ....................................................................605 Dr.SampadaAmolMahajan

PART 4: Biobusiness in India ...............................................619

Chapter 17 Biopharmaceutical Outsourcing: A Comparative Overview of the Landscape between India and China ...........................................................621 MinnaA.Damani

Chapter 18 Biopharmaceutical Research Collaborations between India and the West: A Guide to Prospective Partnerships .................................................661 UriReichman,Ph.D.,M.B.A.,BharatKhurana,D.V.M.,Ph.D.,and StevenM.Ferguson

Chapter 19 Outsourcing R&D to India ......................................................................................723 ProbirRoyChowdhuryandSajaiSingh

INDIA BRIEF 3 Outsourcing Biopharma R&D to India ........................................................................................... 741 JimSchnabel,SeniorResearchAssociate,BioPlanAssociates,Inc.

Chapter 20 Venture Capital in India Today ..............................................................................747 SajaiSinghandProbirRoyChowdhury

14 Application of Recent Advances in Immunology for Developing Novel Biotherapeutics in India

KUMAR SHAH, MD, PresidentAmit Shah, Scientific OfficerDepartment of Research and DevelopmentEndocrine Technology, LLC304 Livingston Street,Brooklyn, NY 11217Phone: 718-222-1065Fax: 718-852-7412E-mail: [email protected]

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Advances in Biopharmaceutical Technology in India

About the Authors

KUMAR SHAH, MD is a Founder and President of Endocrine Technology, LLC in NY, USA. He has over 20 publications and several patents related to the modulation of Factor H. He is a Diplomat in Internal medicine, Diabetes, Endo-crinology and Metabolism. He is in active consulting practice. In India he served as clinical research physician for Roche Products and acted as a consultant to initiate “Cell Transplant Laboratory for the cure of diabetes” for the institute of kidney diseases, Ahmedabad, Gujarat State. He has presented paper in National HIV/AIDS conferences held in Mumbai (HIV Congress: 11-13th March, 2005).

AMit SHAH is a scientific officer of Endocrine Technology, LLC. He is involved in developing immune modulation technology of the Company and in the management of information technology. He has a degree in computer sciences and research interests in biotechnology field.

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CHAPTER 14 n Application of Recent Advances in Immunology for Developing Novel Biotherapeutics

ABSTRACT

Immunity is a major barrier in the translational development of

bio-pharmaceutical drugs. The US Food and Drug Administration

estimates a cost saving of US$100 Million if the human safety of

new drugs could be predicted with 10% accuracy. The recent advances

in the fundamentals of immunology have assigned a host protective role

to Factor H. Factor H is an immune regulatory protein of a billion year

old early human defense system such as Alternate Complement System.

The Alternate Complement System plays a crucial role in activating

host inflammatory and memory responses when foreign material such

as bacteria, viruses, cancer cells, allogenic and xenogenic somatic cells,

biotherapeutics drugs or bioterrorism related organisms interact with

host and its immune system. The potential of Factor H modulation to

develop novel bio-pharmaceutical products to prevent, treat and control

global diseases is detailed. Large drug companies are looking to devel-

oping countries such as India for cost-effective clinical development of

novel biotherapeutic drugs such as vaccines for HIV/AIDS. India offers

the necessary legal and scientific framework for multinational compa-

nies with product patents to develop novel biotherapeutic products

cost-effectively.

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Application of Recent Advances in

immunology for Developing Novel

Biotherapeutics in india

1. introduction

In translational development of biotherapeutic drugs, immunity is a major barrier.1 The human safety issue remains a problem that affects companies in both clinical trials and in post marketing phase.2-4 The

drug industry’s problems associated with meeting the regulatory safety and efficacy standards for new products are analyzed in an FDA report on inno-vation stagnation published in 2004 (FDA).5 The cost of successful product from bench to bed-side has soared to US$1.7 billion by 2002. A growing list of fatal diseases compounds the problem of product pipe line and threatens the global consumers with next wave of morbidity and mortality from HIV/AIDS, tuberculosis, malaria, SARS and bird-flu like fatal pandemics along with evolving threats of bio-terrorism. FDA estimates that if product safety can be predicted with 10% accuracy, it has potential to save up to US$100 million in new product development costs. The recent advances in the fundamentals of immunology have assigned a host protective role to Factor H.6, 7 Factor H is 150 kD immune regulatory protein of a billion year old early human defense system such as Alternate Complement System. The Alternate Complement System plays a crucial role in generating host inflammatory responses and is involved in education, instruction and priming adaptive or memory responses.8, 9 The potential of Factor H modulation to develop novel bio-phar-maceutical products to prevent, treat and control global diseases is detailed.10-12

2. immunity as a Barrier in translational Drug Development

Historically, the critical event in the development of modern biothera-peutic drugs was deciphering the double helix structure of DNA in 1953 by Watson and Crick. Since then, recombinant DNA tech-

nology has given birth to numerous biotherapeutics such as recombinant insulin and erythropoietin. June 26, 2000, another milestone in genetics, is the day scientists announced the sequencing and assembling of the first rough draft –about 99% -of the genetic code that makes up the human genome.

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Novel biotherapeutic products incorporate living cells or subcomponents in the final product for the prevention, treatment and cure of diseases. This approach has the potential to tackle a growing number of deadly diseases. Large drug companies are looking forward to developing countries for the cost-effective clinical development of novel biotherapeutic drugs such as vaccines for HIV/AIDS. TRIP implementation in India offers the necessary legal framework for multinational companies with product patents to cost-effectively develop novel biotherapeutics.

Biotherapeutic products such as vaccine, recombinant proteins and immune related drugs including monoclonal antibodies13 is class of drugs experiencing the fastest rise in the new drug development process. Proteins are dynamic molecules with the ability to adapt to various environment and physiological factors. This flexibility allows a protein to transmit information from one biochemical pathway to another. Changes to the shape of a protein can acti-vate, inactivate, or affect the function of a protein. The importance of sialic acid in the proper function of recombinant protein and antibody is increas-ingly recognized14-16 Recombinant human protein therapeutics; require complex glycosylation, such as sialytation, for stability, solubility, folding, phar-macokinetics, pharmacodynamics activity and to prevent host inflammatory reactions. Developing and marketing biotherapeutics based on recombinant proteins and antibodies or its generic equivalents require specialized dedicated facilitates of cell culture and fermentation technology. Manufacturing and marketing of such products require different mind set and expertise than that is generally required for generic drugs.

