Prepared by:

Brentuximab VedotinAntibody–Drug Conjugate

Brentuximab Vedotin Adcetris ®

Antibody–Drug Conjugate (ADC)

• Anti-CD30 Antibody >> chimeric monoclonal antibody AC10 (cAC10, brentuximab).

• Drug >> monomethyl auristatin E (MMAE) the small-molecule microtubule inhibitor (Anti neoplastic agent )

• Protease cleavable linker

• It is an anti-neoplastic agent used in the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

Lymphoma

• Lymphoma is cancer of the lymphatic systemHodgkin lymphomaNon Hodgkin lymphoma

• In Hodgkin lymphoma, it is cells in the lymph nodes that have become cancerous

Targeting treatment

Significance of ADCs

• Antibody-drug conjugates or ADCs are an important class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of cancer by allow sensitive discrimination between healthy and diseased tissue .

Potency as anticancer Side effect

• Drug >> monomethyl auristatin E (MMAE)

• chimeric monoclonal antibody AC10 (cAC10, brentuximab). >> Anti-CD30 Antibody

• CD30 is a glycoprotein and a member of the tumor necrosis factor (TNF) receptor family.

• CD30 is highly expressed by cells in Hodgkin lymphoma and on anaplastic large cell lymphoma (ALCL) cells.

Brentuximab vedotin

SG30 drug

• Naked antibody cAC10 antibody

SG30 drug

• entered clinical development in 2003

• administered as weekly doses as high as 12 mg/kg,

• In phase 2 trials, the overall response rate (ORR) in ALCL patients was 17 % in HL (0 %ORR) did not warrant further development and therefore a corporate decision was made to discontinue the program.

Appropriate Antibody

• Depends on the cell type receiving the signal • Environment in which the signal is delivered.

Signaling mediated by CD30

cell proliferation

survival

Anti proliferation

cell death.

cAC10 nuclear factor kappa B

The chimeric monoclonal antibody cAC10 binds with CD30 :

• Promote arrest of tumor cell growth • Cause DNA fragmentation

• Targeting the MMAE to the cancer cell

Chemical Structure

Anticancer activity of Brentuximab Vedotin

1) Binding of the ADC to CD30-expressing cells

2)Internalization of the ADC–CD30 complex

3) Release of MMAE via proteolytic cleavage.

4) Binding of MMAE to tubulin

5)Disrupts the microtubule network within the cell.

6)Inducing cell cycle arrest and apoptotic death of the

cells

• Rapidly release of potent cytotoxic component inside the tumor cell >>> Rapid effect

• Limits systemic release of the cytotoxic agent>>> lower systemic side effect.

Benefits of antibody–drug conjugate (ADC)

Pharmacokinetic of drug

• Absorption:intravenous infusion >>> 100% absorption.

• Protein binding:MMAE is highly-protein bound drugs that has a plasma protein binding range of 68-82%.

•  Metabolism:Only a small fraction of MMAE is metabolized primarily via oxidation by CYP3A4 and CYP3A5.

 

• Execration::Monomethyl auristatin E is eliminated by the feces and urine.

 

• Half Life:The terminal half-life is 4-6 days.

•  Clearance:Monomethyl auristatin E is cleared by the liver but not quantitative studies have been performed.

Common side effects•  Numbness or tingling in fingers and toes

It starts within a few days or weeks and usually goes within a few months of finishing treatment.

• Feeling or being sick

• Tiredness and weakness (fatigue)

• Diarrhea

• Constipation

• An increased risk of getting an infection due to a drop in white blood cells.

• Cough, sore throat

• Aching muscles

• A high temperature (fever(

• Headaches

• A skin reaction a rash, itchy and dry skin

• pain passing urine

Toxicity• The most severe toxic reaction seen in patients is

progressive multifocal leukoencephalopathy.

• peripheral neuropathy

• Pancreatitis

• Pulmonary toxicity

• bone marrow suppression

• infusion reactions

• Stevens-Johnson syndrome

• tumor lysis syndrome

• Many other ADCs are in clinical trials and further research towards bi- and multispecific hapten binding antibodies will hopefully lead

to a next generation of ADCs.

Nanobodies

• https://www.youtube.com/watch?v=ZpUMsaclrq8

• https://www.youtube.com/watch?v=oeGQjB395Eo

• https://www.youtube.com/watch?v=xH8xGT1nRu4

• https://www.youtube.com/watch?v=08q2Th3GQ5w

Video animation

How a Drug Becomes a Drug

• https://www.youtube.com/watch?v=U96He401wj4