Abstract 3217: MGD013, a bispecific PD-1 x LAG-3 Dual-Affinity Re-Targeting (DART®) protein with T-cell immunomodulatory activity for cancer treatment

Abstract

Introduction: The combination of monoclonal antibodies (mAbs) that targets the immune checkpoint molecules CTLA-4 and PD-1 has shown clinical benefit beyond that observed with either mAb alone. This finding has prompted exploring whether such an approach could be applied within the context of additional combinations of checkpoint molecules, such as PD-1 and lymphocyte activation gene-3 (LAG-3). Animal tumor models have validated combining anti-PD-1 with anti-LAG-3 mAbs in eliciting synergistic tumor-eradicating immunity 1 ; expression of PD-1 and LAG-3 on exhausted T cells and tumor-infiltrating lymphocytes (TILs) further supports their dual-targeting. We have developed a bispecific DART protein that targets PD-1 and LAG-3, aimed at inducing potent antitumor immunity through simultaneous blockade of non-redundant checkpoint pathways intrinsic to exhausted T cells. Methods: mAbs against PD-1 and LAG-3 were generated and selected for DART conversion based on binding, biophysical and functional blocking against their respective receptor/ligand axes, and functional activity in reactivation of prior superantigen-stimulated T cells or in antigenspecific recall assays. interactions with potency comparable to nivolumab* (anti-PD-1) or 25F7* (anti-LAG-3)-Enhances T-cell responses compared to individual mAb or combination mAb blockade-Demonstrates a PK profile comparable to that of nivolumab* in cynomolgus monkeys Further clinical development of MGD013 as cancer treatment is warranted

LAG-3: from molecular functions to clinical applications

“…Anti-LAG-3 blocking Abs (relatlimab (BMS-986016), Sym022, TSR-033, REGN3767, LAG525, INCAGN2385-101, MK-4280, and BI754111) and antagonistic bispecific Abs (MGD013 (anti-PD-1/LAG-3), FS118 (anti-LAG-3/PD-L1), and XmAb22841 (anti-CTLA-4/LAG-3)) are under clinical trials for various cancers either as monotherapy or in combination primarily with anti-PD-1 or anti-PD-L1 blocking Abs. According to the National Cancer Institute Drug Dictionary ( https://www.cancer.gov/publications/dictionaries/cancer-drug ), meeting abstracts, 105–107 and a published report, 108 most of them are supposed to block the interaction between LAG-3 and MHCII, while their effects on the interaction between LAG-3 and reported ligands other than MHCII are not specified.…”

The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm

“…Most clinical trials are combining LAG-3 blockade with PD-1 or PD-L1 blocking compounds. Moreover, companies such as Fstar and Macrogenics are developing a mAb that simulatenously targets LAG-3 and PD-L1, or PD-1 respectively [ 110 , 111 ]. A schematic illustration of these compounds can be found in Figure 3 .…”

Bispecific, T-Cell-Recruiting Antibodies in B-Cell Malignancies

“…For example, the dual blockade of PD-1 and LAG-3 with monoclonal Abs further suppresses T-cell activation. For instance, an anti-PD-1/anti-LAG-3 DART, called MGD013, binds specifically to both PD-1 and LAG-3 (142). Blocking both pathways enhanced T-cell responses compared to those observed upon independent blockade of either the PD-1 or LAG-3 pathways alone.…”