Bispecific Antibodies Rargeting Multiple Checkpoints or Costimulatory Receptors Promote T Cell Activation

Identification: Clynes, Raphael


Description

Bispecific antibodies targeting multiple Checkpoints or Costimulatory Receptors Promote T Cell Activation
 
Raphael Clynes, Rajat Varma, Matthew Bernett, Greg Moore, Michael Hedvat, Christine Bonzon, Suzanne Schubbert, Sung-Hyung Lee, Kendra Avery, Rumana Rashid, Alex Nisthal, Liz Bogaert, Irene W.L. Leung, Seung Chu, Umesh Muchhal and John Desjarlais
Xencor Inc., 111 W Lemon Ave, Monrovia, CA 91016
 
Tumor infiltrating lymphocytes (TILs) express multiple immune checkpoints and costimulatory receptors. Combination checkpoint blockade has demonstrated increased anti-tumor clinical response rates, albeit with increased immune-related adverse events. We have utilized our bispecific antibody format to develop drugs that act as dual checkpoint blockers or combine a checkpoint blocker with an antibody against a costimulatory receptor. We hypothesize that such targeting has the potential benefit of improved safety, by selective targeting of tumor-reactive TILs, and reduced costs. We present here examples of three such bispecific antibodies that combine targeting to PD-1 and CTLA-4 (PD1 x CTLA4), CTLA-4 and LAG3 (CTLA4 x LAG3), and PD-1 and ICOS (PD1 x ICOS). These bispecific antibodies were optimized for stability and affinity such that they exhibit preferential binding to cells co-expressing the two targeted receptors. In vitro, these novel bispecific antibodies demonstrated increased T cell stimulation activity compared to anti-PD1 in a SEB stimulation assay. We measured in-vivo activity using a mouse model in which human PBMCs were engrafted into NSG mice (huPBMC-NSG). Enhancement of T cell activation was measured by enumerating human CD45+ cells in the blood. Engraftment levels promoted by these bispecific antibodies were generally superior to those found for anti-PD1 treatment alone. The PD1 x CTLA4 and CTLA4 x LAG3 bispecific antibodies promoted a two-fold increase versus anti-PD1 alone, and the CTLA4 x LAG3 activity was further enhanced when it was combined with an anti-PD1 antibody to achieve triple checkpoint blockade. Strikingly, the simultaneous checkpoint/costimulatory targeting mediated by the PD1 x ICOS bispecific antibody mediated a 7-fold increase compared to anti-PD1 monotherapy. We have used our bispecific antibody platform to combine multiple checkpoints or checkpoint with costimulation and demonstrated compelling immune modulatory activity suggesting clinical development is warranted for the treatment of human malignancies.
 

Credits

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