SOUTH SAN FRANCISCO, Calif.—NGM Biopharmaceuticals recently disclosed its third oncology development candidate: NGM438, a novel antagonist antibody that inhibits leukocyte-associated immunoglobulin-like receptor 1 (LAIR1).
LAIR1 is a collagen-binding inhibitory receptor expressed on immune cells. LAIR1 and collagens are upregulated in multiple cancer types where collagens are produced by activated stromal cells, and these stromal-derived suppressive factors are associated with poor responses to checkpoint inhibitors. For these tumors, formation of the LAIR1-collagen complex could act as a stromal checkpoint to both physically exclude immune cells from the tumor and impose signaling-based immune suppression.
“NGM438, a novel immuno-oncology candidate, is yet another example of our team’s biology-driven approach and expertise in tailoring highly specialized antibodies,” said Dr. David J. Woodhouse, CEO of NGM.
NGM believes that LAIR1 inhibition represents a promising therapeutic strategy for treating cancer. By promoting the remodeling of the tumor architecture that restricts T cells from infiltrating the tumor cell mass, and reversing immune suppression in the tumor microenvironment, NGM438 could potentially block the stromal checkpoint and restore antitumor immune responses.
NGM438 was designed to inhibit LAIR1 interactions with stromal-derived collagens. In preclinical studies, the therapy has demonstrated the ability to reprogram collagen-suppressed myeloid cells to a stimulatory phenotype, induce inflammatory cytokine production by myeloid and T cells, and relieve collagen-based suppression of T cell proliferation. The reinvigoration of collagen-suppressed immune cells may address a key resistance mechanism that limits responses to current immunotherapies.
According to a presentation on NGM’s website, “Collagen receptors, such as integrins, represent key stimulatory receptors on myeloid cells. Inhibition of activating receptors via Collagen-LAIR1 signaling promotes a suppressive myeloid cell phenotype. NGM438 blockade of LAIR1-Collagen binding reprograms myeloid cells to be pro-inflammatory. Blockade of Collagen-LAIR1 leads to a potent increase in inflammatory cytokines, including CCL3 and CCL4, that are involved in recruiting lymphocytes to areas of inflammation.”
“NGM438, which inhibits LAIR1, and NGM707, our dual antagonist antibody that inhibits ILT2 and ILT4, are both examples of our strategy to broaden and deepen antitumor immune responses for patients through myeloid reprogramming by addressing key resistance mechanisms and reversing stromal and myeloid checkpoints,” noted Woodhouse.
NGM438 joins NGM707 as the second myeloid reprogramming product candidate in NGM’s oncology portfolio. NGM707 inhibits immunoglobulin-like transcript 2 (ILT2) and immunoglobulin-like transcript 4 (ILT4). The company expects to begin first-in-human testing for NGM707 in mid-2021 and for NGM438 in the fourth quarter of 2021.
Both antibodies were discovered by NGM under its strategic collaboration with Merck & Co. The companies have been working together since 2015, and in March 2019 Merck exercised its option to extend the collaboration through March 2022.
“During the two-year extension period, Merck will continue to fund NGM’s research and development efforts at similar levels to the original collaboration terms and will make additional payments totaling up to $20 million in support of NGM’s research and development activities in 2021 and 2022,” states NGM’s website. “Merck retains one additional two-year extension option that is exercisable in March 2021, which would extend the collaboration from March 2022 to March 2024.”
“Merck has a one-time option to license all resulting collaboration programs following human proof-of-concept trials. Upon exercising such options, Merck will lead global product development and commercialization for the resulting products, if approved. Prior to Merck initiating a Phase 3 study for a licensed program, NGM may elect to either receive milestone and royalty payments or, in certain cases, to co-fund development and participate in a global cost and revenue share arrangement of up to 50 percent,” the website continues. “The agreement also provides NGM with the option to participate in the co-promotion of any co-funded program in the United States.”