maytansine and Carcinoma--Renal-Cell

Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate that selectively targets folate receptor α (FRα). In this phase 1 dose-escalation study, the authors investigated IMGN853 in patients with FRα-positive solid tumors.. Patients received IMGN853 on day 1 of a 21-day cycle (once every 3 weeks dosing), with cycles repeated until patients experienced dose-limiting toxicity or progression. Dose escalation commenced in single-patient cohorts for the first 4 planned dose levels and then followed a standard 3 + 3 scheme. The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Secondary objectives were to determine safety and tolerability, to characterize the pharmacokinetic profile, and to describe preliminary clinical activity.. In total, 44 patients received treatment at doses escalating from 0.15 to 7.0 mg/kg. No meaningful drug accumulation was observed with the dosing regimen of once every 3 weeks. The most common treatment-related adverse events were fatigue, blurred vision, and diarrhea, the majority of which were grade 1 or 2. The dose-limiting toxicities observed were grade 3 hypophosphatemia (5.0 mg/kg) and grade 3 punctate keratitis (7.0 mg/kg). Two patients, both of whom were individuals with epithelial ovarian cancer, achieved confirmed tumor responses according to Response Evaluation Criteria in Solid Tumors 1.1, and each was a partial response.. IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Ovarian Epithelial; Carcinoma, Renal Cell; Diarrhea; Disease Progression; Dose-Response Relationship, Drug; Endometrial Neoplasms; Fatigue; Female; Humans; Hypophosphatemia; Immunoconjugates; Keratitis; Kidney Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Maytansine; Middle Aged; Neoplasms; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Vision Disorders

Conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells. However, many of the compounds used in such antibody-drug conjugates (ADC) are substrates for the multidrug transporter MDR1. To evade the MDR1-mediated resistance, we conjugated the highly cytotoxic maytansinoid DM1 to antibodies via the maleimidyl-based hydrophilic linker PEG(4)Mal. Following uptake into target cells, conjugates made with the PEG(4)Mal linker were processed to a cytotoxic metabolite that was retained by MDR1-expressing cells better than a metabolite of similar conjugates prepared with the nonpolar linker N-succinimidyl-4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC). In accord, PEG(4)Mal-linked conjugates were more potent in killing MDR1-expressing cells in culture. In addition, PEG(4)Mal-linked conjugates were markedly more effective in eradicating MDR1-expressing human xenograft tumors than SMCC-linked conjugates while being tolerated similarly, thus showing an improved therapeutic index. This study points the way to the development of ADCs that bypass multidrug resistance.

Topics: Adenocarcinoma; Animals; Antigens, Neoplasm; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Renal Cell; Cell Adhesion Molecules; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Epithelial Cell Adhesion Molecule; Female; Humans; Immunotoxins; Kidney Neoplasms; Maleimides; Maytansine; Mice; Mice, SCID; Polyethylene Glycols