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938 NATURE BIOTECHNOLOGY VOL 17 OCTOBER 1999 http://biotech.nature.com CORRESPONDENCE Anti-Gal antibodies—where’s the beef? To the editor: In your July issue 1 , Carl Borrebaeck avers that murine glycosylation patterns on murine antibodies, and on human antibod- ies produced in murine cells, will target them for rapid clearance by natural anti-Gal anti- bodies in humans. But the data defy him. First there is no evidence for reactivity in vivo. The detection of weakly reactive anti- bodies in an ELISA assay 1 is not the most appropriate model for what happens in vivo. Many polyreactive antibodies of low affinity exist in serum 2 , but at concentrations is gen- erally well below their K d ; little of the antigen will be bound in complex. Moreover, use of purified preparations for these assays is known to overstate significantly the effective immunotargeting of polyreactivities in serum 3 . If anti-Gal antibody were a real phe- nomenon affecting survival of murine or murine-produced antibodies, it would rou- tinely reveal itself as high levels of HAMAs (or HAHAs) in baseline serum assays in patients, but this is not the case. Second, there is no physical evidence of such complexes in vivo. We have examined dozens of samples of tracer- or therapeutical- ly radiolabeled mouse and human(ized) anti- bodies on HPLC sizing columns, either drawn from patients after infusion or by spik- ing labeled antibody into sera. All show a homogeneous peak in human sera, which is not displaced relative to the same antibody incubated in saline 4 . Yet soluble antigen–anti- body complexes are readily detectable in indi- viduals with high antigen levels 4–7 , in a rela- tion 4,5,7 that is not to be confused with the postulated anti-Gal antibody–antibody com- plexes. If there is an immune recognition of significance against Gal-containing mouse or human antibodies, it should be routinely detectable as complexes in vivo at baseline, but this is not the case. Finally, an abbreviated half-life due to anti-Gal reactivity is simply not true. The humanized anti-Tac antibody, Zenapax, is grown in mouse cells with murine glycosyla- tion patterns. In 92 patients treated, Zenapax had an average survival time of 20 days 10 , essentially indistinguishable from “human- grown” human IgGs (23 ± 4 days) 11 . Similarly for Synnapsis 12 ans ABX-IL8 13 . Thus of three humanized or human antibodies grown in mouse cells for which clinical data are avail- able, none exhibits an accelerated clearance in humans. There is no evidence for a baseline anti- antibody-mediated clearance, by anti-Gal or any other humoral activity. Accordingly, any further debate should be accompanied by new, clinical data that directly addresses the hypothesis, which has so far been lacking. R. P. Junghans Harvard Medical School, Harvard, MA e-mail: [email protected] 1. Borrebaeck, C. Nat. Biotechnol. 17, 621 (1999). 2. Casali, P. et al. Immunol. Today 10, 364–368 (1989). 3. Mouthon, L. J. Immunol. 154, 5769–5778 (1995). 4. Hagg, D.S. et al. J. Immunol. Methods 219, 7–21 (1998). 5. Sharkey, R.M. et al. Cancer Res. 50, 2823–2831 (1990). 6. Junghans, R.P. et al. J. Biol. Chem. 271, 10453–10460 (1996). 7. Junghans, R.P. et al. Proc. Natl. Acad. Sci. USA 95, 1752–1757 (1998). 8. Pimm, M.V. J. Nucl. Med. 26, 1011–1023 (1985). 9. Reynolds, J.C. et al. Int. J. Rad. Appl. Instrum. [B] 16, 121–125 (1989). 10. Vincenti, F. et al. N. Engl. J. Med. 338, 161–165 (1998). 11. Waldmann T. et al. Prog. Allergy 13, 1–110 (1969). 12. The Impact-RSV Study Group. Pediatrics 102, 531–537 (1998). 13. Krueger, J. et al. Presentation, XXII Annual Hawaii Dermatology Seminar (February 1999). Public and private plant breeding To the editors: A survey conducted by Ken Frey at Iowa State University shows that plant breeding research and development in the public sector has decreased 2.5 scientist-years per year from 1990 to 1994 1 . During the same period private industry was found to have an annual net growth of 32 scientist-years. The availability of Plant Variety Certificates, plant patents, and the extension of utility patents to cover new varieties as well as plant tissues and genes has contributed to industrial interest in the area. Indeed, technical advances being made by industry may equal or exceed those being made by the public sector. Thus, it may be necessary for all public programs to contain some level of genetically engineered material from industry. I sent the following survey to 187 public plant breeders; it was subsequently sent to others. The final number who actually received it is unknown. I have spoken with several plant breeders who have told me that difficulties associated with obtaining “pro- tected genetic stocks” from companies has harmed plant breeding in the public sector. I’m trying to determine how widespread this is. 1. Are you having difficulties obtaining genetic stocks from companies? 2. If yes, has this interfered with your plant breeding research? 3. If yes, has this interfered with your ability to release new varieties? 