The carbohydrate antigen sialyl-Lewis a (sLea) is widely expressed on epithelial tumors of the gastrointestinal tract, on breast cancer cells, and also on small cell lung cancer cells but is expressed minimally or not at all on normal tissues. sLea serves as a ligand for epithelial leukocyte adhesion molecules and higher expression of sLea was observed in patients with greater node involvement. Since over-expression of sLea appears to be a key event in invasion and metastasis of many tumor cells and tumor cells expressing sLea are highly susceptible to antibody mediated lysis mechanisms, sLea presents an attractive molecular target for tumor therapy in a minimal disease setting. MSKCC is the only center with the demonstrated ability to consistently induce antibodies against gangliosides and glycolipids including sLea in cancer patients using its unique conjugate vaccines. The MabVax antibody generation technology is designed to utilize B-lymphocytes from in vivo immunized humans to rescue human monoclonal antibodies generated in response to the vaccination. The goals of our initial proposal have been achieved: A pilot trial with the sLea-KLH vaccine in breast cancer patients was initiated. Blood specimens from two patients with high titer responses against sLea have been processed utilizing the MabVax fully human mAb generating technologies, and HumAbs with high affinity and specificity for sLea have been generated. Two of the antibodies, one IgG and one IgM, were shown to possess potent effecter functions against sLea positive cancer cells and both have been converted to fully functional human recombinant antibodies. The proposed work is designed to establish initial proof of in vivo efficacy of the selected antibody candidates, and to advance the most efficacious antibodies further into preclinical development. This includes scaling up recombinant HumAb production, to improve antibody yield, and testing the HumAbs in mouse xenogeneic tumor challenge models. The long-term goal is to select a clinical candidate antibody for further development and commercialization efforts. Since sLea is widely expressed, the lead candidate antibody could eventually find utility in more than half of the new cancer cases occurring each year.
Administered antibodies and antibodies induced by vaccines are well suited for eradication of free circulating tumor cells and micrometastasis. Administered human monoclonal antibodies have additional advantages: Higher concentrations with predictable pharmacodynamic properties are achievable and effector functions can be selectively altered, so eradication of early established metastasis might become more feasible. If antibodies of efficient titer and effector functions against the cell surface antigens most dominant on cancers of the colon and breast (such as sLea) can be safely administered, 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.
