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.
Highlights
Antibody–drug conjugates (ADC) constitute a therapeutic modality in which a cytotoxic agent is chemically linked to an antibody that recognizes a tumor-associated antigen [1]
To inform the design of the anti-5T4 ADC, we sought to determine whether the 5T4-expressing cancer cells were actively proliferating and might be susceptible to an antimitotic agent
When 2 NSCLC samples were costained with antibodies to 5T4 and cell proliferation marker Ki67, considerable overlap was observed (Fig. 1A). These results suggested that 5T4-expressing tumor cells would be sensitive to an antimitotic agent such as auristatin
Summary
Antibody–drug conjugates (ADC) constitute a therapeutic modality in which a cytotoxic agent is chemically linked to an antibody that recognizes a tumor-associated antigen [1]. The basic strategy underlying ADCs is to combine the exquisite target selectivity of monoclonal antibodies with the potent cytotoxic activity of certain natural products and synthetic molecules, with the goal of generating agents that are highly efficacious and safe. The ADC platform currently includes a growing repertoire of cytotoxic payloads, linker technologies, and conjugation methods. Key considerations in generating an optimal ADC include target biology, antibody properties, Authors' Affiliations: 1Oncology Research Unit; 2Pharmacokinetics, Dynamics and Metabolism; 3Drug Safety Research & Development, Pfizer Inc., Pearl River, New York; 4Global BioTherapeutic Technologies, Pfizer Inc., Cambridge, Massachusetts; and 5Worldwide Medicinal Chemistry, Pfizer Inc., Groton, Connecticut. More than half of the ADCs in clinical development are based on auristatin, a synthetic analog of the natural product dolastatin-10 that inhibits tubulin polymerization and induces G2–M cell-cycle arrest and cell death at low picomolar intracellular concentrations [1,2,3,4]
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