Nonclinical Development of SRK-181: An Anti-Latent TGFß1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors.
Int J Toxicol
; 40(3): 226-241, 2021.
Article
in En
| MEDLINE
| ID: mdl-33739172
ABSTRACT
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-ß (TGFß) signaling pathway has been identified as a potential target to overcome primary resistance, although the nonselective inhibition of multiple TGFß isoforms has led to dose-limiting cardiotoxicities. SRK-181 is a high-affinity, fully human antibody that selectively binds to latent TGFß1 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 TGFß1 that does not produce the nonclinical toxicities associated with nonselective TGFß inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transforming Growth Factor beta1
/
Antibodies, Monoclonal, Humanized
/
Neoplasm Metastasis
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Int J Toxicol
Journal subject:
TOXICOLOGIA
Year:
2021
Document type:
Article
Affiliation country:
United States