The biotherapeutics drugs such as recombinant proteins and monoclonal antibodies have added new layers of complexity and cost to the drug devel-opment process. For example, there are differences in the sialic acid binding sites in apes and human. The differences in sialic acid binding between Apes and human beings apparently has contributed to the occurrence of cytokine storm or “Acute inflammatory syndrome” in recently carried out human trial of antibody after it was proved safe in monkey studies. Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel super agonist anti-CD 28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflamma-tory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythrema, vaso-dilatation and hypotension Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure and disseminated intravascular coagulation. After intensive hospital therapies all six patients survived.

The full safety profile of a drug is rarely known at the time of approval by the Food and Drug Administration (FDA). Most drug-development programs are

tRiP implemen-tation in india offers the necessary legal framework for multinational companies with product patents to cost-effectively develop novel biotherapeutics.

568


designed for the treatment of symptomatic indications are under powered to detect any increased risk of rare drug reactions or change in background event rates attributable to the drug. Large, post marketing, randomized, controlled trials provide robust data on drug safety but are subject to multiple source of bias. Observational studies of a drug’s effects in clinical practice can offer addi-tional information on risks. Post-marketing observational studies permit the evaluation of drug safety in large number of patients in a real world setting, where practice patterns, including off label use of his drug can be assessed. Aprotinin was approved by FDA in 1993 as a mean of reducing periopera-tive blood loss in patients undergoing coronary artery bypass grafting. Neither the clinical trial database nor the numerous randomized controlled clinical trials conducted after approval identified an association between aprotinin and any short term increase in the risk of death or nonfatal cardiovascular or any serious renal toxic effects.

Overwhelmingly, the drug development process involves two dimensional models of in-vitro screening of chemotherapeutic drugs for efficacy against pathogens and cancer cells. Such screening efforts do not take into account the third dimension that is how the drug will behave once it is introduced in warm blooded animals. Immune response is different in small animals, large animals and in human models. The drug interacts three dimensionally with host and its immune system most strongly in humans. Sialic acid binding is the common point of interactions. Due to the differences in sialic acid binding, the successful results from small and large animal model often are not translated into human safety and success. The host immune system reacts with endo-toxins, foreign proteins, antibodies and cells to induce inflammatory responses where sialic acid variations and its interactions with the alternate complement system are common denominators. Table 1 summarizes the role of immunity as a barrier in the translational development of drugs.

3. the Changing Role of Fundamentals of immunology:

The studies on immunity during the last few decades have mostly concentrated on the adaptive response in immunology and its hall-marks, that is, the generation of a large repertoire of antigen–recogni-

tion receptors and immunological memory that relates to cellular and antibody responses. Current understandings of immunology are not complete and over the period of time have undergone numerous revisions 17-19 Therapeutic immune suppressive drugs developed and based on above understandings are extremely toxic, have many adverse effects and are associated with increased risk of infection and tumor potentials.20

Recent anthrax event prompted the preparation of a document titled “Stra-tegic Plan for Bio-defense Research” in 2002 by Anthony Fauci, Director of National Institution of Allergy and Infectious diseases (NIAID) branch of National Institute of Health (NIH) in USA (http://biodefense.niaid.nih.gov).

Due to the differences in sialic acid binding, the successful results from small and large animal model often are not translated into human safety and success.

569


From a scientific and medical perspective, this plan is best seen as a variant of the general problem of emerging infectious diseases that have central char-acteristics of high morbidity and mortality due to inadequate diagnostic and therapeutic interventions. The document highlighted the need to study three dimensional interactions of microorganisms with host and its immune system. It was acknowledged in the document that this is the field where experts lacked in-depth understandings. The plan emphasizes the importance of gaining a better understandings in the three dimensional interactions of how pathogens interact with the host and its immune system. The investments were justified by pointing out that such a research and development plan will have potential spin off applications in immune related diseases of developed countries such as in transplants and autoimmune diseases. The research will extend benefits to immune related diseases of developing countries such as in their fight against Tuberculosis, HIV and Malaria. It was suggested that international cooperation with developing countries will facilitate the development of such therapeutics.

tABLE 1: immunity in drug development

S NO PROPERtiES PHARMACEUtiCALS BiOtHERAPEUtiCALS NOVEL BiOtHERAPEUtiCS

1 Type of Drugs Synthetics Derived from live cell Combined with Live

Cell or its Component

2 Molecular Size Small Large Variable

EX: 1.Vaccine

1.Recombinant Proteins 2.Cell Transplant

2.Antibodies

3 Drug Discovery Structural Analogs Cell Culture System, IN-VIVO

of synthetic Fermentation Combination

compound Technology of cell or its

By PhD (IN VITRO) Components

scientist /chemist

4 Product short life Long Short sensitive Shorter

to temp changes Sensitive to temp

Changes

5 Adverse Effects Hapten based 1.Endotoxin 1.Endotoxin

(Immune Related)

2.Sialic acid difference 2.Sialic acid difference

3.Early Immune reaction 3.Allo/xenogenic

4.Infection Risk

5.Early Immune Related

6.Delay Immune Related

6 COST <US$1 billion >US$1 billion >US$1.5 billion

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One of the major failing of the fundamentals of immunology is incomplete understandings as to how the immune system protects itself when acti-vated against foreign intruders. Currently scientists believe that the host is protected because of the presence of immune regulatory receptors in the cell membrane.21 In humans, immune regulatory proteins embedded in the host membrane are encoded by a cluster of genes located on the long arm of chromosome 1 (1Q32). This region is called as the regulator of complement activation (RCA) gene cluster. Although the proteins within the RCA family may vary in size, they share significant primary amino acid structure similari-ties. They are organized in tandem structural units termed as short consensus repeats (SCRs). The evolutionary relationships suggest membrane bound RCA proteins are functionally related.

