Wu and Seung et al. developed CD38/CD3×CD28 trispecific IgG4s mutated to negate FcR binding and non-specific cytokine release. Crystal structures showed solvent-exposed CDRs and modeling showed trispecific molecules binding opposite each other to CD28 dimer. In vitro, each variable fragment contributed to human TCM, TH1, and antigen-specific T cell proliferation. CD28 on CD38+ myeloma cells enhanced targeting and contributed to trispecific antibody-mediated human T cell lysis of myeloma cells in vitro and myeloma growth inhibition in a humanized mouse model. Immune effects were observed in non-human primates at tolerated doses.

Contributed by Paula Hochman

Despite the significant therapeutic advances provided by immune-checkpoint blockade and chimeric antigen receptor T cell treatments, many malignancies remain unresponsive to immunotherapy. Bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown some clinical efficacy; however, providing co-stimulatory signals may improve T cell responses against tumors. Here, we developed a trispecific antibody that interacts with CD38, CD3 and CD28 to enhance both T cell activation and tumor targeting. The engagement of both CD3 and CD28 affords efficient T cell stimulation, whereas the anti-CD38 domain directs T cells to myeloma cells, as well as to certain lymphomas and leukemias. In vivo administration of this antibody suppressed myeloma growth in a humanized mouse model and also stimulated memory/effector T cell prolifera- tion and reduced regulatory T cells in non-human primates at well-tolerated doses. Collectively, trispecific antibodies represent a promising platform for cancer immunotherapy.

Author Info: (1) Sanofi Research and Development, Sanofi North America, Cambridge, MA, USA; (2) Sanofi Research and Development, Sanofi Frankfurt, Frankfurt, Germany; (3) Sanofi Research and De

Author Info: (1) Sanofi Research and Development, Sanofi North America, Cambridge, MA, USA; (2) Sanofi Research and Development, Sanofi Frankfurt, Frankfurt, Germany; (3) Sanofi Research and Development, Sanofi Vitry, Paris, France. * corresponding authors.