Background: Collagen is an abundant component of the extracellular matrix-enriched stromal microenvironment of solid cancers. Emerging research suggests that effective anti-tumor immunity and responsiveness to immune checkpoint inhibitor (CPI) therapy, may be subverted by the presence of collagen and tumor stroma. LAIR1 functions as an inhibitory receptor for collagen, and is highly expressed on tumor-associated macrophages, and to an extent on T cells. LAIR1 expression correlates with poor overall survival and CPI therapy resistance. To test the hypothesis that LAIR1 mediates tumor stroma-driven immune suppression and promotes CPI resistance, we generated NGM438, a monoclonal mAb to antagonize LAIR1 activity in solid cancers. Herein, we describe NGM438, characterize LAIR1 expression and distribution in human tumors, and provide evidence that LAIR1 antagonism reverses collagen-driven immune suppression and improves CPI responsiveness in immune cell-based assays and preclinical animal models.
Methods: NGM438 was identified and developed based on its ability to bind specifically to LAIR1, antagonize ligand binding, and reverse collagen-based immune suppression. NGM438 was tested using several immune cell-based functional assays, alone and in combination with the anti-PD1 mAb, pembrolizumab. Expression and distribution of LAIR1 was evaluated using flow cytometry and immunohistochemistry on healthy donor and cancer patient samples. A surrogate anti-mouse LAIR1 antagonist mAb was also developed and evaluated in preclinical animal models in combination with anti-PD1 mAbs.
Results: NGM438 reversed collagen-induced immune suppression in myeloid cells and promoted anti-PD1 mAb-driven T cell responses in immune cell-based functional assays. LAIR1 was expressed on circulating immune cells from cancer patients actively receiving CPI therapy, and was elevated on patient-matched intratumoral macrophages. Histological assessments revealed LAIR1 expression on mononuclear immune cells that infiltrated the parenchyma and collagen-rich tumor stroma across indications. Finally, LAIR1 antagonism, in combination with anti-PD1 mAb treatment, led to significant tumor growth inhibition in a preclinical model resistant to either treatment alone.
Conclusions: NGM438 is a novel LAIR1 antagonist mAb that reverses collagen-based immune suppression. LAIR1 was expressed on cancer patient circulating and intratumoral immune cells, and LAIR1-expressing cells were often found in collagen-rich tumor stroma. Preclinical data demonstrated that LAIR1 antagonism sensitized a resistant mouse tumor model to respond to anti-PD1 mAb treatment. These data support clinical evaluation of LAIR1 antagonist mAb NGM438. We aim to test the hypothesis that LAIR1 mediates collagen-driven immune suppression, alone and in combination with PD1 inhibition, in patients with solid cancers. As such, we will be advancing NGM438 to the clinic in early 2022.
Citation Format: Sisi He, Jiawei Huang, Leticia Rodriguez, Czrina Cortez, Betty Li, Carmence Ho, Amir Ashique, Kalyani Mondal, Vicky Lin, Julie Roda, Hui Tian, Yan Wang, Bin Fan, Igor Mikaelian, James Sissons, Lee Rivera, Don Gibbons, Jonathan Sitrin. Preclinical development of NGM438, a novel anti-LAIR1 antagonist monoclonal antibody for the treatment of collagen-rich solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB219.