The recent advances in immunology have shifted attention to the working of early human defense systems and the potential to educate, prime and develop memory based immune responses. Evolutionary immunologists date innate or natural defense system back 700 million years or more. The complement system is an ancient microbial defense system. This is a system of fluid prote-ases that interact with immune cells and its receptors to protect human beings from ancient time against foreign intruders. The individual fluid proteases are numbered C1-C9. The complement system has three ways to activate and augment human defense system. One is antibody based that lead to the acti-vation of classical complement system. The second approach is lectin based that is activated in response to presence of lectin based pathogen recogni-tion molecules and third is through Alternate Complement system. As shown in Figure 1, the objective of three pathways of complement system, C3 is to generate common molecule C3. According to the recent advances in Immu-nology, the innate complement system differentiates self, and non-self, through generation of common molecule C3 and its active catalyzed product C3b. C3b is constantly generated in body fluid due to “enzyme tick-over hypoth-esis” by Alternate Complement System. If non-self or bacteria is identified because of carbohydrate signature it carries, C3b preferentially binds to Factor B to generate C3bB. This is further acted upon by Factor D to generate C3b convertase, C3bBb. Factor D is 25 kD immune activating circulatory protein of Alternate Complement System. It is mainly synthesized in adipose tissues. It also amplifies the activated responses of Classical and Lectin based comple-ment system. Factor H now regulate the complement activation by breaking down C3bBb to inactive C3bH. Active C3 fragmented products, C3a-C5a and C5b-C9, membrane attack complex have inflammatory components and stimulate the production of inflammatory cytokines. C5b-C9 in addition has cytotoxic component that form membrane attack complex and cause cytolysis. C5b-C9 cytotoxic immune responses are fluid counter part of cellular cyto-toxic immune responses initiated by Natural killer cells. Factor H also act as a controlling point in the amplifying cascade and is involved in inhibiting

in humans, immune regulatory proteins embedded in the host membrane are encoded by a cluster of genes located on the long arm of chromosome 1 (1Q32).

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Legend: Figure 1

1. C3, three activating pathways of the complement system vis: Alternate, Lectin-based and Classical complement pathways

2. C3, Common end product of 1.

3. C3b, an activated C3 with thioester bond removed.

4. Factor D, serine protease activiating protein of Alternate complement activating pathway

5. C3bBb, C3 convertase that flag foreign pathogens

6. Factor H, complement regulatory protein that has been assigned new role of recognizing self, host tissue as per recent advances in immunology. Microbes pirate this protein to mask its identity as self.

7. C3a-C5a, activating intermediary complement products with host inflammatory actions.

8. Macrophage, also CD 4 or immature dendritic cell in which entry of bacteria is facilitated through its surface receptors.

9. CD 4 T matured dendritic cell where processed pathogen by 8 through phagocytosis express foreign signal by depositing peptide fragments in MHC 1 and MHC 11 groove

10. CD 4 T cell of adaptive immunity that sense foreign signal according to “two Signal hypoth-esis”.

11. Th 2 subtype of CD 4T cell that is involved in humeral cellular responses.

12. Ab, antibody that is formed by stimulation of B cells by 11.

+

+

Factor B

Factor D

Factor H

Factor I

C3

C3b

C3bB

C3bBb

C3bH

IC3b C3a-C5a

Phagocytosis

C3

Ab

B cell

Th 2

CD4T

CD4 Mature

CD4 Immature

NK cells

C5b-C9

CD8Tcells

Th 1 cellsCYTOTOXICRESPONSES

Activation of Human Defence Responses

+ IC3b Breakdown Product Costimulate B Cells

Figure 1: Recent advances in immunology

572


the formation of “Membrane attack complex” and at the same time inacti-vating C3b. The inactivated products of C3b such as iC3b, C3d, C3dg etc act as opsonin or natural adjuvant that attach breakdown products of foreign pathogen. Both inflammatory cytokines and natural adjuvant help in the maturation of dendritic cells by expression of co receptor function such as B 7 molecule. This according to “Two signal hypothesis” prime T cell responses. Another route by which iC3b and its breakdown product are involved in priming antibody responses is by acting as a natural adjuvant by binding to B cell receptors that amplify plasma cell function. Both T and B cell responses are involved in generating memory responses.

In the absence of foreign pathogen, C3b binds with Factor H to form C3bH. Factor H mainly bind to sialic acid binding sites on the host cell surface. Factor H is a circulatory complement regulatory protein of Alternate Comple-ment System. It has unique structure of twenty short consensus repeat (SCR) domain. Each SCR contain approximately 60 amino acids. Factor H is heavily glycosylated and has high sialic acid content. Factor H is the key self- recog-nition protein that discriminates host –like features on microorganisms and generate spectrum of activation rates for the complement system in different microorganisms. A central question in innate immunity is how its various systems distinguish between potential targets and hosts. Factor H uses its 20 SCR domains to search for and interact with many ligands on a given target. Each SCR domain contributes to the recognition pattern, and if these sites work cooperatively in the groups of twos, threes and fours, etc, then by simple combinational math Factor H would have ability to discriminate among over 106 target surfaces. In the absence of foreign pathogen C3b does not form C3b convertase.

The importance of recent advances in immunology emphasizing shift to early human defense system and is ability to educate, initiate and prime delayed adaptive immune responses is summarized in Table 2.

The dominant role of circulating immune regulatory proteins to protect host cells against activated immune system is slowly being recognized. In evaluating the structure-function relationship of circulating immune regulatory proteins with membrane bound proteins, a study of genes involved in the regulation of complement activation (RCA) is particularly instructive. Both membrane bound and circulatory immune regulatory proteins are related. However, circu-latory immune regulatory immune proteins appear to be a dominant compo-nent in this relationship.

Both t and B cell responses are involved in generating memory responses.

