On November 3, 2023 Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company developing engineered antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported data from multiple preclinical-stage XmAb programs at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) in San Diego (Press release, Xencor, NOV 3, 2023, View Source [SID1234636904]).
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"Xencor aims to stay on the leading edge of molecular engineering, using and improving upon our XmAb technologies to create molecules with enhanced functionality or new therapeutic mechanisms. At SITC (Free SITC Whitepaper), we are presenting new preclinical data from two research-stage programs—engineered, decoy-resistant IL18-Fc fusions and our multi-valent NK cell engagers targeted to MICA and MICB, which are tumor antigens upregulated in the tumor microenvironment," said John Desjarlais, Ph.D., executive vice president and chief scientific officer at Xencor. "Later this year, we expect to submit an investigational new drug application for XmAb541, an XmAb 2+1 format CLDN6 x CD3 bispecific antibody that we are developing for patients with ovarian cancer and other tumor types. We are also developing additional CD3 and CD28 T cell engaging bispecific antibodies against solid tumor targets."
Posters will be available in the poster hall and virtually to registrants of the SITC (Free SITC Whitepaper) Annual Meeting. In the poster hall, odd-numbered posters will be displayed on Friday, November 3, and even-numbered posters will be displayed on Saturday, November 4. Xencor’s posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.
Clinical Trials in Progress
Abstract 764, "A Phase 1, first-in-human (FIH), open-label, dose-finding and expansion study of XmAb808, a B7H3 x CD28 bispecific antibody, in combination with pembrolizumab in patients with advanced solid tumors"
Xencor is conducting a Phase 1 study of XmAb808 in patients with advanced solid tumors. XmAb808 is a tumor-selective, co-stimulatory XmAb 2+1 bispecific antibody designed to bind to the broadly expressed tumor antigen B7-H3 and selectively to the CD28 T-cell co-receptor only when bound to tumor cells, which was demonstrated in vitro. Strong potentiation of checkpoint and CD3 cytotoxic activity was also observed in vivo. XmAb808 is a wholly owned Xencor program.
The clinical trials in progress poster reviews the design of XmAb808 and the rationale of using CD28 bispecific antibodies to expand the utility of checkpoint blockade and CD3 T cell engagers. The poster also provides study objectives, key eligibility criteria and study schema.
Preclinical Programs
Abstract 1060, "Optimally engineered IL18-Fc fusion proteins balance potency and pharmacokinetics to promote strong anti-tumor activity"
IL-18 is a proinflammatory cytokine that modulates both the innate and adaptive immune responses. Preclinical studies of IL-18 have demonstrated its anti-tumor activity, including synergy with immune checkpoint inhibitors and CAR-T therapies. In contrast with other potent cytokines, IL-18 has been well tolerated in clinical trials but demonstrated a lack of efficacy despite heavy dosing. IL-18 induces a negative feedback loop with its high affinity natural inhibitor, IL18BP, which was upregulated in early phase clinical studies and may have limited IL-18’s clinical performance.
Xencor engineered stabilized, potency-modulated IL-18 cytokines fused to an XmAb heterodimeric Fc domain with Xtend Fc technology for longer half-life (IL18-Fc). In addition, Xencor engineered bispecific IL18-Fc cytokines targeted to PD-1, a checkpoint receptor on T cells. Importantly, these molecules were engineered to avoid binding IL18BP.
Xencor’s IL18-Fc fusions and PD1 x IL18-Fc bispecific inhibited tumor growth in a dose- and potency-dependent manner, outperforming a wild-type IL18-Fc fusion, in vivo. Further preclinical studies of the engineered IL18-Fc fusions demonstrated pharmacodynamic profiles similar to wild-type IL18-Fc. Notably, a set of surviving tumor-engrafted mice, which had previously received engineered IL18-Fc fusions, had no tumor growth upon rechallenge.
Abstract 1193, "Synergistic targeting of multiple activating pathways with Natural Killer cell Engagers"
Xencor’s XmAb natural killer cell engagers (NKEs) are multifunctional antibodies that target multiple activating receptors on the surface of NK cells and bind to tumor-associated antigens.
MICA and MICB (MICA/B) are stress-induced tumor antigens expressed in a range of cancers. MICA/B antigens are recognized by NKG2D, an activating receptor on NK and CD8+ T cells. While membrane-bound, MICA/B is immuno-stimulatory; however, the cleaved and soluble form, found in the tumor microenvironment, prevents NKG2D from recognizing tumor cells. Xencor engineered anti-MICA/B antibodies with enhanced effector function in order to block the cleavage of MICA/B antigens and promote NK cell engagement. These antibodies increased MICA/B membrane surface density and led to tumor cell killing with MICA/B binding to NKG2D on immune cells. To enhance the anti-tumor activity, Xencor engineered multi-specific NK cell-engaging antibodies that simultaneously target MICA/B antigens and an orthogonal activating receptor on NK cells, NKp46. These multi-specific NK cell-engaging antibodies demonstrated enhanced functional activity compared to the antibodies targeting only MICA/B.