Anti-Sstr2 X Anti-Cd3 Bispecific Antibody Induces Potent Killing Of Human Tumor Cells In Vitro And In Mice, And Stimulates Target-Dependent T Cell Activation In Monkeys: A Potential Immunotherapy For Neuroendocrine Tumors

Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors (NETs) and small cell lung cancer (SCLC). Treatment options for NETs include somatostatin analogs and radionuclides; however, such therapies suffer from short half-life, modest efficacy, and toxicities due to inhibition of other SSTRs. Reasoning that a targeted immunotherapy against SSTR2 would provide a new therapeutic modality for NETs, we designed XmAb18087, a humanized and affinity-optimized bispecific antibody that engages T cells to stimulate redirected T cell-mediated cytotoxicity (RTCC) of SSTR2 + tumor cells. XmAb18087 possesses an Fc domain that maintains long half-life, yet lacks binding to Fcγ receptors to reduce Fc-mediated effector functions. XmAb18087 stimulated robust RTCC of SSTR2 + cell lines including medullary thyroid carcinoma (TT), lung carcinoma (A549), and CHO cells overexpressing SSTR2, with EC50s of ~1 to 100 ng/ml. XmAb18087 also upregulated CD69 and CD25 activation markers on CD4 and CD8 T cells. T cell responses were target-specific, because SSTR2¯ cell lines were not depleted, and because a control bispecific (anti-RSV x CD3) was ineffective. In addition, XmAb18087 (3 mg/kg weekly) reduced tumor burden of an established A549 xenograft in NSG mice engrafted with 10 7 human PBMC. We next assessed XmAb18087 activity in cynomolgus monkeys. As SSTR2 is not expressed in peripheral blood, target cell depletion cannot be monitored in vivo. However, CD3 bispecifics induce effects such as lymphocyte extravasation, cytokine induction, and T cell activation, which can serve as pharmacologic markers for activity in target organs. XmAb18087 dosed once at 30 or 60 μg/kg rapidly activated peripheral T cells, as quantified by CD69 and CD25 induction (peaking at ~8-12 hr). T cells rapidly extravasated from blood, with a nadir by 8 hr. Cytokines IL6 and TNF were rapidly induced, peaking at ~1-8 hr and returning to baseline by 48 hr. To explore repeat dosing, XmAb18087 was dosed at 1 or 10 μg/kg on Days 0 and 7 in a second study. The first dose of both 1 and 10 μg/kg again stimulated peripheral T cell activation, extravasation, and cytokine induction. These responses decreased markedly after the second dose, suggesting that SSTR2 + target cells remained depleted for at least 7 days. In summary, these results on human cells, in mice, and in monkeys support clinical assessment of XmAb18087 in SSTR2 + cancers including NETs and SCLC. In monkeys, T cell activation, extravasation, and cytokine induction were readily measured in peripheral blood and are indicative of T cell-mediated depletion of SSTR2 + target cells. Importantly, these responses may also serve as useful surrogate markers of NET depletion in clinical trials of XmAb18087. Citation Format: Sung-Hyung Lee, Seung Y. Chu, Rumana Rashid, Sheryl Phung, Irene W. Leung, Umesh S. Muchhal, Gregory L. Moore, Matthew J. Bernett, Suzanne Schubbert, Connie Ardila, Christine Bonzon, Paul Foster, David E. Szymkowski, John R. Desjarlais. Anti-SSTR2 × anti-CD3 bispecific antibody induces potent killing of human tumor cells in vitro and in mice, and stimulates target-dependent T cell activation in monkeys: A potential immunotherapy for neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3633. doi:10.1158/1538-7445.AM2017-3633