Biocytogen’s In Vivo Drug Screening Platform Accelerated 4-1BB Agonistic Antibody Development
4-1BB (TNFRSF9/CD137) belongs to the TNFR superfamily. 4-1BB is expressed by activated CD4 helper T cells, B cells, natural killer cells, natural killer T cells, dendritic cells, and activated endothelium. A majority of regulatory T cells (Tregs) also express 4-1BB, but it remains unclear whether agonistic antibody treatment exerts pro- or anti-suppressive effect on these cells. 4-1BB enhances tumor rejection because it is upregulated on T cells following activation and its engagement increases T cell proliferation and proinflammatory cytokine production. The clinical development of 4-1BB targeting therapy was slow due to the toxicity associated with overt immune activation. Fortunately, new therapeutic modalities using 4-1BB targeting aptamers as well as therapeutic combinations with other immuno-modulatory and traditional anti-cancer treatments have revived excitement for the use of 4-1BB agonists in the clinic.
We are interested in discovering novel 4-1BB therapeutic antibodies for cancer patients. Candidate molecules obtained through the classical hybridoma technology were screened by high-throughput flow cytometry. Then, we took the advantages of Biocytogen’s humanized mice and screened the purified antibodies in B-h4-1BB mice bearing MC-38 tumor cells. We found some antibodies that worked as equivalent as BMS’s urelumab. To determine which isotype should be adopted, we engrafted the antigen binding domain onto various human Fc backbones. Interestingly, we found that the human IgG1 isotype appeared more effective against tumor than other isotypes in B-4-1BB mice bering MC-38 tumors. This study provides a reliable basis for our follow-up mechanism research and clinical evaluation on this target.