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4. the Market Opportunity:

India is increasingly being promoted as an outsourcing destination for the development of biotherapeutic drugs. The advantages cited are lower costs, and shorter time duration for development of new drugs.22-23 The

United States market is the most matured and advanced in terms of patent laws, drug development process, regulatory oversight to protect public safety, the market approval of drugs, and reimbursement systems. The US market is therefore most lucrative for novel drugs. The US has a health care cost of $ 1 trillion in the year 2000. This cost will climb to $2.3 trillion by 2015.24 TRIP implementation in the developing world coincides with the loss of patent protection on numerous drugs and biotechnology products in US. This provides new incentives for drug companies in developing countries. India’s manufacturing and formulation experiences over the past three decades comes in handy for generic drugs where patents have expired. The cost of new drug discovery and its clinical trials are soaring. The cost structure to develop new drug in developed world is very high. Multinational drug companies are therefore moving to developing countries to lower their costs and to tap new markets. The drug companies in developing countries have tremendous incen-tives to rapidly adapt US based regulatory standards and business norms. The compliance by drug companies will facilitate their participation in developing and manufacturing generic and biogeneric drugs for developed markets. It

tABLE 2 Recent Advances in the Fundamentals of immunology

Complement System Pathways S NO PROPERtiES CLASSiCAL LECtiN ALtERNAtE1 RECOGNITION Ab-Complex MBL-Carbohydrate C3b-Microbe

2 COMMON MOLECULE C3 C3 C3

3 AMPLIFICATION ALTERNATE PATHWAY ALTERNATE PATHWAY ALTERNATE PATHWAY

4 REGULATION FACTOR H FACTOR H FACTOR H

5 EFFECTOR

tYPE

1.C3b Convertase

FUNCtiON

Tagging of foreign particle-

SiGNiFiCANCE

Pathogen

RESPONSES 2.C3a-C5a Chemo taxis Inflammation

3.C5b-C9b Cytotoxic Cell Lysis

4a.C3b CR1 Binding

4b.iC3b CR3/CR4 Binding

4c.C3d CR2 Binding

6 ADAPTIVE 2+3 of item 5 T Cell Responses Memory Responses

RESPONSES 4a to 4c of item 5 B Cell Responses Memory Responses

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will help them to form collaborative partnerships with multinational drug companies and outsource their needs for new drug discovery, clinical trials, manufacturing and marketing. Developing countries such as India and China are experiencing rapid expansion of their health care markets. The consumer base in China and India covers 30 % or more of the global population. The ongoing trend to outsource medical care from the developed world to the developing world has accelerated. Both are adding new market opportunities in developing World. There are over 4000 biotechnology companies globally trying to compete to develop safe and effective products. By 2015, as TRIP implementation extends to under developed countries, the drug companies globally will compete for expanding market share.

A critical insight or an improved understanding of human biology, particularly in the fundamentals of immunology for example at the molecular level have the potential to improve safety of drugs in translational drug development program and also has the potential to provide better solutions to diseases that affect global populations. In the modern drug development process immunity is a common barrier for current and future therapeutics. As pointed out earlier, circulating immune regulatory proteins such as Factor H bind to the poly anionic or sialic acid residues present on the host cells. Factor H along with membrane immune regulatory receptors neutralize activated immune proteins on the cell surface. Bacteria and viruses co-evolved with human existence. They constantly fight with human defense system for their survival advan-tages. The presence of sialic acid content in their cell membrane allows them to mask their identity as self. Many bacteria and viruses such as avian, feline, murine and simian RNA viruses are inactivated and lysed by human serum. In recent years, a large number of bacteria, viruses, parasites, and cancer cells are identified that pirate the functioning of human defense system by binding to the circulating immune regulatory protein or its downstream breakdown prod-ucts. This is due to their sialic acid content. Therapeutic modulation of Factor H and its potential to develop novel biotherapeutic drugs in different diseases is detailed as under.

5. therapeutic Applications of Factor H modulation A. Atypical Hemolytic Uremia Syndrome (aHUS):

Hemolytic Uremic Syndrome (HUS) is a severe disease frequently leading to end stage renal failure. Clinical features include rapid deterioration of renal function, anemia, low platelet count and frag-

mented red blood cells in the blood.

Current classification of HUS delineates two major types. Classical HUS occurs almost exclusively in childhood and is caused by bacteria releasing Shigela-like toxins. The disease starts with signs of enteritis, generally initiated by Escheria Coli strains, mainly 0157. Atypical HUS (aHUS) usually occurs in adults, and has been reported in association with a variety of conditions

the consumer base in China and india covers 30 % or more of the global population.

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such as therapeutic drug usage (Ovulation inhibitors and immunosuppres-sive drugs) diseases such as malignancies and systemic lupus erythramatosus), Pregnancy and after child birth. Familial occurrence of aHUS is reported in siblings and in a few families with autosomal dominant inheritance and rarely with autosomal recessive transmission. According to one study of 111 patients with aHUS, 14 % patients had FH1 germ line mutations.25, 26 To understand the dominant relationship of circulatory immune proteins over membrane bound immune regulatory proteins, it will be useful to consider what happens in the absence of Factor H. Congenital deficiency of Factor H or its mutation, leads to the activation of Alternate Complement System due to unopposed action of Factor D. Since activated immune proteins are either not inactivated or partially inactivated by membrane immune regulatory proteins, it leads to “Atypical hemolytic uremia syndrome” (aHUS). The therapy at clinical level is to replace Factor H that is mainly synthesized in liver. An alternate approach is to inhibit activated complement system such as by modulation of Factor H. Thus Factor H modulation could be life saving in these patients.

B. HIV/AIDS Therapeutics: i. The Role of India: There is a perception that successful drug companies with novel products such as an HIV vaccine must balance ethics and morality in business practices, and issues of profiting from deadly yet preventable and treatable diseases such as HIV must be considered. This has played a role in encouraging India generic drug companies to take advantage of the Indian patent laws of the 1970s that allowed them to meet growing public demand for cost-effective medicines. It is a surprise to many people including Indian government officials that it is estimated there are close to 6 million HIV patients in India and. HIV is expected to grow four folds to 25 M by 2025. There is an added risk that 50 % of these patients will have reactivated tuber-culosis that may be resistant to currently available drugs. Since half of HIV patients in developing countries may harbor tuberculosis that may be resis-tant to multiple drugs, the future scenario of public health in India is a chal-lenge. In March 2005, the Indian parliament passed the third amendment to the Indian Patent Act (1970) that led to the introduction of “Product Patent regime”. This has raised serious questions regarding the role of generic drug industry and its ability to compete and at the same time provide the continuing availability of essential medicines at affordable prices.

