Abstract 4090: Defeating primary checkpoint resistance: SRTβ1-Ab3 is a first-in-class, fully human antibody that renders resistant tumors sensitive to anti-PD-1
Authors: Schürpf Thomas , Martin Constance J. , Littlefield Christopher , Chapron Christopher , Wawersik Stefan , Kalra Ashish , Simpson Allison , Danehy Francis , Boston Christopher , Nikiforov Anastasia , Lin Susan , Jackson Justin , Carven Gregory J. , Buckler Alan , Datta Abhishek 
Published: August 2019

Abstract
Despite the clinical breakthroughs achieved by checkpoint blockade therapy (CBT), a majority of patients treated with PD-(L)1 inhibitors fail to respond due to primary or acquired resistance. TGFβ signaling has recently been implicated as a mechanism of primary resistance to CBT, very likely via mechanisms that include immune exclusion. However, therapeutic targeting of the TGFβ pathway has been hindered by dose-limiting cardiotoxicities, most likely due to inhibition of signaling from multiple TGFβ isoforms. Upon secretion, TGFβ growth factor is held dormant in a latent complex with its non-covalently associated prodomain. TGFβ activation is triggered by extracellular events, such as integrin binding or proteolytic cleavage, that release the growth factor from this latent complex. We have demonstrated that isoform-specific inhibition of TGFβ activation can be achieved by targeting the prodomain to stabilize the latent TGFβ complex. We recently identified TGFβ1 as the predominant isoform in many human cancers, especially those for which CBT is approved for therapeutic intervention. SRTβ1-Ab3 is a fully-human antibody against latent TGFβ1 that inhibits its activation without binding or inhibiting latent TGFβ2, latent TGFβ3, or the active TGFβ1 growth factor. In syngeneic tumor models of primary CBT resistance, pharmacologic blockade of TGFβ1 activation with SRTβ1-Ab3 is sufficient to sensitize TGFβ1-predominant tumors to PD-1 inhibition. Mechanistically, combination treatment with anti-PD-1/SRTβ1-Ab3 overcomes immune exclusion in these models, induces CD8+ T cell infiltration into the tumors, and results in a reduction of myeloid immunosuppressive cells. In contrast, monotherapy with either anti-PD-1 or SRTβ1-Ab3 alone has only modest effects on these cell populations. Gene expression profiling of single vs. combination treated tumor samples provides a molecular view of effects on signaling pathways, cell populations, and activation status of these cells. These data demonstrate the efficacy of TGFβ1-specific inhibition in combination with anti-PD-1 in multiple mouse models of primary checkpoint resistance. Taken together, these synergistic effects at the tumor, cellular, and molecular levels, the preclinical safety profile, and the pharmacokinetic properties of SRTβ1-Ab3 establish a strong rationale for advancing the development of SRTβ1-Ab3 toward clinical application in cancer immunotherapy.
Citation Format: Thomas Schürpf, Constance J. Martin, Christopher Littlefield, Christopher Chapron, Stefan Wawersik, Ashish Kalra, Allison Simpson, Francis Danehy, Christopher Boston, Anastasia Nikiforov, Susan Lin, Justin Jackson, Gregory J. Carven, Alan Buckler, Abhishek Datta. Defeating primary checkpoint resistance: SRTβ1-Ab3 is a first-in-class, fully human antibody that renders resistant tumors sensitive to anti-PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4090.