Lifastuzumab vedotin, also known as DNIB0600A and RG-7599, is a novel antibody-drug conjugate being developed by Genentech/Roche, in clinical trials. The investigational drug is being compared to pegylated liposomal doxorubicin for the treatment of patients with platinum-resistant ovarian cancer.
A humanized anti-NaPi2b antibody targeting SLC34A2 (solute carrier family 34 sodium phosphate member 2, sodium/phosphate cotransporter 2B, NaPi2b, NaPi3b, NAPI-3B) is conjugated with monomethyl auristatin E (MMAE) via a cleavable maleimidocaproyl-valyl-citrullinyl-p-aminobenzyloxycarbonyl (mc-val-cit-PABC) type linker on an average of 3-4 cysteinyl.
Auristatins, including monomethyl auristatin E, are water-soluble dolastatin analogs of dolastatin 10. Dolastatin 10 belongs to dolastatin family and binds bind to tubulin, thus inhibiting polymerization mediated through the binding to the vinca alkaloid binding domain. It causes cell to accumulate in metaphase arrest.
Clinical phase I trail results presented during the 2014 annual meeting of the American Society of Clinical Oncology (ASCO) demonstrated a 41% (7/17) response rate in ovarian cancer patients with high expression of NaPi2b and a 10% response rate in NaPi2b+ lung cancer. This led to the initiation of a randomized phase II comparing lifastuzumab vedotin vs. Doxil in ovarian cancer.
Although clinical investigators expected that positive results from this trial could lead to a phase III trial with a high likelihood of success, Genentech discontinued further development of the agent.
Editorial Review: May 10, 2016
