title: Long-term tumor regression induced by an antibody-drug conjugate that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells.
abstract: Antibody-drug conjugates (ADC) represent a promising therapeutic modality for the clinical management of cancer. We sought to develop a novel ADC that targets 5T4, an oncofetal antigen expressed on tumor-initiating cells (TIC), which comprise the most aggressive cell population in the tumor. We optimized an anti-5T4 ADC (A1mcMMAF) by sulfydryl-based conjugation of the humanized A1 antibody to the tubulin inhibitor monomethylauristatin F (MMAF) via a maleimidocaproyl linker. A1mcMMAF exhibited potent in vivo antitumor activity in a variety of tumor models and induced long-term regressions for up to 100 days after the last dose. Strikingly, animals showed pathologic complete response in each model with doses as low as 3 mg antibody/kg dosed every 4 days. In a non-small cell lung cancer patient-derived xenograft model, in which 5T4 is preferentially expressed on the less differentiated tumor cells, A1mcMMAF treatment resulted in sustained tumor regressions and reduced TIC frequency. These results highlight the potential of ADCs that target the most aggressive cell populations within tumors, such as TICs. In exploratory safety studies, A1mcMMAF exhibited no overt toxicities when administered to cynomolgus monkeys at doses up to 10 mg antibody/kg/cycle × 2 and displayed a half-life of 5 days. The preclinical efficacy and safety data established a promising therapeutic index that supports clinical testing of A1mcMMAF.
authors.affiliation: Oncology Research Unit, Pfizer Inc., Pearl River, NY 10965, USA. puja.sapra@pfizer.com
authors.forename: Puja
authors.initials: P
authors.lastname: Sapra
authors.forename: Marc
authors.initials: M
authors.lastname: Damelin
authors.forename: John
authors.initials: J
authors.lastname: Dijoseph
authors.forename: Kimberly
authors.initials: K
authors.lastname: Marquette
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Geles
authors.forename: Jonathon
authors.initials: J
authors.lastname: Golas
authors.forename: Maureen
authors.initials: M
authors.lastname: Dougher
authors.forename: Bitha
authors.initials: B
authors.lastname: Narayanan
authors.forename: Andreas
authors.initials: A
authors.lastname: Giannakou
authors.forename: Kiran
authors.initials: K
authors.lastname: Khandke
authors.forename: Russell
authors.initials: R
authors.lastname: Dushin
authors.forename: Elana
authors.initials: E
authors.lastname: Ernstoff
authors.forename: Judy
authors.initials: J
authors.lastname: Lucas
authors.forename: Mauricio
authors.initials: M
authors.lastname: Leal
authors.forename: George
authors.initials: G
authors.lastname: Hu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Lioudmila
authors.initials: L
authors.lastname: Tchistiakova
authors.forename: Robert T
authors.initials: RT
authors.lastname: Abraham
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gerber
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D020714:Maximum Tolerated Dose; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D012074:Remission Induction; D014018:Tissue Distribution; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C581920:A1mcMMAF; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D050257:Tubulin Modulators; C063709:trophoblastic glycoprotein 5T4, human