Denintuzumab mafodotin

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.

Antibody-drug conjugates (ADCs) are bifunctional molecules combining the targeting potential of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs. This simple yet intelligently designed system directly addresses the lack of specificity encountered with conventional anti-cancer treatment regimes. However, despite their initial success, the generation of clinically sustainable and effective ADCs has been plagued by poor tumor penetration, undefined chemical linkages, unpredictable pharmacokinetic profiles, and heterogeneous mixtures of products. To this end, we generated a SNAP-tag-based fusion protein targeting the epidermal growth factor receptor (EGFR)-a biomarker of aggressive and drug-resistant cancers. Here, we demonstrate the use of a novel click coupling strategy to engineer a benzylguanine (BG)-linker-auristatin F (AuriF) piece that can be covalently tethered to the EGFR-targeting SNAP-tag-based fusion protein in an irreversible 1:1 stoichiometric reaction to form a homogeneous product. Furthermore, using these recombinant ADCs to target EGFR-overexpressing tumor cells, we provide a proof-of-principle for generating biologically active antimitotic therapeutic proteins capable of inducing cell death in a dose-dependent manner, thus alleviating some of the challenges of early ADC development.