Background Antibody drugs which block engagement of the T cell co-inhibitory receptor programmed cell death-1 (PD-1) or its cognate ligand programmed death-1 ligand-1 (PD-L1) are a key pillar of modern oncology. While the impact of these drugs has been profound, their efficacy remains limited to cancers with pre-existing immune infiltration and/or higher numbers of mutational neoantigens. To expand the percentage of cancer patients that benefit from immunotherapy, drugs are needed which can diminish multi-modal immune suppression in immune excluded tumors to the extent that T cells can accumulate and expand sufficiently to benefit from PD-1 pathway blockade. Thus, we characterized IMGS-001, a human monoclonal antibody against PD-L1 and PD-L2 with effector functions, developed in collaboration with MD Anderson. IMGS-001 is being tested in vitro and in vivo to support clinical development in patients resistant or naïve to immuno-oncology (IO) treatment.
Methods In vivo dose-regimen anti-tumor activity was analyzed using syngeneic mouse models of colon cancer (CT26-expresing mouse PD-L2, MC38) and melanoma (B16F10 expressing mouse PD-L2). Tumor-bearing mice were treated with IMGS-001 at 5-10-20 mg/kg twice a week for 3 weeks. In addition, IMGS-001 mediated antibody dependent cellular cytotoxicity (ADCC) was assessed in immune-competent and immune-deficient mice (nu/nu) injected with CT26-PD-L2 and MDA-MB-231, respectively. In both studies, mice were treated with IMGS-001 twice a week for 3 weeks while a second group (only CT-26-PD-L2 model) was first depleted of natural killer (NK) cells.
Results IMGS-001 significantly inhibited CT26-PD-L2 tumor growth compared to PBS treatment (p=0.0239) and extended survival (p=0.0007) with an optimal dose of 10 mg/kg. Against MC38, 70% of animals treated with ≥10mg/kg IMGS-001 were alive with no evidence of tumor 70 days post-inoculation. IMGS-001 (10mg/kg) showed 90% inhibition of B16F10-PD-L2 tumor volume compared to the control (p<0.0001). In mice lacking T cells, IMGS-001 significantly inhibited MDA-MB-231 tumor growth at 10 mg/kg, indicating a mechanism of action driven by ADCC. Moreover, in NK-depleted immune-competent mice, IMGS-001 lost activity against CT26-PD-L2 (p=0.0403).
Conclusions These data suggest 10 mg/kg of IMGS-001 being the optimal dose to induce a strong anti-tumor activity in vivo. Moreover, IMGS-001 displayed a mechanism of action driven by the cytoreduction of immune suppressive stroma in vivo via ADCC. These results, with a favorable PK, the absence of off-target activity and a clean toxicology profile, support the clinical development of IMGS-001. IMG-S001 would increase the benefit of IO therapy for patients with immune-infiltrated tumors and could mediate significant clinical responses against immune-excluded cancers.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.