XmAb808, a B7H3-targeted CD28 bispecific antibody, costimulates T cells enhancing the anti-tumor activity of clinically active CD3 T cell engagers
Presenter: Michael Hedvat, PhD Session: Redefining Targeted Therapy: Bispecific T-Cell Engagers and Antibody-Drug Conjugates 1 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Michael Hedvat , Veronica Zeng , Mayra Montes-Camacho , Charles G. Bakhit , Alex K. Lam , Lizett E. Scott , Jessica Reyes , Heather P. Jimenez , Rosio Padilla , Scott Taylor , Jose Serrato Bucio , Matthew A. Dragovich , Sung-Hyung Lee , Katrina Bykova , Yoon K. Kim , Suzanne Schubbert , Christine Bonzon , Seung Y. Chu , Gregory L. Moore , F. Rena Bahjat , John R. Desjarlais Xencor, Inc., Pasadena, CA
Abstract
CD3 bispecific T-cell engagers (CD3-TCEs) represent a promising therapeutic modality for solid tumors, with multiple candidates in clinical development. These agents bridge tumor-associated antigens and CD3 on T cells to form an immune synapse, delivering Signal 1 for T-cell activation. However, solid tumors, unlike professional antigen-presenting cells, typically lack CD28 ligands required for Signal 2 costimulation. T cells receiving Signal 1 without Signal 2 risk developing anergy, potentially limiting CD3-TCE efficacy. A key advancement in costimulatory immunotherapy involves tumor-targeted CD28 bispecific antibodies that strictly depend on concurrent Signal 1 for activation. These bispecifics engage tumor associated antigens to cluster CD28 at the immune synapse, delivering Signal 2 to T cells. We developed XmAb808, a novel B7H3xCD28 bispecific incorporating a nonsuperagonistic, monovalent CD28-binding domain and a high-avidity, bivalent B7H3-binding domain. In proof-of-concept studies, XmAb808 potently amplified the in vitro and in vivo anti-tumor efficacy of CD3-TCEs targeting prototype tumor antigens. Exploring potential combination opportunities, we found co-expression of B7H3 with CLDN6 in ovarian tumors and co-expression with STEAP1 in prostate tumors. Notably, XmAb808 synergistically enhanced the activity of XmAb541 (CLDN6xCD3) and an analog of xaluritamig (STEAP1xCD3), two programs with clinically observed anti-tumor activity. These XmAb808 combinations induced robust IL-2 secretion from activated T cells, which in turn promoted T cell proliferation and Bcl-xL-dependent survival. Moreover, in a T cell restimulation assay, XmAb808 was able to overcome apparent T cell exhaustion promoted by xaluritamig, strongly recovering xaluritamig’s reduced anti-tumor activity weeks into the assay. The addition of targeted costimulation translated to superior T cell-mediated cytotoxicity in vitro and markedly improved anti-tumor responses in humanized xenograft models, highlighting XmAb808’s potential to synergize with TCE-based immunotherapies.
Disclosure
M. Hedvat, Xencor, Inc. Employment, Stock, Stock Option. V. Zeng, Xencor Inc. Employment, Stock, Stock Option. M. Montes-Camacho, Xencor, Inc. Employment, Stock, Stock Option. C. G. Bakhit, Xencor, Inc. Employment, Stock, Stock Option. A. K. Lam, Xencor, Inc. Employment, Stock, Stock Option. L. E. Scott, Xencor, Inc. Employment, Stock, Stock Option. J. Reyes, Xencor, Inc. Employment, Stock, Stock Option. H. P. Jimenez, Xencor, Inc. Employment, Stock, Stock Option. R. Padilla, Xencor, Inc. Employment, Stock, Stock Option. S. Taylor, Xencor, Inc. Employment, Stock, Stock Option. J. Serrato Bucio, Xencor, Inc. Employment, Stock, Stock Option. M. A. Dragovich, Xencor, Inc. Employment, Stock, Stock Option. S. Lee, Xencor, Inc. Employment, Stock, Stock Option. K. Bykova, Xencor, Inc. Employment, Stock, Stock Option. Y. K. Kim, Xencor, Inc. Employment, Stock, Stock Option. S. Schubbert, Xencor, Inc. Employment, Stock, Stock Option. C. Bonzon, Xencor, Inc. Employment, Stock, Stock Option. S. Y. Chu, Xencor, Inc. Employment, Stock, Stock Option. G. L. Moore, Xencor, Inc. Employment, Stock, Stock Option. F. Bahjat, Xencor, Inc. Employment, Stock, Stock Option. J. R. Desjarlais, Xencor, Inc. Employment, Stock, Stock Option.
Cited in
Control: 2540 · Presentation Id: 9652 · Meeting 21436