CP-675,206 anti-CTLA4 antibody clinical candidate enhances IL-2 production in cancer patient T cells in vitro regardless of tumor type or stage of disease
Paul C. Canniff, Carol B. Donovan, Jeffrey J. Burkwit, Matthew J. Bruns, Vahe Bedian, Steven H. Bernstein, Douglas C. Hanson. Pfizer Global Research & Development, Groton, CT and Roswell Park Cancer Institute, Buffalo, NY.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a cell surface receptor expressed on activated T cells. The natural B7 ligands for CTLA4 are expressed on antigen-presenting cells. Experimental evidence indicates that binding of B7 to CTLA4 delivers a negative regulatory signal to T cells, and that blocking this negative signal results in markedly enhanced T cell immune function and antitumor activity in animal models. A fully human potent anti-huCTLA4 antagonist IgG2 antibody, CP-675,206, was generated in XenoMouse® mice at abgenix, Inc. CP-675,206 was tested for its ability to enhance IL-2 production in normal and cancer patient whole blood (WB) and peripheral blood mononuclear cells (PBMC) stimulated with staphylococcal enterotoxin A (SEA) superantigen. WB and PBMC cultures were stimulated with SEA and anti-CTLA4 mAb, or an isotype-matched control mAb, for 72 hours at 37°C and assayed for secreted IL-2 by ELISA. Blood samples were obtained from normal donors and patients with cancers at different stages. Cancer types included prostate, renal, colon, rectal, ovarian, melanoma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. The percentage of positive responses, average magnitude of IL-2 enhancement, and average IL-2 fold increase were generally similar for normal and cancer patient WB or PBMC cultures treated with CP-675,206 mAb (30 ug/ml). Remarkably, CP-675,206 concentration response profiles (0.1 to 100 ug/ml) from normal and cancer patient samples were comparable regardless of cancer type or disease stage. Additional studies showed that soluble CTLA4 levels determined by ELISA were undetectable (<9 ng/ml) in both normal and cancer patient samples. Flow cytometric analyses showed no significant differences in levels of CTLA4 expression (cell surface plus intracellular) in SEA-activated PBMC. In summary, in vitro studies of superantigen-stimulated WB and PBMC showed that CP-675,206 induced robust IL-2 enhancement in samples from both normal donors and a wide range of cancer patients regardless of tumor stage. These findings support conducting clinical trials with this antibody in a variety of cancer patient types with different stages of disease.
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[Maybe Medarex has some competition in the anti-CTLA-4 area.
Erik] |
