Preclinical development of IMGS-001, a novel anti-PD-L1/PD-L2 monoclonal antibody with effector function
Introduction
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. Here we summarize preclinical data for IMGS-001 which supported its successful application as an investigational new drug.
Methods
Affinities were measured with the Octet system. Reporter cell assays assessed PD-1 pathway blockade, antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP). In vivo, dose-regimen anti-tumor activity were 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 three weeks. In addition, IMGS-001 mediated ADCC was assessed in the CT26-PDL2 model. Mice were treated with IMGS-001 twice a week for three weeks with or without first depleting natural killer (NK) cells.
Results
The affinity of IMGS-001 to monomeric PD-L1 and PD-L2 is 7.62nM and 1.90nM, respectively. It has an EC50 of 0.3-1.1nM in a PD-1 blockade assay, within the same range as approved drugs pembrolizumab and avelumab. IMGS-001 has an EC50 of <0.5nM in ADCC and ADCP assays. IMGS-001 significantly inhibited CT26-PDL2 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-PDL2 tumor volume compared to the control (p<0.0001). In NK-depleted immune-competent mice, IMGS-001 lost activity some against CT26-PD-L2 (p=0.0403).
Conclusion
These data demonstrate that IMGS-001 binds PD-L1 and PD-L2 and functions per its design. It’s mechanisms of elimination of immunosuppressive cells with PD-1 pathway blockade could benefit patients that are resistant to existing PD-(L)1 drugs by restoring immune driven anti-tumor activity. IMGS-001 is poised to enter clinical trial in immune excluded tumors. IMGS-001 would increase the benefit of IO therapy for patients with immune-infiltrated tumors and could mediate significant clinical responses against immune-excluded cancers.