4. If yes, has this interfered with training of gradu- ate students? I received 86 responses, representing 25 US universities and 41 crops. Forty-eight percent indicated that they had experienced difficulty in obtaining genetic stocks from private companies; 45% indicated that this had interfered with their research; 28% felt that it had interfered with their ability to release new varieties, and a shocking 23% reported that it had interfered with the train- ing of graduate students. This informal survey raises a number of questions: (1) What is role of public breeding? Is it in the public interest to have future varietal releases done predominantly by industry, especially in light of the iindustry consolida- tions, with a concomitant potential decrease in genetic variability? (2) Should more pub- lic money be used to maintain a critical mass of public plant breeders? (3) Should industry be content to train plant breeders? If the numbers of plant breeders are decreasing, what does this mean for the future supply of plant breeders for industry? Many of these problems trace back to “material transfer agreements” (MTAs). Negotiating these will continue to be diffi- cult until the public and private sectors agree on a common culture. This will probably include an acknowledgment that: (1) Title to inventions and/or varieties made will reside with universities; this is mandated by most universities’ policy, culture, and federal law. (2) Universities will be required to grant exclusive licenses to industry. (3) Industry will be required to pay royalties for licenses (whether exclusive or nonexclusive) to plant materials developed by universities. Individuals at the highest levels in indus- try and academia must meet to discuss these issues. If every MTA starts with each side putting its most onerous terms forward, then negotiations will continue to be slow and the public sector breeders will be hurt in the near term; in the long run, companies may be hurt by a decrease in trained plant breeders. Finally, the public may be hurt by decreased genetic diversity resulting in fewer varietal choices. Steven C. Price University of Wisconsin, Madison, WI 53705 e-mail: [email protected] 1. Iowa State Univ, National plant breeding study. (1996). Erratum In the August Business and Regulatory News (Nature Biotechnology 17, 744–745, 1999), the article states that Japan will create a repository of 70,000 cDNA clones obtained from the Japanese population. The figure should have read 30,000 cDNA clones. The article was also incorrect in stat- ing that a database of SNP map data will be created using SNPs within protein-coding sequences by analyzing full-length human cDNA. The database will comprise SNPs in the promoter region, coding sequences, and the adjacent introns, using genomic DNA from 50 individuals. Letters may be edited for space and clarity. They should be addressed to: Correspondence Nature Biotechnology 345 Park Avenue South New York, NY 10010-1707, USA or sent by e-mail to [email protected] Please include your telephone and fax numbers. © 1999 Nature America Inc. • http://biotech.nature.com © 1999 Nature America Inc. • http://biotech.nature.com
Transcript of document
938 NATURE BIOTECHNOLOGY VOL 17 OCTOBER 1999 http://biotech.nature.com
CORRESPONDENCE
Anti-Gal antibodies—where’s the beef?To the editor:In your July issue1, Carl Borrebaeck aversthat murine glycosylation patterns onmurine antibodies, and on human antibod-ies produced in murine cells, will target themfor rapid clearance by natural anti-Gal anti-bodies in humans. But the data defy him.
First there is no evidence for reactivity invivo. The detection of weakly reactive anti-bodies in an ELISA assay1 is not the mostappropriate model for what happens in vivo.Many polyreactive antibodies of low affinityexist in serum2, but at concentrations is gen-erally well below their Kd; little of the antigenwill be bound in complex. Moreover, use ofpurified preparations for these assays isknown to overstate significantly the effectiveimmunotargeting of polyreactivities inserum3. If anti-Gal antibody were a real phe-nomenon affecting survival of murine ormurine-produced antibodies, it would rou-tinely reveal itself as high levels of HAMAs (orHAHAs) in baseline serum assays in patients,but this is not the case.
Second, there is no physical evidence ofsuch complexes in vivo. We have examineddozens of samples of tracer- or therapeutical-ly radiolabeled mouse and human(ized) anti-bodies on HPLC sizing columns, eitherdrawn from patients after infusion or by spik-ing labeled antibody into sera. All show ahomogeneous peak in human sera, which isnot displaced relative to the same antibodyincubated in saline4. Yet soluble antigen–anti-body complexes are readily detectable in indi-viduals with high antigen levels4–7, in a rela-tion4,5,7 that is not to be confused with thepostulated anti-Gal antibody–antibody com-plexes. If there is an immune recognition ofsignificance against Gal-containing mouse orhuman antibodies, it should be routinelydetectable as complexes in vivo at baseline,but this is not the case.
Finally, an abbreviated half-life due toanti-Gal reactivity is simply not true. Thehumanized anti-Tac antibody, Zenapax, isgrown in mouse cells with murine glycosyla-tion patterns. In 92 patients treated, Zenapaxhad an average survival time of 20 days10,essentially indistinguishable from “human-grown” human IgGs (23 ± 4 days)11. Similarlyfor Synnapsis12 ans ABX-IL813. Thus of threehumanized or human antibodies grown inmouse cells for which clinical data are avail-
able, none exhibits an accelerated clearancein humans.
There is no evidence for a baseline anti-antibody-mediated clearance, by anti-Gal orany other humoral activity. Accordingly, anyfurther debate should be accompanied bynew, clinical data that directly addresses thehypothesis, which has so far been lacking.