ii. The Dilemma of Brand vs. Generic Drugs: New drug development in developed countries is costly. It is a high risk venture that takes 10-15 years of sustained effort. The chances of success is only 30 % after animal tests are completed. In 20th century the traditional pharmaceutical industry played a dominant role in the control of major infectious and chronic diseases. This reduced greatly the morbidity and mortality for example HIV/AIDS in devel-oped countries. The high charges for new medicines by major pharmaceutical companies were justified in developed countries. The medical management

there is a perception that successful drug companies with novel products such as an HiV vaccine must balance ethics and morality in business practices…

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of patients in developed countries is supported by adequate reimbursements for new technology and patented drugs. Perhaps, the high reimbursement rate and profits in developed country could be used effectively to innovate at marketing level to lower the cost of drugs through outsourcing. However, high cost drug models in developing and under developed countries is problematic. There are no adequate laws to protect patented inventions. There is no reim-bursement mechanism for marketed patented products. The ongoing drama of affordability of essential medicines for example in HIV/AIDS is played out in major news papers.

In the 1970s India introduced product process patent laws. The laws were mainly geared to stimulating competitive capabilities of local drug industries. It was an enormously frustrating experience at the regulatory level to introduce advanced products based on Western patents. Indian patent laws of the 1970s provided a way for Indian drug companies to do what was legally allowed: copy patented products by bypassing the manufacturing and drug development process. From a regulatory point of view the generic drug company only needs to prove that their products are bioequivalent to patented drugs. Thereby, the Indian drug companies reduced the cost of drug development to 1/1000th of patented cost. This allowed the Indian drug industry to flourish in developing and third world countries. It allowed them to compete with multinational drug companies effectively. Copied products were marketed at a fraction of the cost that was charged by multinational companies. This benefited consumers to meet their dire needs for products that were safe, low cost and quality based. In the public eyes generic drug companies were perceived as benefactors of humanity and multinational drug companies were branded as exploiters of human rights.

Despite scientific progress and therapeutic advances –cost ineffective medicines and cheap generic counterparts have proliferated and the demand –supply gap for truly life saving drugs have widened. This is a true international emergency of the 21st Century. Leaders around the world are scrambling to find mean-ingful solutions to contain the rapid global spread of infectious disease such as HIV/AIDS.

iii. The Adverse Impact of Patent laws of 1970s: The patent laws of the 1970s included controversial Section 5(1) which provided for process patents and stifled innovation in India. There is no market mechanism to adequately reimburse patented products. The invention and discovery of new drug development is considered costly, economically not viable, and wasteful of time, money and energy by academic centers, financial centers and experts in India. This inertia is reflected in poor venture capital investment in research and development of new drugs. The hospital system, the education system and medical industry in general remained apathetic and negligent in their mission objectives to serve humanity. Availability of cheap drugs and lack of appro-priate reimbursement mechanisms or insurance system led to the neglect of

[t]he indian drug companies reduced the cost of drug development to 1/1000th of patented cost.

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medical illnesses and its follow up in developing countries. This has put India innovation several years behind developed countries.

iv. New Patent regime in India: The Indian parliament’s third amend-ment to the Indian Patent Act (1970) that led to the introduction of “Product Patent regime” raised serious questions regarding the role of generic drug industry and its ability to compete and at the same time provide the continuing availability of essential medicines at affordable prices. The recent introduc-tion of Trade related intellectual Property Agreements (TRIP) is intended to correct the past imbalance by creating level Plainfield where an individual or a small company can compete with giant drug companies based on intellectual properties.

In the US, the patent process is governed by ’Prior User’s right’ while in Europe it is governed by ’First to file’. The typical requirement for an invention patented in the US is that it has to be useful, new and not obvious.27

India have adapted Trade Related Intellectual Property Agreements (TRIPs) and raised the bar for patented inventions to avoid spurious claims. In order to develop successful patent under section 2 (i) (j) of Indian patent act, a new definition for “new invention” has been added. ‘New invention’ is defined as, “any invention or technology which has not been anticipated by the publica-tion in any document or used in the country or else where in the world before the date of filing of the application with complete specification, i.e. the subject matter has not fallen in public domain or that it does not form part of the state of art”.

Patents and Gleevec:

Gleevec (spelled Glivac outside the United States) is used to treat chronic myeloid leukemia. This drug has been patented by a multinational drug company in 35 countries and is sold for $26,000/year. The drug was rejected in India under section 3(d) and is a subject of ongoing legal battle. Gleevac, the brand name version of imatinab mesylate is offered by generic drug companies at 1/10th price by obviating the need for clinical trials. (28).

Under the amended section 3(d) of Indian patent act the mere discovery of new use, new property, use of a known process, machine or apparatus or combination of two products is not patentable if it does not result in new product with increased efficacy of known compound. According to current Indian patent laws not patentable clause under section 3 (i) include “any process for the medicinal, surgical, curative, prophylactic, diagnostic or therapeutic or other treatment of human beings or any process for a similar treatment of animals to render them free of disease or to increase their economic value or that of products.”

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With reference to the inventive step, the Indian Patent Act states:

“‘Inventive step’ means a feature of an invention that involves technical advance as compared to existing knowledge or having economic significance or both that makes the invention not obvious to a person skilled in the art”.

