ASN004, A 5T4-targeting scFv-Fc Antibody-Drug Conjugate with High Drug-to-Antibody Ratio, Induces Complete and Durable Tumor Regressions in Preclinical Models.

Abstract

The 5T4 oncofetal antigen (trophoblast glycoprotein) is expressed in a wide range of malignant tumors but shows very limited expression in normal adult tissues. ASN004 is a 5T4-targeted antibody-drug conjugate (ADC) that incorporates a novel single-chain Fv-Fc antibody and Dolaflexin drug-linker technology, with an Auristatin F hydroxypropylamide payload drug-to-antibody ratio of approximately 10-12. The pharmacology, toxicology, and pharmacokinetic properties of ASN004 and its components were investigated in vitro and in vivo ASN004 showed high affinity for the 5T4 antigen and was selectively bound to and internalized into 5T4-expressing tumor cells, and potent cytotoxicity was demonstrated for a diverse panel of solid tumor cell lines. ASN004 induced complete and durable tumor regression in multiple tumor xenograft models, derived from human lung, breast, cervical, and gastric tumor cell lines having a wide range of 5T4 expression levels. A single dose of ASN004, as low as 1 mg/kg i.v., achieved complete tumor regression leading to tumor-free survivors in the A431 cervical cancer model. In head-to-head studies, superior activity of ASN004 was demonstrated against trastuzumab-DM1, in a low-5T4/high-HER2 expressing gastric tumor model, and 10-fold greater potency was found for ASN004 against the 5T4-targeted ADC PF-06263507 in a lung tumor model. In marmoset monkeys, ASN004 was well tolerated at doses up to 1.5 mg/kg Q3W i.v., and showed dose-dependent exposure, linear pharmacokinetics, and markedly low exposure of free payload drug. Taken together, these findings identify ASN004 as a promising new ADC therapeutic for clinical evaluation in a broad range of solid tumor types.

• Authors: Roger A Smith, David J Zammit, Nitin K Damle, Helen Usansky, Sanjeeva P Reddy, Jun-Hsiang Lin, Mahesh Mistry, Niranjan S Rao, Louis J Denis, Sandeep Gupta
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 8 Pg. 1327-1337 (08 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 34045226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Immunoconjugates
• Membrane Glycoproteins
• Single-Chain Antibodies
• trophoblastic glycoprotein 5T4, human

Topics

• Animals
• Antibodies, Monoclonal, Humanized (chemistry)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Breast Neoplasms (drug therapy, immunology, metabolism, pathology)
• Cell Proliferation
• Female
• Humans
• Immunoconjugates (pharmacology)
• Lung Neoplasms (drug therapy, immunology, metabolism, pathology)
• Membrane Glycoproteins (antagonists & inhibitors)
• Mice
• Mice, Nude
• Mice, SCID
• Single-Chain Antibodies (chemistry)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays