The Need

Although immune checkpoint blockade (ICB) has emerged as a promising cancer immunotherapy, a majority of tumors fail to respond to ICB. A potential mechanism driving this failed response is the accumulation of TGF-β1 in the tumor microenvironment (TME), which drives immune dysfunction by inducing regulatory T cells (Tregs), while excluding and inhibiting the function of effector CD8+ T cells, among others. Given the pleotropic, multifunctional nature of TGF-β, systemic inhibition has multiple side effects and been clinically challenging. As such, developing translatable approaches to inhibit TGFβ locally in the TME is of paramount importance.

The Technology

Researchers at The Ohio State University, led by Dr. Zihai Li, have developed an antibody (PIIO-1) that binds to glycoprotein-A repetitions predominant (GARP) and inhibits the activation of GARP-bound latent TGFβ and downstream signaling. GARP, encoded by Lrrc32, is a cell surface, non-signaling, docking, and activating receptor for latent TGFβ that is highly expressed in cancer cells, activated Tregs, and platelets. Blocking this signaling pathway has been shown to overcome tumor resistance to ICB.

Therapeutic targeting of TGFβ is expected to have beneficial effects through two mechanisms: via its direct effect on tumor cells, and via modulation of the TME that leads to increased immunosurveillance. The Li team discovered that genetic deletion of Lrrc32 in Tregs or platelets enhanced protection against inflammation-associated colorectal cancer and MC38 colon cancer. They validated GARP as a therapeutic target by generating a monoclonal antibody and demonstrated enhanced antitumor immunity when combined with PD1 blockade in a mouse model of triple-negative breast cancer. The antibody treatment diminishes TGFβ signaling in the TME and significantly reduces metastasis. The antibody has been humanized (as PIIO-1), and a novel human LRRC32 knock-in mouse generated to the endogenous Lrrc32 locus to further test this therapeutic. In models of breast cancer, they found that PIIO-1 therapy reduced lung metastases and Tregs (Fig 1 A-C), and augmented efficacy when combined with chemotherapy (Fig 1 D-F). Furthermore, in other murine tumor models, PIIO-1 has single agent activity and is able to promote CD8+ T cell function, as evidenced by reduction of exhausted CD8+ T cells and increased effector CXCR3+CD8+ T cells in the TME. Furthermore, they successfully generated PIIO-1-based chimeric antigen receptor (CAR) against GARP and made GARP-targeted CAR-T and -NK cells. Finally, they found that PIIO-1 improves therapeutic efficacy of PD-1 blockade against Lewis lung carcinoma and CMT-167 lung cancer.

Ongoing and Future Development

The Li lab has generated additional robust pre-clinical data (presently unpublished). Work is under way to produce clinical-grade product for use in IND-enabling studies against preclinical models of cancer, alone or in combination with ICBs.

Commercial Applications

• Targeted cancer therapy
• Modulation of inflammatory diseases
• Monoclonal antibodies
• Combination with anti-PD[L]-1 blockade or other ICBs

Benefits/Advantages

Although several other anti-GARP antibodies are being developed, this PIIO-1 anti-GARP antibody will be a better therapeutic alone and in combination with PD-1 blockade because it can inhibit all three TGF-β isoforms. Treatment with PIIO-1 modulates the tumor immune environment and yields a tumor that is more responsive to other treatments, such as ICB and chemotherap

Patent Filing(s)

U.S. Appl. 63/254,182

Publications

GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon Cancer Res (2019) 79 (6): 1178–1190. https://cancerres.aacrjournals.org/content/79/6/1178

Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Cancer Res (2016) 76 (24): 7106–7117. https://cancerres.aacrjournals.org/content/76/24/7106.long