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Treatment of B cell lymphoma by V4-34 encoded antibodies

Treatment of B cell lymphoma by V4-34 encoded antibodies

Blood 96(11 Part 1): 731a, November 16

Our earlier studies have shown that human mAbs derived from the V4-34 gene bind to and are cytotoxic to human B lymphocytes. Cell death following this novel autoreactivity is mediated by temperature dependent cross-linking of the ligand without complement or ADCC. Engagement of the cytoskeletal matrix associated B cell antigen disrupts the membrane integrity, leading to the formation of large membrane pores, within minutes of exposure to cytotoxic Ab. Alternatively, toxicity can also be mediated by complement fixation. The degree of cytotoxicity exhibited by V4-34 derived mAbs (n=25) varies from strong to weak, correlating directly with its B cell binding intensity. Sequence analysis of these mAbs shows that V4-34 gene in near germ-line configuration and a VH-CDR3 enriched in basic amino acids are essential for B cell binding. 216, the most cytotoxic human mAb from our library, kills a variety of human B cell lines representing various types of lymphomas (lymphoblastoid, Burkitts, DLC). 216 is also cytotoxic to a variety of primary B cell lymphomas obtained from patient biopsies. In NOD/LtSz-scid/scid mice increased survival of group treated with 216 (in some experiments complete cure) was observed in a lymphoma model with human pre-B cell line, Nalm-6. Pharmacokinetics and toxicity studies in mice have shown that 216 has a good half life and is completely non toxic. These studies recommend an evaluation of 216 in phase I trials for B cell lymphoma. 216, with its low risk-benefit ratio, could avoid many of the complications associated with immunotherapy. Normal B lymphocytes will repopulate since 216 does not bind stem cells. Since it is a naturally occurring human Ab, HAMA-like responses will not occur. Because further molecular modifications (humanization or conjugation to radionuclides/toxins) are not needed, 216 is ready to begin clinical trials. The pore formation, which probably occurs to different degrees, could enhance delivery of chemotherapeutic drugs to the lymphoma cells. Using lymphoma cell lines we have shown no down regulation of the antigen, hence development of resistant tumor should not be an issue. Since the B cell ligand recognized by 216 is physically distinct from CD20, it can be used in conjunction with other existing immunotherapies offered by chimeric/humanized Abs. Furthermore, since 216 shows increased toxicity towards cycling cells, V4-34 mAb based therapy can be additive with drugs that block cell cycle progression. In conclusion, this effector independent, radionuclide/toxin free treatment with a completely human Ab will lead to better patient management and once GMP production has been established the production cost should be similar to Rituximab and therapy would be less expensive than the labeled mAbs (including side effects).

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Accession: 035980335

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