Clearing the checkpoints

Scholar Rock preclinical study shows SRK-181 can reverse immune cell exclusion

Lori Lesko
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CAMBRIDGE, Mass.—Targeted toward reversing immune cell exclusion, Scholar Rock researchers may have found a solution for combating transforming growth factor-beta 1 (TGFβ1) activation and overcoming the primary resistance to checkpoint inhibitor therapy. In a preclinical study published in Science Translational Medicine, a Scholar Rock team describes the ability of SRK-181 to selectively inhibit TGFβ1 and allow the treatment and healing process to begin.
SRK-181 is a potent and highly selective inhibitor of TGFβ1 activation.
This investigational product candidate is being developed to overcome primary resistance to checkpoint inhibitor therapy such as anti-PD-(L)1 antibodies. TGFβ1 is the predominant TGFβ isoform expressed in many human tumors, particularly in tumor types for which checkpoint therapies are currently approved.
Drug developers continue to target TGFβ1 because it is immunosuppressive in the tumor microenvironment, playing a key role in excluding immune cell entry, preventing normal immune function and contributing to resistance to anti-PD-(L)1 therapies. The problem is, these efforts have been hindered by dose-limiting cardiotoxicity, possibly due to non-selective inhibition of multiple TGBβ isoforms.
Scholar Rock’s study in Science Translational Medicine describes the company’s reverse-translated observations from clinical tumor samples by selecting different mouse tumor models that recapitulate key features of primary resistance to CPIs. Co-administration of SRK-181-mIgG1 and an anti–PD-1 antibody in mice harboring syngeneic tumors refractory to anti–PD-1 treatment induced profound antitumor responses and survival benefit.
“With this journal publication, we are sharing the strong body of preclinical evidence we have built supporting the clinically-derived rationale for evaluating TGFβ1’s key role in primary resistance to checkpoint inhibitor therapy, and potential of a highly specific inhibitor of TGFβ1 activation to overcome this challenge,” explains Alan Buckler, chief scientific officer of Scholar Rock. “In the second half of this year, we may gain early insights from our Phase 1 proof-of-concept trial in patients with solid tumors on SRK-181’s potential to overcome the immune exclusion that we believe leads to primary resistance to anti-PD-(L)1 therapy.”
“Moreover, these published data provide further validation of Scholar Rock’s proprietary platform to develop antibodies that locally and selectively target the precursor form of growth factors, with the aim of avoiding the dose-limiting toxicities that have hindered traditional approaches to targeting growth factors,” he adds.
The introduction of immunotherapy, including checkpoint inhibitor therapy, has revolutionized the treatment of a wide variety of cancers, though patient response is uneven across the board.
“While checkpoint inhibition therapies (CPIs) have transformed the treatment of many solid tumor types, the majority of patients do not respond to these therapies,” says Scholar Rock CEO Nagesh Mahanthappa. “Recent studies have discovered that TGFβ signaling in human tumors is a significant contributor to lack of clinical response to CPIs such as anti-PD-1 or anti-PD-L1. This suggests that blocking TGFβ signaling may provide a benefit to patients who would otherwise not respond to anti-PD-(L)1.”
“Scholar Rock generated SRK-181, a highly selective, fully human antibody that blocks the activation of latent TGFβ1 without blocking the other two TGFβ isoforms,” Mahanthappa notes. “Preclinical results across multiple resistant mouse tumor models demonstrated that highly selective inhibition of TGFβ1 activation with SRK-181-mIgG1 overcomes this key mechanism of primary resistance to checkpoint inhibition therapy.”
Scholar Rock’s published preclinical study found several promising key points :
  • SRK-181 demonstrated high selectivity to TGFβ1, with no binding to TGFβ2 and TGFβ3 isoforms.
  • SRK-181, in combination with an anti-PD1 immunotherapy, drove tumor regression or control resulting in significant survival benefit in models of primary resistance to checkpoint inhibition.
  • SRK-181 overcame immune cell exclusion from tumors.
The company initiated a Phase 1 trial of SRK-181 in patients with solid tumors in March that will determine SRK-181’s safety and pharmacokinetics, as well as its efficacy when combined with anti-PD-(L)1 therapy, according to Mahanthappa. Initial data are expected in the second half of this year.
Scholar Rock’s “goal is for SRK-181 to help meaningfully expand the number of patients who could benefit from checkpoint inhibitor therapy,” he says

Lori Lesko

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