The off label use of the drug can be patented as method of treatment in devel-oped countries. It is stated that medical –process patents threaten to complicate medical practice, increase cost, and restrict access to new procedures. Owing to such concerns, nearly 80 countries refuse to grant patents on medical proce-dure.29 Adaptation of US patent laws of ’Prior user right’ as opposed to ‘First to file’ European and Indian patent laws have the potential to remove abusive practices and may contribute to healthy industry competition. The patient is benefited by having access to needed drugs and the industry experiences healthier competition. The outcome of the implementation of TRIP laws in India is that in August and September 2006, patients with cancer, lawyers for patient advocacy groups, and representatives of nongovernmental organiza-tions (NGOs) converged on the offices of a multinational drug company in Mumbai, India, to protest the company’s efforts to obtain an Indian patent. This situation where novel applications of an established drug, in a new formu-lation and in new devices is of growing importance with the rapidly rising cost of drug development in resource limited country such as India. There is an urgent need to develop innovative and new solutions at the clinical level. Although, most physicians are allowed to use established drugs for new appli-cations, in a given patient the safety and efficacy of the off label drug use remains questionable. If an off label drug in a new formulation is effective in a fatal disease – there is nothing wrong in patenting the drug and it should be welcome. From regulatory perspectives, the drug authorities have taken a stand to allow the use of such drugs only after adequate clinical trials. This has a fixed clinical trial cost. The off label uses of the drug for new disease applica-tions either in existing or new formulation is a commercial activity. Another important step taken by US FDA is to punish the drug company with severe penalties for promoting the off-label use of drugs to physicians. Since clinical trials of a drug itself is a costly enterprise, there is very little incentive on the part of physicians or the drug industry to undertake large clinical trials to assess the importance of existing drugs in new deadly diseases unless they can patent it and prevent competition from generic companies. Patenting of new applications of existing drugs in new formulations is the fastest way to generate new therapeutic drugs at cost effective prices. It obviates the need for manu-facturing that can be outsourced. This can result in saving of US$200 million in up front cost. According to the US FDA, if the safety of the drug is known or if it can be predictable by 10 % it has potential to save US$100 million in drug development costs. The existing drug in new formulations has predictive potential of safety by at least 50 %. This should reduce the cost of drug devel-opment by US$500 million.

[P]atients with cancer, lawyers for patient advocacy groups, and representatives of nongovernmental organizations (NGOs) converged on the offices of a multinational drug company in Mumbai, india, to protest the company’s efforts to obtain an indian patent.

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In the era of new patent regimes, the mindset of Indian drug companies and government organization is tuned to serve the need of multinational drug companies as outsourcing partner and offset the impact of TRIP by finding new opportunities in the developed world. A large number of patented drugs that have annual sales of over US$100 billion in the US face expiry of patents. This is a new opportunity for Indian drug companies to compete internation-ally in developed countries for the generic drug market. Implementation of TRIPs coincides with the global explosion of knowledge. India has proven expertise in the management of information technology and its evolving tools. It is this leadership that is combined with patented technology that is helping Indian companies to handle knowledge base at global level. This is defining the new levels of competition and cooperation to gain new leadership role in the fight against global diseases.

v. Factor H Modulation for HIV Therapy: Responding to the rising problem of drug resistance, experts have opined for the need for better, simpler and safer drugs that target the HIV genomic structure in a novel way and at multiple points so that the risk of resistance obtained with current antiretro-viral drugs could be reduced.30 Another leading expert in immunology has commented that in view of the limited therapeutic efficacy of current Highly Active Anti Retroviral Therapy (HAART) regimes, there is an urgent need to combine such therapy with immune based approaches that may improve therapeutic efficacy of cocktail therapies.31 The modern drug discovery begins with genomics and proteomics. Thus for example the role of proteomics is evaluated to identify HIV-1 therapeutic targets in host proteome. Identification of novel targets for therapy that may not develop resistance is sorely needed. Therefore, the effects of Tat protein on cellular gene expression during various phases of the cell cycle of HIV replication have been studied. This has led to identification of several host proteins including Factor H that may offer novel therapeutic target.32 In the basic science literature the in-vitro experiments done with serum of HIV patients has shown that Factor H modulation kill HIV outside the immune cells.33 The recent advances in the fundamentals of immunology have identified the growing importance of Factor H in host protection. Factor H is an immune regulatory protein of Ancient human defense system, Alternate Complement System. Factor H is pirated by HIV while simultaneously it also activates complement system. The combina-tion of piracy of Factor H and activation of complement system allows HIV to neutralize and prevent the generation of fluid based cytotoxic immune responses. The breakdown products of immune activation play an important role in persistence of HIV infection in HIV treated patients and contribute to future resistance pattern.34, 35 Factor H modulation therefore has potential to prevent, treat and cure HIV. 36 However, the translational development of an antibody therapy is problematic. Differences in sialic acid between apes and human beings may precipitate ’acute inflammatory syndrome.’ Similar

A large number of patented drugs that have annual sales of over US$100 billion in the US face expiry of patents. this is a new opportunity for indian drug companies to compete…

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syndrome may also be precipitated with the development of Factor H anti-body. The congenital deficiency of Factor H leads to Atypical acute hemolytic uremia syndrome (aHUS) characterized by hemolysis, hypotension and renal failure. A novel therapeutic approach that inhibit Factor H while regulating the activation of Factor D is urgently needed to overcome above risk and enhance safety of novel biotherapeutic products.

Figure 2A details how HIV pirates the functioning of human defense system. HIV is an enveloped virus and has allo MHC 1 and MHC 2 proteins of the primary host as well as the immune regulatory machinery on its surface membrane. Once HIV enters the host body, it is efficiently sensed by comple-ment system. Both Classical and lectin based complement system is activated. This effort is amplified by Alternate complement system to generate C3b Convertase, 11, 12 and its down stream products such as C3a-C5a and C5b to C9. However, HIV simultaneously binds to circulating Factor H on its surface to form C3bH-HIV, 13 that inactivate C3b Convertase on its surface to prevent C5b-C9 cytotoxic immune response. The exact details of HIV binding site to Factor H has been detailed and appear to be on gp 120 as well as on gp 41. C3a-C5a draws immune cells to inflammatory sites to cause host damage, 14. The inactivated C3b products are used as natural opsonin to bind to HIV particle. Inflammatory milieu is used to facilitate HIV entry inside CD 4 cells. HIV multiplies and repeats its cycle of freshly infecting new immune cells. Inactivated C3 products such as iC3b and its breakdown products along with C3a-C5a that normally prime dendritic cell maturation is circumvented by HIV. HIV uses complement breakdown products as opsonins and use comple-ment receptors on the cell surface also to shuttle to follicular dendritic cells and persist there. This is the underlying mechanism for the failure of HAART regime. The crucial role played by Factor H in protecting HIV is evident if HIV is incubated in Factor H depleted sera from HIV patients. The absence of Factor H leads antibodies of HIV to sense the presence of HIV as foreign molecule and leads to prompt cytotoxic immune response to kill HIV outside the cell in the serum with 80% efficiency. Use of membrane bound immune regulatory Antibody, however brings only marginal improvements. Several new advances in the understanding of microbial interaction with Factor H have occurred. One critical problem is how one will control the prevention of atypical hemolytic uremia. One approach is controlled manipulation of Factor H and Factor D by developing a fusion molecule. Such an approach will lead to inhibit Factor H while preventing the over activation of Factor D. Dual strategy should work well to improve current methods of HAAART therapy. One potential advantage is by targeting immune evasion mechanism, the future risk of mutation and potential outbreak of new viruses could be prevented.

