Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation
Spotlight Lan Wu (1,4) , Edward Seung (1,4) , Ling Xu (1) , Ercole Rao (2) , Dana M. Lord (1) , Ronnie R. Wei (1) , Virna Cortez-Retamozo (1) , Beatriz Ospina (1) , Valeriya Posternak (1) , Gregory Ulinski (1) , Peter Piepenhagen (1) , Elisa Francesconi( 3) , Nizar El-Murr (3) , Christian Beil (2) , Patrick Kirby (1) , Aiqun Li (1) , Jennifer Fretland (1) , Rita Vicente (3) , Gejing Deng (1) , Tarik Dabdoubi (3) , Beatrice Cameron (3) , Thomas Bertrand (3), Paul Ferrari (3) , Stéphanie Pouzieux (3) , Cendrine Lemoine (3) , Catherine Prades (3) , Anna Park (1) , Huawei Qiu (1) , Zhili Song (1) , Bailin Zhang (1) , Fangxian Sun (1) , Marielle Chiron (3) , Srinivas Rao (1) , Katarina Radošević (3) , Zhi-yong Yang ( 1*) and Gary J. Nabel ( 1*)
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
Lan Wu (1,4) , Edward Seung (1,4) , Ling Xu (1) , Ercole Rao (2) , Dana M. Lord (1) , Ronnie R. Wei (1) , Virna Cortez-Retamozo (1) , Beatriz Ospina (1) , Valeriya Posternak (1) , Gregory Ulinski (1) , Peter Piepenhagen (1) , Elisa Francesconi( 3) , Nizar El-Murr (3) , Christian Beil (2) , Patrick Kirby (1) , Aiqun Li (1) , Jennifer Fretland (1) , Rita Vicente (3) , Gejing Deng (1) , Tarik Dabdoubi (3) , Beatrice Cameron (3) , Thomas Bertrand (3), Paul Ferrari (3) , Stéphanie Pouzieux (3) , Cendrine Lemoine (3) , Catherine Prades (3) , Anna Park (1) , Huawei Qiu (1) , Zhili Song (1) , Bailin Zhang (1) , Fangxian Sun (1) , Marielle Chiron (3) , Srinivas Rao (1) , Katarina Radošević (3) , Zhi-yong Yang ( 1*) and Gary J. Nabel ( 1*)
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.
