Microtubule inhibitor-based antibody–drug conjugates for cancer therapy

Abstract

The specificity of monoclonal antibodies represents a potential therapeutic advantage, but their use as single agents in oncology has proven limited to date. The development of antibody-drug conjugates (ADCs) takes advantage of the specificity of the monoclonal antibody and potent cytotoxic effect of chemotherapy, leading to enhanced cytotoxicity in target cells and limiting toxicity to normal tissue. Microtubules represent a validated oncologic target in a range of tumor types, with a number of anti-microtubule targeting cytotoxic drugs approved for cancer use. The systemic use of potent microtubule-binding agents is limited by their effects in normal cells, which leads to toxicity including myelosuppression and peripheral neuropathy. Linking these agents to monoclonal antibodies may limit toxicity to normal tissues and increase drug concentration in target tissues, also allowing the use of more potent agents which would be too toxic to administer in their unbound form. Two such ADCs have been approved for clinical use and many others are in development. Here we review the characteristics of each of the ADC components that have led to efficacious therapies and discuss some of the tubulin inhibitor-based ADCs in development for cancer therapy.

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression

“…Briefly, HER2 immunohistochemical staining was performed on paraffin-embedded 5 µm sections of cell blocks after deparaffinisation and rehydration, using the c-erbB-2 antibody (Thermo Fisher Scientific, Fremont, CA) at 1:800 dilution. HER2 staining intensity was graded per the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) 2013 breast scoring criteria (20). Appropriate positive and negative controls were used with each case.…”

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

“…A major advantage of ADCs is their ability to deliver a toxic payload directly to a tumor, bypassing downstream resistance mechanisms 8. Depatuxizumab mafodotin (depatux‐m) (formerly ABT‐414) is a novel ADC targeting EGFR in which cysteine (cys) residues of the depatux antibody were conjugated to a potent antimicrotubule agent, monomethyl auristatin F (MMAF), through a noncleavable maleimidocaproyl (mc) linker (mc‐MMAF [mafodotin]) 5, 9.…”

Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling

“…When J591 binds to the external domain of PSMA on LNCaP prostate cancer cells, the J591/PSMA complex undergoes endocytosis via clathrin-coated pits and accumulates in endosomes (3). Indeed, the surface binding and subsequent internalization are the fundamental rationale for using J591 as a carrier for residualizing radiometals and cytotoxic drug conjugates [ 11 – 13 ] that rely on such internalization to maximize their therapeutic effectiveness.…”