As shown in Figure 2B, HIV interacts with Factor D, Factor H and CD 4 T cells. Therapeutic strategy aimed to control Factor D will reduce host related

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Factor D

Factor H

C3

C3b

C3bBb

C3a-C5a

C3

Ab

B cell

Th 2

CD4T

CD4 Mature

CD4 Immature

HIV

Host In�ammation

Figure 2B: HiV piracy of Factor H

C3

C3b C3bBC3bH-HIV

C3bH-HIVNew HIV

Host Damage

C3bBb

DC MatureCD 4 Cell

DC ImmatureCD 4 Cell

T Cell Memory Response

Self Non-self (Level of Hierarchy)

Aborted

Aborted

Aborted

Factor D

Factor BFactor H

11

12

13

14

15

Figure 2A: HiV piracy of Factor H

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inflammatory damage by HIV and will prevent its persistence in follicular dendritic cells. This strategy will improve outcome of HAART regime. The persistence of HIV and the risk of resistance can be reduced. An alternative strategy is to inhibit Factor H to stimulate Alternate complement system. Since in blood of HIV patients there are already circulating Antibody, removal of Factor H will unmask the identity of HIV as foreign pathogen. Circulating Antibody will initiate cytotoxic immune responses to kill HIV. Incorporation of this strategy in most modern vaccines will lead to expedient solution to HIV/AIDS crisis.

Figure 3 shows the interaction of HIV with Factor D and Factor H is outside the CD 4 cells. Thus Factor H modulation will kill HIV outside the cells while protecting host from undue activation of Factor D.

Figure 3

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5 C. HIV Vaccine and its Availability: Historically, vaccination is the best method of preventing infection.37, 38 Among the difficulties confronting researchers are viral heterogeneity, the lack of practical animal model and ethical dilemmas involved in conducting primary prevention trials in the United States and abroad. India is being promoted as an outsourcing destination to develop novel biotherapeutic drugs. Interna-tional Association of Vaccine (IAVI) has spearheaded the project to do HIV vaccine trials in India. A large number of drug companies have responded to this call and are heading to India to initiate vaccine trials. HIV/AIDS vaccine is a reference example of novel bio-therapeutic product that includes a compo-nent of viral particle. The critical problems are the ethics, human rights and need to protect volunteers. HIV has sialic acid binding sites. This binding site is in the cell membrane and is located at gp120/41. This apparently has resulted in the difference in simian virus and HIV in human beings. Thus for example, Simian virus doesn’t progress to AIDS in monkeys. The vaccine for HIV developed and tested in monkey model has yet to prove its clinical merit in human trials. In human beings HIV readily progress to AIDS. The vaccine data generated in monkeys therefore is not predictive of its capability to block or prevent progression of HIV to AIDS. Most modern HIV vaccine efforts are generated to develop vaccine responses that target Gp 120/41. However, due to Factor H binding, they are not able to generate antibody responses. This is the reason for current failure of HIV Vaccine to induce cytotoxic immune responses.

The crucial role played by Factor H in protecting HIV is evident if HIV is incubated in Factor H depleted sera from HIV patients. The absence of Factor H leads antibodies of HIV to sense the presence of HIV as foreign molecule and leads to prompt cytotoxic immune response to kill HIV outside the cell in the serum with 80% efficiency. Use of membrane bound immune regulatory Antibody, however brings only marginal improvements. One potential advan-tage is by targeting immune evasion mechanism, the future risk of mutation and potential outbreak of new viruses could be prevented. On the basis of this data, Factor H modulation is considered by experts as novel “Complemen-tary AIDS Vaccine.39, 40 Since in HIV vaccine trials ethics is a major concern, Factor H modulation is a stand alone HIV Vaccine approach where there is no HIV particle is incorporated.

D. Age-related macular disease: One additional approach to drug discovery is information- Information of specific genes and its related proteins. These tools begin with bioinformatics and exploration of public gene bank data sites. To create a protein, messenger RNA (mRNA) – a copy of one DNA strand of a gene – is sent out of the cell’s nucleus and into cytoplasm, where protein is synthesized by ribosome that recognize and link to gather specific amino acid chains that make up a protein. Single Nucleotide Polymorphism (SNP) is a technique to study genes

india is being promoted as an outsourcing destination to develop novel biotherapeutic drugs.

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and its variations in amino acid and mutation. In the spectrum of blindness, few rival Age-related Macular Disease (AMD). With aging population, AMD is rapidly identified as novel area for drug development by multinational compa-nies.41 Modern drug discovery efforts have expanded to take advantage of new discovery tools of genomics.42-44 Macula is the portion of retina that perceives the sharpest external image. With aging, the cells of macula undergo degen-erative changes. The whole mark of AMD is an inflammatory lesion called as Drusen’s lesion. Several drug companies have products under development to inhibit the molecular target identified as angiogenesis. However, therapeutic manipulation of this target is applicable to less than 10% of advanced cases limiting therapeutic efficacy and market size. Several large scale trials have found that in 50% or more cases of AMD, Factor H is mutated leading to the activation of Alternate Complement System.

