دورية أكاديمية
ASN004, A 5T4-targeting scFv-Fc Antibody-Drug Conjugate with High Drug-to-Antibody Ratio, Induces Complete and Durable Tumor Regressions in Preclinical Models.
| العنوان: | ASN004, A 5T4-targeting scFv-Fc Antibody-Drug Conjugate with High Drug-to-Antibody Ratio, Induces Complete and Durable Tumor Regressions in Preclinical Models. |
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| المؤلفون: | Smith RA; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey. roger.smith@asanabio.com., Zammit DJ; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Damle NK; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Usansky H; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Reddy SP; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Lin JH; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Mistry M; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Rao NS; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Denis LJ; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey., Gupta S; Asana BioSciences, Princeton Pike Corporate Center, Lawrenceville, New Jersey. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2021 Aug; Vol. 20 (8), pp. 1327-1337. Date of Electronic Publication: 2021 May 27. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Antibodies, Monoclonal, Humanized/*chemistry , Antineoplastic Agents/*pharmacology , Breast Neoplasms/*drug therapy , Immunoconjugates/*pharmacology , Lung Neoplasms/*drug therapy , Membrane Glycoproteins/*antagonists & inhibitors , Single-Chain Antibodies/*chemistry, Animals ; Apoptosis ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Proliferation ; Female ; Humans ; Lung Neoplasms/immunology ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Mice, Nude ; Mice, SCID ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays |
| مستخلص: | 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. (©2021 American Association for Cancer Research.) |
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| المشرفين على المادة: | 0 (Antibodies, Monoclonal, Humanized) 0 (Antineoplastic Agents) 0 (Immunoconjugates) 0 (Membrane Glycoproteins) 0 (Single-Chain Antibodies) 0 (trophoblastic glycoprotein 5T4, human) |
| تواريخ الأحداث: | Date Created: 20210528 Date Completed: 20220217 Latest Revision: 20220217 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1158/1535-7163.MCT-20-0565 |
| PMID: | 34045226 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
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| DOI: | 10.1158/1535-7163.MCT-20-0565 |