On November 9, 2020 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies for the treatment of cancer and autoimmune diseases, reported the presentation of new data from multiple preclinical XmAb bispecific antibody programs and its preclinical IL-12-Fc cytokine program at the 35th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (Press release, Xencor, NOV 9, 2020, View Source [SID1234570528]).
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"Our XmAb bispecific Fc domains were specifically created to enable the rapid design and simplified development of a wide range of multi-specific antibodies and other protein structures, such as our engineered cytokines," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "At SITC (Free SITC Whitepaper), we are presenting new data from multiple preclinical programs, including CD28 bispecific antibodies, our second class of T cell engagers, that we have designed to conditionally co-stimulate T cells when they are bound to tumor cells. For the first time, we also show data from two selective TGFβ inhibitors engineered with XmAb bispecific Fc domains."
Poster presentations and audio descriptions are available to registrants of the SITC (Free SITC Whitepaper) Annual Meeting. The posters will also be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.
CD28 Bispecific Antibody Platform
Poster 697, "Tumor-targeted CD28 costimulatory bispecific antibodies enhance T cell activation in solid tumors"
T cells in the tumor microenvironment require both T cell receptor (TCR) and co-stimulatory receptor engagement to achieve full activation. CD28 is a key immune co-stimulatory receptor on T cells; however, the ligands that activate T cells through CD28 are often not expressed on tumor cells. Targeted CD28 bispecific antibodies may provide conditional co-stimulation of T cells, for example, to T cells recognizing neoantigens or in concert with CD3 T-cell engaging bispecific antibodies.
Xencor engineered two XmAb bispecific antibodies, B7-H3 x CD28 and PD-L1 x CD28, to provide conditional co-stimulation of T cells, activating them when bound to tumor cells. B7-H3 is an immune receptor highly expressed on a wide range of solid tumors and has low expression on normal tissue, and it is associated with poor clinical outcomes. PD-L1, which is also expressed on many types of tumors, suppresses anti-tumor responses by the immune system.
The B7-H3 x CD28 bispecific antibody activated T cells only in the presence of the B7-H3 antigen and did not demonstrate super-agonism, consistent with Xencor’s CD28 platform design. The combination of B7-H3 x CD28 and a PSMA x CD3 T cell engaging bispecific antibody generated enhanced T cell activation and proliferation in a PSMA-positive cell line compared to the PSMA x CD3 alone; importantly, no activity was observed in a PSMA-negative cell line, demonstrating that both antigens are required for T cell activation. A combination of B7-H3 x CD28 and a B7-H3 x CD3 bispecific antibody enhanced anti-tumor activity compared to either bispecific antibody alone in an in vivo model of breast cancer.
Further, the combination of the PD-L1 x CD28 and a B7-H3 x CD3 T cell engaging bispecific antibody demonstrated superior T cell activation and proliferation compared to a bivalent anti-PD-L1 antibody and B7-H3 x CD3 combination. In vivo, PD-L1 x CD28 inhibited tumor growth more effectively than a bivalent anti-PD-L1 antibody.
PD-1 x TGFβR2 Bispecific Antibody Program
Poster 714, "PD-1 x TGFβR2 bispecifics selectively block TGFβR2 on PD-1-positive T cells, promote T cell activation, and elicit an anti-tumor response in solid tumors"
TGFβ is an inhibitory cytokine, and its production by solid tumors and the tumor microenvironment is a significant mechanism used by tumors to avoid recognition by the immune system. While TGFβ inhibition is expected to promote an anti-tumor response, systemic blockade of TGFβ has also been associated with toxicity.
Xencor engineered two XmAb bispecific antibodies, PD-1 x TGFβR2 and CD5 x TGFβR2, to selectively block the suppressive activity of TGFβ on specific T-cell populations and to enhance their anti-tumor activity while avoiding the toxicity associated with systemic blockade. PD-1 and CD5 were selected to direct TGFβ blockade to activated or all T cells, respectively.
In vitro, both bispecific antibodies exhibited highly selective blocking of TGFβ activity in PD-1-high and CD5-high T cell populations. Additionally, PD-1 x TGFβR2 was active in vivo and promoted T cell engraftment and anti-tumor response. Anti-tumor activity was enhanced when combined with an anti-PD-1 antibody, compared to anti-PD-1 alone or an anti-PD-L1/TGFβ trap. Similar in vivo evaluation of CD5 x TGFβR2 is underway.
IL-12-Fc
Poster 564, "Potency-reduced and extended half-life IL-12 heterodimeric Fc-fusions exhibit strong antitumor activity with potentially improved therapeutic index compared to native IL-12 agents"
IL-12 is a proinflammatory cytokine produced by activated antigen-presenting cells, and it leads to proliferation of T cells and NK cells and increased cytotoxicity through high levels of interferon gamma signaling. As a potent immune stimulating protein, IL-12 can have a significant effect on shrinking tumors; however, prior clinical studies have demonstrated it to have a narrow therapeutic window, limiting potential response rates.
Xencor’s IL-12-Fc cytokine program builds on Xencor’s prior work with IL-15-Fc fusions in oncology, where reduced potency led to improved pharmacokinetics, pharmacodynamics and safety in preclinical studies. IL-12-Fc fusions were engineered with reduced potency in order to improve potential tolerability, slow receptor-mediated clearance and prolong the fusions’ half-lives in vivo, compared to native IL-12. These potency-reduced IL-12-Fc fusions demonstrated significant anti-tumor activity concurrent with activation and proliferation of CD8+ T cells, increased PD-1 checkpoint expression and increased levels of interferon gamma in serum. Anti-tumor activity was enhanced when combined with an anti-PD-1 antibody.