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 activation 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, its systemic inhibition has multiple side effects and has been a clinically challenging pathway to target. 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: (i) a direct effect on tumor cells, and (ii) modulation of the TME and 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 is humanized, and a novel human LRRC32 knock-in mouse was generated to the endogenous Lrrc32 locus to enable murine evaluation of 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. 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 confirm a PIIO-1 as a clinical candidate and initiate cell-line development for production of clinical-grade product in IND-enabling studies. In a parallel effort, the Li lab has successfully designed a chimeric antigen receptor (CAR) against GARP using the same CDR sequences as PIIO-1, and generated GARP-targeting CAR-T and CAR-NK cells.

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 chemotherapy.

Patent Filing(s)

PCT publication WO2023064779A1

Publications

Selective targeting of GARP-LTGFβ axis in the tumor microenvironment augments PD-1 blockade via enhancing CD8+ T cell antitumor immunity. J Immunother Cancer. 2022 Sep;10(9):e005433. https://doi.org/10.1136/jitc-2022-005433.

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