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Figure S7 from Inhibition of LILRB2 by a Novel Blocking Antibody Designed to Reprogram Immunosuppressive Macrophages to Drive T-Cell Activation in Tumors

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posted on 2023-04-03, 08:40 authored by Ben Umiker, Yasmin Hashambhoy-Ramsay, Jeff Smith, Tanzila Rahman, Amy Mueller, Rachel Davidson, Christina Meyer, Gayatri Patankar, Mohammad Murshid Alam, Sarah Jaffe, Kristin Krukenberg, Allison Goodman, Vikki Spaulding, Michelle Priess, Abha Dhaneshwar, Masie Wong, Alexa Diiorio, Kristin O'Malley, Lara McGrath, Margaret Willer, Lauren Pepper, Monica Gostissa, Katalin Kis-Toth, Dmitri Wiederschain, Heather Cohen, Donald R. Shaffer

A set of 23 anti-LILRB2 antibodies were tested for their ability to block HLA-G tetramer binding to LILRB2 and induce TNF alpha in a macrophage activation assay.

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Jounce Therapeutics (Jounce Therapeutics, Inc.)

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ARTICLE ABSTRACT

Tumor-associated macrophages (TAM) play an important role in maintaining the immunosuppressive state of the tumor microenvironment (TME). High levels of CD163+ TAMs specifically are associated with poor prognosis in many solid tumor types. Targeting TAMs may represent a key approach in development of the next generation of cancer immune therapeutics. Members of the leukocyte immunoglobulin-like receptor B (LILRB) family, including LILRB2 (ILT4), are known to transmit inhibitory signals in macrophages and other myeloid cells. Leveraging bulk and single cell RNA-sequencing datasets, as well as extensive immunophenotyping of human tumors, we found that LILRB2 is highly expressed on CD163+ CD11b+ cells in the TME and that LILRB2 expression correlates with CD163 expression across many tumor types. To target LILRB2, we have developed JTX-8064, a highly potent and selective antagonistic mAb. JTX-8064 blocks LILRB2 binding to its cognate ligands, including classical and nonclassical MHC molecules. In vitro, JTX-8064 drives the polarization of human macrophages and dendritic cells toward an immunostimulatory phenotype. As a result, human macrophages treated with a LILRB2 blocker are reprogrammed to increase the activation of autologous T cells in co-culture systems. Furthermore, JTX-8064 significantly potentiates the activity of anti-PD-1 in allogeneic mixed lymphocyte reaction. In a human tumor explant culture, pharmacodynamic activity of JTX-8064 was observed in monotherapy and in combination with anti-PD-1. Collectively, our work provides strong translational and preclinical rationale to target LILRB2 in cancer.

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    Molecular Cancer Therapeutics

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