E. The Cure of Type 1 Diabetes: The use of recombinant insulin, its novel formulations and newer better oral hypoglycemic agents have improved therapeutic results in the management of diabetic patients. However, these efforts have not cured diabetes. It is not only a disease of developed countries but also a major problem in developing coun-tries. The globalization trends along with rising standards is creating eating patterns that is not healthy and contributing to obesity, diabetes and increased cardiovascular diseases.45 First generation of biotechnology companies success-fully manufactured recombinant insulin and its varied formulations are now available in clinical practice. The cure of diabetes by pancreas transplant is now an accepted clinical procedure and has success rate of 80-90% in the first year while by five year it declines to 57%.46 A successful cure of diabetes and proof of concept was provided for this method in 1993 by using biocompat-ible membrane that is substantially free from endotoxin content.47 Current methods to cure of diabetes require that biocompatible material used to encapsulate insulin producing cells must be substantially free from endotoxin content. Advances in immunology are leading to the better understandings of the immune rejection process. In spite of these advances, the currently prac-ticed technology for the cure of diabetes has many flows and requires further improvements. In 400 plus patients transplanted the success rate of cure of diabetes drops from 50% in first year to 33% by third year and to less than 10% by 5th year. Insulin producing cells get immune rejected. Prior to the year 2000 the yield of insulin producing cells was less than 10 % per pancreas and required as much as 5.6 pancreas to cure one patient with Type 1 Diabetes. By 2006, the technology has been improved, reducing the need for pancreas from 5.8 to one.48 A further technology advancement involving stem cells to manufacture insulin producing cells will outdate the need for donor pancreas in next few years.49 Such an advance will allow one to cure Type 1 diabetes at an earlier stage and in a broader level. It is estimated that in the USA total supply of pancreas is 6000 per year. Since, the cure of diabetes by single

the globalization trends along with rising standards is creating eating patterns that is not healthy and contributing to obesity, diabetes and increased cardiovascular diseases.

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pancreas in 2006, is reported, it is expected that number of islet cell transplant will rise dramatically in coming decade. Economics of each cure of diabetes cost approximately US$150,000/year that has current success rate of 50% at one year but drops to 10% by 5th year.50 Technology improvements may open up a huge market opportunity. With organ donation laws in place in India, where no islet cell transplants are performed, this provides an opportunity to collaborate and cooperate. The model example could be extended to clinical trials of other diseases. Collaborative sharing of data and open access to trial data, will speed the introduction of new biotherapeutics, identify early deadly complications and adverse effects and provide a mechanism of accelerating the clearance of regulatory hurdles.

F. Therapy for Renal Diseases: In 1995, Institute of kidney diseases in Ahmedabad, GS. initiated “Cell Transplant Laboratory for the cure of diabetes.” However, due to difficulties involved in curing diabetes, they shifted attention to developing stem cell tech-nologies to address immune rejection problems in kidney transplant patients. The Institute of Kidney diseases, incidentally is a largest transplantation center in Asia offering low cost renal transplants. The key problem identified in kidney transplant patients has been the development of memory responses leading to immune rejection and inadequate response to immune suppressive drugs. The Institute of Kidney Diseases has shown their stem cell technology advances and how CD 34 cells from donor bone marrow could be transplanted into recipient patients.51 This procedure helped to reduce cost and effec-tively reduced the need for immune rejection drugs leading to the successful outcome in transplanted patients. Many of the transplanted patients however, were related donors where immune system responses are likely to be weaker. The institute presented several cases of renal diseases as a part of continuing medical education. New advances in the fundamentals of immunology have thrown new lights on the cause and occurrences of adverse effects. This will lead to better safe immune suppressive drugs with least adverse effects.52

G. Cancer Metastasis: The human immune system is designed to defeat disease and has the ability to combat cancer cells. Recent advances of immunology explain and provide new insight into how cancer cells evade immune responses.53 A large number of cancers such as breast, bladder, cervix, lung, prostate, ovarian, tropho-blastic tumors, and thyroid and glioblastoma multiformes are identified that secrete Factor H or pirate its functioning.54-57) The piracy of Factor H allows cancer cells to protect against complement mediated formation of Membrane Attack Complex (MAC). Cancer cells may either prevent the formation of C3 convertase or inactivate MAC on its surface. Therapeutic implications are that incorporation of Factor H modulator can be exploited strategically to generate vaccine responses in cancers or to provide immunotherapy.

the institute of Kidney diseases, incidentally is a largest transplantation center in Asia offering low cost renal transplants.

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Endocrine Technology, LLC

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Amgen, Inc.

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Ad

vAn

CES In � �Biopharm

aceuticalTechnology �in �India

1060757819349

ISBN 978-1-934106-07-5

About Advances Biopharmaceutical Technology in India

The biopharmaceutical industry in India has grown dramatically over the past few years, and sales have exceeded US$1.5 billion. This study describes the Indian

biopharmaceutical industry, its history, its advantages and opportunities, as well as its challenges and risks. Today, the biopharmaceutical industry in India has brought several protein drugs to market and is developing many more. The next several years will be interesting as India takes its place on the global stage. Biopharmaceutical products have a long history in India, and trace their roots back several thousand years through schools of healing practice. The Indian government is currently working towards developing that experience into a sound biotech industry. The country’s objective is to help minimize foreign dependence, especially in high-tech areas. This study describes the industry’s history, and the Indian government policies that have helped enable the manufacture of modern biotech products at affordable prices. We discuss the patent factors and history that have shaped the Indian industry, including the industry’s reliance on production of outside-of-patent products. As the Indian government continues its efforts to create alliances between private industry and research institutes, the next decade should show a significant growth in the Indian biotech industry, and novel biotech drugs may ultimately dominate. India is expected to emerge as a strong player in the production and sale of biotech products in the coming years, as local consumption rises, and as its local biotech industry takes steps to develop a globally competitive local industry that stands on a foundation of basic research.

Authors �from: �M J Biopharm Pvt. Ltd.

Bharat Biotech International Ltd.

neo BioMed Services

beòcarta Ltd.

Chiltern International Pvt. Ltd.

Jim Schnabel, BioPlan Associates, Inc.

John Curling Consulting AB

ProMetic BioTherapeutics, Inc.

Celestial Biologicals Ltd

dow AgroSciences LLC

GAEA Resources Inc.

Finston Consulting, LLC

Chiltern International Private Ltd.

Health Interactions

national Institute of Health

Uniformed Services University of the Health Sciences

national Institute of Science Technology and development Studies

Advance in biopharma_india_ch_14_shah

Technology

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