Tumor infiltrating lymphocytes express multiple immune checkpoints and co-stimulatory receptors. Xencor’s bispecific tumor microenvironment (TME) activators seek to more effectively reactivate these tumor-killing T cells by engaging multiple T-cell targets simultaneously. This approach eliminates the need for the multiple antibodies and allows for more selective targeting of T cells with high checkpoint expression, which may potentially improve the therapeutic index of combination immunotherapies.
XmAb717 (previously XmAb20717) is a bispecific antibody that simultaneously targets immune checkpoint receptors PD-1 and CTLA-4 and is designed to promote tumor-selective T-cell activation. Xencor’s XmAb® Bispecific Fc Domain serves as the scaffold for these two antigen binding domains and confers long circulating half-life, stability and ease of manufacture on XmAb717. XmAb bispecific Fc domains have been engineered to eliminate Fc gamma receptor (FcγR) binding, with the intent to prevent activation and/or depletion of T cells via engagement by FcγR-expressing cells. In preclinical studies, dual blockade of PD-1 and CTLA-4 with XmAb717 significantly enhanced T cell proliferation and activation, and anti-tumor activity in vivo.
Data from the Phase 1 study were presented at the Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in November 2020. XmAb717 was generally well-tolerated, and the most common treatment-related adverse events were immune-related (irAEs), though rates of irAEs, including colitis, were lower than typically observed with CTLA-4 blockade. The efficacy analysis included evaluable patients at the recommended dose level, 10.0 mg/kg, and the objective response rate across cohorts was 19%. Approximately half of evaluable patients had at least 10% tumor shrinkage from baseline assessments, and nearly all these reductions occurred in patients with prior checkpoint inhibitor treatment. Nine patients with prostate cancer had baseline and follow-up PSA assessments. One patient achieved a PSA reduction of greater than 50 percent, and two other patients achieved reductions of greater than 30 percent, one of whom had an unconfirmed partial response by RECIST. Six of nine patients remained on therapy as of the cut-off date.
Xencor is initiating a Phase 2 study for patients with CRPC, as a monotherapy or in combination depending on subtype.
Each of Xencor’s three bispecific TME activators tests a distinct mechanism of TME activation. XmAb841 and XmAb104 are also being evaluated in Phase 1 clinical studies.