Abstract
The Human Combinatorial Antibody Library (HuCAL) was screened for antibodies specific to human leukocyte antigen-DR (HLA-DR) that induce programmed death of lymphoma/leukemia cells expressing the target antigen. The active Fab fragments were affinity-matured, and engineered to IgG4 antibodies of sub-nanomolar affinity. The antibodies exhibited potent in vitro tumoricidal activity on several lymphoma and leukemia cell lines and on chronic lymphocytic leukemia patient samples. They were also active in vivo in xenograft models of non-Hodgkin lymphoma. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms, and was selective to activated/tumor-transformed cells. Although the expression of HLA-DR on normal hematopoietic cells is a potential safety concern, the antibodies caused no long-lasting hematological toxicity in primates, in vivo. Such monoclonal antibodies offer the potential for a novel therapeutic approach to lymphoid malignancies.
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Acknowledgements
We thank K. Ito and M. Sandor for cell lines and antibodies; S. Messemer and L. Fontanelle for the xenograft experiments; and the entire team of technicians at MorphoSys AG for technical assistance.
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It is a policy at GPC that every employee receives a stock option upon employment. All authors affiliated with GPC Biotech AG, or GPC Biotech Inc., namely, Z.A.N., S.L., E.M.S., A.Z., C.B., K.L., B.R., S.A. and M.D. are holders of GPC stock options. To date, these authors, except C.B., are GPC employees. Authors affiliated with Morphosys AG, namely, B.H. C.L., R.R., S.R., E.T.-W., T.K. and M.T. are employees of Morphosys AG and hold stock options of Morphosys. S.Z. was employed at Morphosys AG while engaged in this project.
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Nagy, Z., Hubner, B., Löhning, C. et al. Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells. Nat Med 8, 801–807 (2002). https://doi.org/10.1038/nm736
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DOI: https://doi.org/10.1038/nm736
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