PF-06263507

This is a case of a 74 yr old man with a history of IgGkappa MM from 2009.He had undergone treatment with Bortezomib-Dexamethasone at diagnosis, which was repeated 6 years afterwards followed by ASCT and Lenalidomide maintenance.Belamaf is a first-in-class humanized IgG1 ADC targeting B-cell maturation antigen (BCMA), covalently linked via a cysteine linker to the microtubule inhibitor monomethyl auristatin F (MMAF), which is released after internalization of the ADC to BCMA on tumor plasma cell, and inhibits its polymerization with the arrest of G2/M caspase dependent apoptosis.The patient received Levofloxacin 12-wk prophylaxis, acyclovir and co-trimoxazole prophylaxis, hydromellose eye drops throughout the treatment period, a coolant eye mask during every Belamaf infusion, and was ophthalmologicaly assessed before each cycle.2 Wk later, patient was urgently re-admitted with consciousness disturbances, weight gain, abdominal pain, defecation incapacity, and significant hyperbilirubinemia (total bilirubin: 6 mg/dL, direct bilirubin: 3 mg/dL, indirect bilirubin: 3 mg/dL).Our patient had never received an Allo-SCT, he had undergone an Autologous SCT many years before the VOD presentation and he had received several lines of treatment without presenting signs of hepatic toxicity.In conclusion, we described a rare case of VOD, histol. proven, in a MM patient on Belamaf-a novel ADC approved for treatment of relapsed or refractory MM.

Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use in several types of cancer, however, resistance often occurs motivating the development of novel drugs. We have recently investigated a drug conjugate consisting of an affibody molecule targeting the human epidermal growth factor receptor 2 (HER2), fused to an albumin-binding domain (ABD) for half-life extension, loaded with the cytotoxic maytansine derivative DM1. In this study, we investigated the impact of the cytotoxic payload on binding properties, cytotoxicity and biodistribution by comparing DM1 with the auristatins MMAE and MMAF, as part of the drug conjugate. All constructs had specific and high affinity binding to HER2, human and mouse albumins with values in the low- to sub-nM range. Z_HER2-ABD-mcMMAF demonstrated the most potent cytotoxic effect on several HER2-over-expressing cell lines. In an experimental therapy study, the MMAF-based conjugate provided complete tumor regression in 50% of BALB/c nu/nu mice bearing HER2-over-expressing SKOV3 tumors at a 2.9 mg/kg dose, while the same dose of Z_HER2-ABD-mcDM1 provided only a moderate anti-tumor effect. A comparison with the non-targeting Z_Taq-ABD-mcMMAF control demonstrated HER2-targeting specificity. In conclusion, a combination of potent cytotoxicity in vitro, with minimal uptake in normal organs in vivo, and efficient delivery to tumors provided a superior anti-tumor effect of Z_HER2-ABD-mcMMAF, while maintaining a favorable toxicity profile with no observed adverse effects.