TGFβ1 Immuno-Oncology

Scholar Rock is developing highly specific inhibitors of the activation of latent TGFβ1 and plans to nominate a product candidate and first indication in oncology, immuno-oncology or fibrosis by the end of the first half of 2019.

Despite the clinical breakthroughs achieved by cancer immunotherapy, there remains significant unmet need with a majority of patients failing to respond to checkpoint inhibition. Immune checkpoints are cellular mechanisms that act as a brake on the immune system, and tumors express these proteins in the tumor microenvironment to create an immunosuppressive environment to evade the host’s immune system. Immune checkpoint proteins, such as PD-1 and PD-L1, have therefore become key therapeutic targets in the tumor microenvironment. By inhibiting these proteins, the brakes on the immune system are released, allowing the T cells to kill the cancer cells. There are currently multiple approved immunotherapies that target the PD-1/PD-L1 pathway. However, a significant proportion of patients fail to respond to checkpoint inhibition therapy because their cancers have pre-existing resistance to immunotherapy. In some cases, patients’ tumors initially respond to checkpoint blockade but subsequently acquire resistance.

Multiple peer-reviewed studies have implicated TGFβ signaling in primary resistance to checkpoint blockade. Our analysis of publicly available human tumor data has identified TGFβ1 as the predominant TGFβ isoform in many human tumors, particularly for those cancers, such as bladder, lung and melanoma, where checkpoint therapies are already approved. TGFβ1 works to exclude effector cell proliferation and entry into the tumor, thereby preventing the immune system from doing its job. By specifically inhibiting the activation of latent TGFβ1, our antibodies could allow effector cell entry and access to their target, after which the brakes on the immune system can be released and potentially lead to tumor regression.

Conventional TGFβ antagonists do not discriminate among the three isoforms of TGFβ. We have hypothesized that this lack of isoform-selectivity may at least in part underlie the toxicities observed in both preclinical and human studies. To achieve improved safety, our antibodies are designed to selectively target the latent TGFβ1 complex, without materially affecting the other isoforms.

We believe that our preclinical data suggest that specific inhibition of the activation of latent TGFβ1 in combination with checkpoint inhibitors may provide a meaningful impact in treating primary resistance to checkpoint immunotherapies.  We presented positive preclinical data at the Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting in November 2018 in a poster titled “Defeating checkpoint resistance: Highly specific inhibition of latent TGFβ1 activation renders resistant solid tumors vulnerable to PD-1 blockade” (Poster #550).

In syngeneic mouse tumor models that reflect human primary resistance to checkpoint therapy, treatment with a highly specific inhibitor of TGFβ1, SRTβ1-Ab3, rendered the MBT-2 (bladder cancer) and Cloudman S91 (melanoma) tumors vulnerable to anti-PD1 therapy. Combination treatment with SRTβ1-Ab3 and an anti-PD1 antibody resulted in tumor regression or tumor control as well as statistically significant survival benefit when compared to anti-PD1 monotherapy. In addition, adult rats treated with SRTβ1-Ab3 with weekly doses up to 100mg/kg for 4 weeks showed an improved preclinical toxicity profile compared to pan-TGFβ inhibition. Detailed result available here.

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