SRK-181 (TGFβ1 Inhibitor) for Immuno-Oncology

Scholar Rock has selected SRK-181, a highly specific inhibitor of the activation of latent TGFβ1, as the first product candidate in its cancer immunotherapy program based on the strength of its preclinical data and human translational insights.  We believe SRK-181 has the potential to render resistant solid tumors vulnerable to immune checkpoint inhibitors such as anti-PD1/PDL1 therapies and drive tumor regression through combination therapy. Scholar Rock anticipates initiating a Phase 1 clinical trial evaluating SRK-181 in patients with solid tumors in mid-2020.

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. Or in some cases, patients’ tumors initially respond to checkpoint blockade but subsequently acquire resistance.

Selective Inhibition of TGFβ1 Could Be Key in Unlocking Immune Exclusion

Multiple peer-reviewed studies have implicated TGFβ signaling as a key driver 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. Preclinical and translational data suggest that TGFβ1 works to exclude effector cell proliferation and entry into the tumor, thereby preventing the immune system from exerting anti-tumor activity. By specifically inhibiting the activation of latent TGFβ1, our antibodies may 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 (and a therapeutic window enabling higher levels of dosing), our antibodies are designed and aimed at selectively targeting the latent TGFβ1 complex, without meaningfully 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, has the potential to make a meaningful impact in the treatment of tumors with primary resistance to checkpoint immunotherapies.  Scholar Rock presented positive preclinical data at the Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting in November 2018 and at the American Association for Cancer Research (AACR) Annual Meeting in April 2019 demonstrating the ability of SRK-181-mIgG1 (the murine version of SRK-181) to render tumors vulnerable to anti-PD1 therapy across multiple syngeneic mouse models of primary resistance to checkpoint blockade therapy (CBT).

SITC poster titled: “Defeating checkpoint resistance: Highly specific inhibition of latent TGFβ1 activation renders resistant solid tumors vulnerable to PD-1 blockade” (Poster #550)

AACR poster titled: “Defeating primary checkpoint resistance: SRK-181 is a first-in-class, fully human antibody that renders resistant tumors sensitive to anti-PD-1” (Poster #4090)

“Scholar Rock” is a registered trademark of Scholar Rock, Inc.  |  © 2020 Scholar Rock All Rights Reserved.
Back to Top

The site you are about to visit is maintained by another organization, which is solely responsible for its content. As we cannot control the content or privacy practices of any third-party websites, we encourage you to read the privacy policy of every website you visit.

Continue   Cancel