On June 22, 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 preclinical data from three XmAb 2+1 bispecific antibody programs and its IL-12-Fc cytokine program during the second session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (Press release, Xencor, JUN 22, 2020, View Source [SID1234561353]). Poster presentations and audio descriptions are available to registrants of the AACR (Free AACR Whitepaper) Virtual Annual Meeting.
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"Compared to many therapeutic targets for blood cancers like CD19 or CD20, which are generally restricted to specific cell populations, solid tumor targets often are expressed on a range of normal tissues, including critical organs, which can limit the therapeutic index for drug candidates," said John Desjarlais, Ph.D., senior vice president and chief scientific officer at Xencor. "The XmAb 2+1 bispecific antibody format has two domains that bind the tumor target, and this bivalent binding can preferentially bind tumor cells with high target expression, potentially sparing low-expression normal tissues. This selectivity and potency tuning of T-cell activation may provide for higher efficacy and tolerability compared to other bispecific antibody formats.
"We have also presented data from our IL-12-Fc cytokine program, which builds off of our prior work with IL-15 and IL-2. IL-12 is a potent immune signaling protein that can have a dramatic effect on shrinking tumors; however, prior clinical studies have demonstrated IL-12 to have a narrow therapeutic window, limiting potential response rates. We created an IL-12 Fc-fusion with reduced potency in order to improve tolerability, slow receptor-mediated clearance and prolong the molecule’s half-life," said Dr. Desjarlais.
XmAb 2+1 Bispecific Antibodies
Poster: 2286, "XmAb30819, an XmAb 2+1 ENPP3 x CD3 bispecific antibody for RCC, demonstrates safety and efficacy in in-vivo preclinical studies"
Poster: 5663, "Affinity tuned XmAb 2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models"
Poster: 5654, "Affinity tuned XmAb 2+1 anti-mesothelin x anti-CD3 bispecific antibody induces selective T cell directed cell cytotoxicity of human ovarian cancer cells"
ENPP3, PSMA and MSLN are tumor-associated antigens associated with renal cell carcinoma (RCC), prostate cancer and ovarian cancer, respectively, but they are not restricted to tumors and exhibit base level expression on normal tissues. Xencor has expanded its T-cell redirecting CD3 class of bispecific antibodies to create an XmAb 2+1 bispecific antibody format, utilizing an engineered heterodimeric Fc domain, two identical tumor targeting domains and one CD3 targeting domain. The affinities for antigen binding are reduced, which allows for selective engagement of high antigen-expressing tumor cells over low antigen-expressing normal cells. In preclinical models, XmAb 2+1 bispecific antibodies bound preferentially to tumor cells compared to normal cells and effectively recruited T cells to kill tumor cells selectively. Additional data presented on XmAb 2+1 PSMA x CD3 bispecific antibody candidates and XmAb30819, a first-in-class XmAb 2+1 ENPP3 x CD3 bispecific antibody, demonstrated strong reversal of tumor growth in human-cell engrafted mouse models of disease. Further data presented from preclinical studies of XmAb30819 in non-human primates demonstrated it was well-tolerated with expected pharmacodynamics and an antibody-like half-life.
IL-12-Fc Cytokine
Poster: 5549, "Potency-reduced IL-12 heterodimeric Fc-fusions exhibit strong anti-tumor activity"
IL-12 is a heterodimeric 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. IL-12-Fc fusions were engineered with potency-reduced IL-12 to improve its potential tolerability, slow receptor-mediated clearance and prolong its half-life in vivo. In preclinical models, 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.
The posters will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.