Human Monoclonal Antibodies from Immunized Patient Lymphocytes

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DESCRIPTION (provided by applicant): This Phase I STTR application is to support the development of a panel of human monoclonal antibodies (HmAbs) against sLea (also known as CA 19.9), a ganglioside extensively expressed at the cell surface of colon cancers but also the majority of breast cancers. sLea is highly susceptible as a target for lysis by antibody directed mechanisms and since sLea serves as a ligand for epithelial leukocyte adhesion molecule, sLea antibodies may also have direct impact on metastatic potential. MSKCC is the only center with the demonstrated ability to consistently induce antibodies against gangliosides such as sLea in cancer patients using its unique conjugate vaccines. MabVax is the only company currently using B- lymphocytes from in vivo immunized humans to obtain human mAbs. The MabVax Technology transfers PBL from immune human donors to SCID mice for further expansion, prepares hybridomas using human lymphocytes from selected SCID mice, and finally clones the heavy and light chain variable regions into CHO-K1 cells for expansion, selection and scale up. Initial induction in the human tissue environment (decreasing the chance of generating self reacting monoclonal antibodies), high affinity due to repeated immunizations in vivo and maintenance of the original heavy and light chain pairing are the major advantages of the MabVax Technology. If impact of treatment on clinical course is to be tested with human mAbs against sLea, an MSKCC-MabVax collaboration will be required. Establishment of multiple such CHO-K1 cell lines against sLea will be the starting point for a subsequent Phase 2 STTR application. The focus of the Phase 2 application will be scaling up HmAb production; further improving antibody yield, affinity and possibly effector functions; and testing the resulting HmAbs in mouse xenogeneic tumor challenge models. Administered antibodies and antibodies induced by vaccines are well suited for eradication of free circulating tumor cells and micrometastasis. Administered monoclonal antibodies may have the additional advantage due to higher concentrations and selected effector functions of being able to eradicate early established metastasis as well. If antibodies of efficient titer and effector functions can be administered against the cell surface antigens most dominant on cancers of the colon and breast (such as sLea), this would dramatically change our approach to treating the cancer patient. Establishment of new metastasis would no longer be possible so aggressive local therapies including surgery or radiation therapy might result in long term control of even metastatic cancers.