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. |
---|---|
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.) |
References: | Stern PL, Harrop R. 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer. Cancer Immunol Immunother. 2017;66:415–26. Zhao Y, Malinauskas T, Harlos K, Jones EY. Structural insights into the inhibition of Wnt signaling by cancer antigen 5T4/Wnt-activated inhibitory factor 1. Structure. 2014;22:612–20. Starzynska T, Wiechowska-Kozlowska A, Marlicz K, Bromley M, Roberts SA, Lawniczak M, et al. 5T4 oncofetal antigen in gastric carcinoma and its clinical significance. Eur J Gastroenterol Hepatol. 1998;10:479–84. Harrop R, O'Neill E, Stern PL. Cancer stem cell mobilization and therapeutic targeting of the 5T4 oncofetal antigen. Ther Adv Vaccines Immunother. 2019;7:1–17. Starzynska T, Marsh PJ, Schofield PF, Roberts SA, Myers KA, Stern PL. Prognostic significance of 5T4 oncofetal antigen expression in colorectal carcinoma. Br J Cancer. 1994;69:899–902. Wang R, Lai Q, Tang L, Tao Y, Yao Y, Liu Y, et al. A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models. Am J Cancer Res. 2018;8:610–23. Damelin M, Geles KG, Follettie MT, Yuan P, Baxter M, Golas J, et al. Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells. Cancer Res. 2011;71:4236–46. Kerk SA, Finkel KA, Pearson AT, Warner KA, Zhang Z, Nör F, et al. 5T4-targeted therapy ablates cancer stem cells and prevents recurrence of head and neck squamous cell carcinoma. Clin Cancer Res. 2017;23:2516–27. Wan YL, Sapra P, Bolton J, Chua JX, Durrant LG, Stern PL. Combination treatment with an antibody-drug conjugate (A1mcMMAF) targeting the oncofetal glycoprotein 5T4 and carboplatin improves survival in a xenograft model of ovarian cancer. Targeted Oncol. 2019;14:465–77. Hawkins RE, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, et al. A randomized phase II/III Study of naptumomab estafenatox + IFNα versus IFNα in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clin Cancer Res. 2016;22:3172–81. Lester JF, Casbard AC, Al-Taei S, Harrop R, Katona L, Attanoos RL, et al. A single centre phase II trial to assess the immunological activity of TroVax plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma - the SKOPOS trial. OncoImmunology. 2018;7:e1457597. Sapra P, Damelin M, DiJoseph J, Marquette K, Geles KG, Golas J, et al. Long-term tumor regression induced by an antibody–drug conjugate that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells. Mol Cancer Ther. 2013;12:38–47. Shapiro GI, Vaishampayan UN, LoRusso P, Barton J, Hua S, Reich SD, et al. First-in-human trial of an anti-5T4 antibody-monomethylauristatin conjugate, PF-06263507, in patients with advanced solid tumors. Invest New Drugs. 2017;35:315–23. Harper J, Lloyd C, Dimasi N, Toader D, Marwood R, Lewis L, et al. Preclinical evaluation of MEDI0641, a pyrrolobenzodiazepine-conjugated antibody-drug conjugate targeting 5T4. Mol Cancer Ther. 2017;16:1576–87. Shi B, Wu M, Li Z, Xie Z, Wei X, Fan J, et al. Antitumor activity of a 5T4 targeting antibody drug conjugate with a novel payload derived from MMAF via C-Lock linker. Cancer Med. 2019;8:1793–805. Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov. 2017;16:315–37. Coats S, Williams M, Kebble B, Dixit R, Tseng L, Yao N-S, et al. Antibody–drug conjugates: future directions in clinical and translational strategies to improve the therapeutic index. Clin Cancer Res. 2019;25:5441–8. Yurkovetskiy AV, Yin M, Bodyak N, Stevenson CA, Thomas JD, Hammond CE, et al. A polymer-based antibody–vinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res. 2015;75:3365–72. Yurkovetskiy A, Bodyak N, Yin M, Thomas JD, Clardy SM, Conlon PR, et al. Dolaflexin: a novel antibody-drug conjugate platform featuring high drug loading and a controlled bystander effect. Mol Cancer Ther. 2021;20:885–95. Hamilton EP, Barve MA, Bardia A, Beeram M, Bendell JC, Mosher R, et al. Phase 1 dose escalation of XMT-1522, a novel HER2-targeting antibody-drug conjugate (ADC), in patients (pts) with HER2-expressing breast, lung and gastric tumors. J Clin Oncol. 2018;36. Tolcher AW, Ulahannan SV, Papadopoulos KP, Edenfield WJ, Matulonis UA, Burns TF, et al. Phase 1 dose escalation study of XMT-1536, a novel NaPi2b-targeting antibody-drug conjugate (ADC), in patients (pts) with solid tumors likely to express NaPi2b. J Clin Oncol. 2019;37. Damle N, Venkatesan A, Krishnan S, Pattanaik P, Joshi S. 5T4-Targeted immunofusion molecule and methods. 2014. Gerber HP, DiJoseph JF, Khandke KM, Marquette KA, Sapra P, Tchistiakova LG. Antibody-drug conjugates. Forsberg G, Forsgren M, Jaki M, Norin M, Sterky C, Enherning A, et al. Identification of framework residues in a secreted recombinant antibody fragment that control production level and localization in Escherichia coli. J Biol Chem. 1997;272:12430–6. Wang X, Katayama A, Wang Y, Yu L, Favoino E, Sakakura K, et al. Functional characterization of an scFv-Fc antibody that immunotherapeutically targets the common cancer cell surface proteoglycan CSPG4. Cancer Res. 2011;71:7410–22. Yokota T, Milenic DE, Whitlow M, Schlom J. Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res. 1992;52:3402–8. Orsi A, Rees D, Andreini I, Venturella S, Cinelli S, Oberto G. Overview of the marmoset as a model in nonclinical development of pharmaceutical products. Regul Toxicol Pharmacol. 2011;59:19–27. Barok M, Tanner M, Köninki K, Isola J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett. 2011;306:171–9. Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22:5097–108. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8:659–71. Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody–drug conjugates in human clinical trials. J Ocular Pharmacol Ther. 2015;31:589–604. Li F, Emmerton KK, Jonas M, Zhang X, Miyamoto JB, Setter JR, et al. Extracellular released payload influences potency and bystander-killing effects of antibody-drug conjugates in preclinical models. Cancer Res. 2016;76:2710–9. |
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 |
---|---|
DOI: | 10.1158/1535-7163.MCT-20-0565 |