R. P. JunghansHarvard Medical School, Harvard, MA
e-mail: [email protected]
1. Borrebaeck, C. Nat. Biotechnol. 17, 621 (1999).2. Casali, P. et al. Immunol. Today 10, 364–368 (1989).3. Mouthon, L. J. Immunol. 154, 5769–5778 (1995).4. Hagg, D.S. et al. J. Immunol. Methods 219, 7–21 (1998).5. Sharkey, R.M. et al. Cancer Res. 50, 2823–2831 (1990).6. Junghans, R.P. et al. J. Biol. Chem. 271,
10453–10460 (1996).7. Junghans, R.P. et al. Proc. Natl. Acad. Sci. USA 95,
1752–1757 (1998).8. Pimm, M.V. J. Nucl. Med. 26, 1011–1023 (1985).9. Reynolds, J.C. et al. Int. J. Rad. Appl. Instrum. [B]
16, 121–125 (1989).10. Vincenti, F. et al. N. Engl. J. Med. 338, 161–165
(1998).11. Waldmann T. et al. Prog. Allergy 13, 1–110 (1969).12. The Impact-RSV Study Group. Pediatrics 102,
531–537 (1998).13. Krueger, J. et al. Presentation, XXII Annual Hawaii
Dermatology Seminar (February 1999).
Public and private plant breedingTo the editors:A survey conducted by Ken Frey at Iowa StateUniversity shows that plant breeding researchand development in the public sector hasdecreased 2.5 scientist-years per year from1990 to 19941. During the same period privateindustry was found to have an annual netgrowth of 32 scientist-years. The availability ofPlant Variety Certificates, plant patents, andthe extension of utility patents to cover newvarieties as well as plant tissues and genes hascontributed to industrial interest in the area.Indeed, technical advances being made byindustry may equal or exceed those being madeby the public sector. Thus, it may be necessaryfor all public programs to contain some level ofgenetically engineered material from industry.
I sent the following survey to 187 publicplant breeders; it was subsequently sent toothers. The final number who actuallyreceived it is unknown.
I have spoken with several plant breeders who havetold me that difficulties associated with obtaining “pro-tected genetic stocks” from companies has harmed plantbreeding in the public sector. I’m trying to determinehow widespread this is.
1. Are you having difficulties obtaining geneticstocks from companies?
2. If yes, has this interfered with your plant breedingresearch?
3. If yes, has this interfered with your ability torelease new varieties?
4. If yes, has this interfered with training of gradu-ate students?
I received 86 responses, representing 25US universities and 41 crops. Forty-eightpercent indicated that they had experienceddifficulty in obtaining genetic stocks fromprivate companies; 45% indicated that this
had interfered with their research; 28% feltthat it had interfered with their ability torelease new varieties, and a shocking 23%reported that it had interfered with the train-ing of graduate students.
This informal survey raises a number ofquestions:
(1) What is role of public breeding? Is itin the public interest to have future varietalreleases done predominantly by industry,especially in light of the iindustry consolida-tions, with a concomitant potential decreasein genetic variability? (2) Should more pub-lic money be used to maintain a critical massof public plant breeders? (3) Should industrybe content to train plant breeders? If thenumbers of plant breeders are decreasing,what does this mean for the future supply ofplant breeders for industry?
Many of these problems trace back to“material transfer agreements” (MTAs).Negotiating these will continue to be diffi-cult until the public and private sectors agreeon a common culture. This will probablyinclude an acknowledgment that: (1) Title toinventions and/or varieties made will residewith universities; this is mandated by mostuniversities’ policy, culture, and federal law.(2) Universities will be required to grantexclusive licenses to industry. (3) Industrywill be required to pay royalties for licenses(whether exclusive or nonexclusive) to plantmaterials developed by universities.
Individuals at the highest levels in indus-try and academia must meet to discuss theseissues. If every MTA starts with each sideputting its most onerous terms forward,then negotiations will continue to be slowand the public sector breeders will be hurt inthe near term; in the long run, companiesmay be hurt by a decrease in trained plantbreeders. Finally, the public may be hurt bydecreased genetic diversity resulting in fewervarietal choices.
Steven C. PriceUniversity of Wisconsin, Madison, WI 53705
e-mail: [email protected]
1. Iowa State Univ, National plant breeding study. (1996).
ErratumIn the August Business and Regulatory News(Nature Biotechnology 17, 744–745, 1999),the article states that Japan will create arepository of 70,000 cDNA clones obtainedfrom the Japanese population.
The figure should have read 30,000 cDNAclones. The article was also incorrect in stat-ing that a database of SNP map data will becreated using SNPs within protein-codingsequences by analyzing full-length humancDNA. The database will comprise SNPs inthe promoter region, coding sequences, andthe adjacent introns, using genomic DNAfrom 50 individuals.
Letters may be edited for space and clarity.They should be addressed to:CorrespondenceNature Biotechnology345 Park Avenue SouthNew York, NY 10010-1707, USAor sent by e-mail to [email protected] include your telephone and fax numbers.
© 1999 Nature America Inc. • http://biotech.nature.com©
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