Enhancing T-Cell Responses: The Development and Potential of MGD013 in Cancer Therapy

The study explores the potential of combining monoclonal antibodies (mAbs) against immune checkpoint molecules, specifically CTLA-4 and PD-1, which have shown greater clinical benefits than individual mAbs. This has led to the investigation of other combinations, such as PD-1 with LAG-3, in animal models. The research has confirmed that the dual targeting of PD-1 and LAG-3 on exhausted T cells and tumor-infiltrating lymphocytes (TILs) can elicit synergistic antitumor immunity. A bispecific DART protein has been developed to target both PD-1 and LAG-3, aiming to enhance antitumor immunity by blocking these non-redundant checkpoint pathways.

The methodology involved generating and selecting mAbs against PD-1 and LAG-3 for DART conversion, based on their binding, biophysical properties, and ability to block their respective receptor/ligand axes and re-activate T cells. The lead mAbs were humanized and showed restricted lymphocyte expression in human tissues with overlapping expression in TILs. The humanized mAbs were combined to create MGD013, a DART protein that exhibits favorable biophysical and manufacturing traits.

MGD013 specifically binds with high affinity to both PD-1 and LAG-3, as well as to target-expressing cell lines and chronically activated T cells. It effectively blocks the interactions of PD-1/PD-L1, PD-1/PD-L2, and LAG-3/HLA (MHC-II) and inhibits PD-1 signaling. The functional characterization of MGD013 showed increased cytokine secretion upon antigenic re-challenge of previously stimulated T cells, surpassing the effects of blocking either PD-1 or LAG-3 alone. Moreover, MGD013 induced a greater cytokine response than the combination of equivalent doses of nivolumab and 25F7, both of which are undergoing clinical testing. Cynomolgus monkey pharmacokinetic studies indicated that MGD013 has a prolonged circulating half-life, consistent with Fc-bearing molecules.

The conclusion of the study is that MGD013, by blocking both PD-1 and LAG-3 pathways, enhances T-cell responses more than single or combined mAb blockade. The favorable pharmacokinetic profile in cynomolgus monkeys supports the further clinical development of MGD013. The research was presented at the 107th Annual Meeting of the American Association for Cancer Research and published in the Cancer Research journal.