Nonclinical Development of SRK-181: An Anti-Latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors.
Brian T WelshRyan FaucetteSanela BilicConstance J MartinThomas SchürpfDavid ChenSamantha NichollsJanice LansitaAshish KalraPublished in: International journal of toxicology (2021)
Checkpoint inhibitors offer a promising immunotherapy strategy for cancer treatment; however, due to primary or acquired resistance, many patients do not achieve lasting clinical responses. Recently, the transforming growth factor-β (TGFβ) signaling pathway has been identified as a potential target to overcome primary resistance, although the nonselective inhibition of multiple TGFβ isoforms has led to dose-limiting cardiotoxicities. SRK-181 is a high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. To support SRK-181 clinical development, we present here a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies showed that SRK-181 has no effect on human platelet function and does not induce cytokine release in human peripheral blood. Four-week toxicology studies with SRK-181 showed that weekly intravenous administration achieved sustained serum exposure and was well tolerated in rats and monkeys, with no treatment-related adverse findings. The no-observed-adverse-effect levels levels were 200 mg/kg in rats and 300 mg/kg in monkeys, the highest doses tested, and provide a nonclinical safety factor of up to 813-fold (based on Cmax) above the phase 1 starting dose of 80 mg every 3 weeks. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that SRK-181 is a selective inhibitor of latent TGFβ1 that does not produce the nonclinical toxicities associated with nonselective TGFβ inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.
Keyphrases
- transforming growth factor
- epithelial mesenchymal transition
- endothelial cells
- signaling pathway
- monoclonal antibody
- peripheral blood
- squamous cell carcinoma
- advanced cancer
- induced pluripotent stem cells
- locally advanced
- palliative care
- pluripotent stem cells
- small cell lung cancer
- end stage renal disease
- radiation therapy
- randomized controlled trial
- rectal cancer
- stem cells
- big data
- bone marrow
- low dose
- prognostic factors
- cell proliferation
- peritoneal dialysis
- high dose
- deep learning
- artificial intelligence
- climate change
- placebo controlled
- adverse drug