Nonclinical Development of SRK-181: An Anti-Latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors

Welsh, Brian T.; Faucette, Ryan; Bilic, Sanela; Martin, Constance; Schürpf, Thomas; Chen, David; Nicholls, Samantha B.; Lansita, Janice A.; Kalra, Ashish

doi:10.1177/1091581821998945

Cited by 17 publications

(13 citation statements)

References 32 publications

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“…Antibodies to TGF-β ligand (both to individual and to all TGFβ isoforms) also exist, as do ligand traps (124,(129)(130)(131). Agents targeted at preventing L-TGF-β activation such as integrin inhibitors have already entered clinical trials of inflammatory diseases (125), and antibodies and small molecules blocking L-TGF-β are in preclinical development (132,133). Angiotensin converting enzyme inhibitors and angiotensin-II receptor blockers such as losartan has been evaluated in clinical trials of COVID-19 (NCT04312009 and NCT04312009) given their low cost, worldwide availability as approved drugs for hypertension and heart failure, and their potential modulation of surface expression of the ACE2 receptor where the SARS-CoV-2 spike protein binds for its cellular uptake route.…”

Section: Tgf-β Pathway Inhibitors May Ameliorate Tgf-β Driven Thrombo...mentioning

confidence: 99%

Microvascular significance of TGF-β axis activation in COVID-19

Arguinchona

Zagona-Prizio

Joyce

et al. 2023

Front. Cardiovasc. Med.

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As 2023 approaches, the COVID-19 pandemic has killed millions. While vaccines have been a crucial intervention, only a few effective medications exist for prevention and treatment of COVID-19 in breakthrough cases or in unvaccinated or immunocompromised patients. SARS-CoV-2 displays early and unusual features of micro-thrombosis and immune dysregulation that target endothelial beds of the lungs, skin, and other organs. Notably, anticoagulation improves outcomes in some COVID-19 patients. The protein transforming growth factor-beta (TGF-β1) has constitutive roles in maintaining a healthy microvasculature through its roles in regulating inflammation, clotting, and wound healing. However, after infection (including viral infection) TGF-β1 activation may augment coagulation, cause immune dysregulation, and direct a path toward tissue fibrosis. Dysregulation of TGF-β signaling in immune cells and its localization in areas of microvascular injury are now well-described in COVID-19, and such events may contribute to the acute respiratory distress syndrome and skin micro-thrombosis outcomes frequently seen in severe COVID-19. The high concentration of TGF-β in platelets and in other cells within microvascular thrombi, its ability to activate the clotting cascade and dysregulate immune pathways, and its pro-fibrotic properties all contribute to a unique milieu in the COVID-19 microvasculature. This unique environment allows for propagation of microvascular clotting and immune dysregulation. In this review we summarize the physiological functions of TGF-β and detail the evidence for its effects on the microvasculature in COVID-19. In addition, we explore the potential role of existing TGF-β inhibitors for the prevention and treatment of COVID-19 associated microvascular thrombosis and immune dysregulation.

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Section: Tgf-β Pathway Inhibitors May Ameliorate Tgf-β Driven Thrombo...mentioning

confidence: 99%

Microvascular significance of TGF-β axis activation in COVID-19

Arguinchona

Zagona-Prizio

Joyce

et al. 2023

Front. Cardiovasc. Med.

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“…The agent SRK-181 is a high-affinity, fully humanized monoclonal antibody that inhibits latent TGF-β1 activation. Preclinical work has displayed little to no binding to latent TGF-β2 and TGF-β3 isoforms or to active TGF-β growth factors [59]. In mouse tumor models (bladder, melanoma, and breast cancer), SRK-181 (in combination with anti-PD1 therapy) overcame primary anti-PD-1 resistance and showed survival benefit [58].…”

Section: Srk-181mentioning

confidence: 99%

Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy

Tschernia

Gulley

2022

BioDrugs

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Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumors as metastatic melanoma and non-small cell-lung cancer, in which immune checkpoint inhibition has become the first-line treatment of choice, only a minority of patients will benefit considerably from these treatments. This has been attributed to a number of factors, including an immune-suppressive tumor microenvironment (TME). Using different modalities to break these barriers is of utmost importance to expand the population of patients that benefit from immune checkpoint inhibition. The multifunctional cytokine transforming growth factor-β (TGF-β) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-β, yet most of these have since been discontinued. The combination of anti-TGF-β agents with immune checkpoint inhibitors now has the potential to revive this target as a viable immunomodulatory therapeutic approach. Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review.

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“…A review of 23 mAbs authorized by the European Medicines Agency between 2016 and 2019 6 indicated that short-term toxicity studies were conducted in 2 species for 35% of the mAbs, with the majority of these reducing to 1 species (the NHP in all cases) for the long-term studies. Other publications contain case study examples 7 , 8 or reports for individual mAbs 9 , 10 , 11 that describe the use of 2 species for short and/or long-term studies.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Definition of “Similar Toxicities”: Case Studies Illustrating Industry and Regulatory Interpretation of ICH S6(R1) for Long-Term Toxicity Studies in One or Two Species

Prior

Clarke

Jones³

et al. 2022

Int J Toxicol

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ICH S6 (R1) states that safety evaluation of biotherapeutics should normally include 2 relevant species when available (i.e., a rodent and non-rodent species in which the test material is pharmacologically active), at least for short-term toxicology studies (generally supporting Phase I trials). For subsequent long-term toxicology studies (e.g., chronic studies up to 6 months dosing duration), there are options to reduce to only one species when justified, including when the mechanism of action of the biologic is well-understood or the toxicity findings in the short-term studies are “similar” in both the rodent and non-rodent species. Across the industry, around 25 to 33% of biologics assess multiple species within short-term toxicity studies but it is often unclear how different companies and regulators are applying the ICH S6 (R1) principles of “similar toxicity profiles” to progress with either 1 or 2 species in the long-term studies, in particular whether the absence of toxicities is considered within this definition. Sponsors may potentially continue to use 2 species to avoid regulatory risk and potential delays in development timelines, representing missed opportunities for reducing animal use, particularly of non-human primates, during drug development. This article summarizes presentations from a symposium at the 41st Annual meeting of the American College of Toxicology (ACT) in November 2020, in which industry case studies and regulatory perspectives addressed considerations and decisions for using 1 or 2 species for long-term toxicity studies, highlighting any common themes or experience that could be applicable for use in future decision-making.

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Nonclinical Development of SRK-181: An Anti-Latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors

Cited by 17 publications

References 32 publications

Microvascular significance of TGF-β axis activation in COVID-19

Microvascular significance of TGF-β axis activation in COVID-19

Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy

Exploring the Definition of “Similar Toxicities”: Case Studies Illustrating Industry and Regulatory Interpretation of ICH S6(R1) for Long-Term Toxicity Studies in One or Two Species

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