HDP-101, an Anti-BCMA Antibody-Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells.

Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.

A three component mix of thioredoxin-L2 antigens elicits broadly neutralizing responses against oncogenic human papillomaviruses.

Current human papillomavirus (HPV) vaccines based on major capsid protein L1 virus-like particles (VLP) provide potent type-specific protection against vaccine-type viruses (mainly HPV16 and 18), but cross-protect against only a small subset of the approximately 15 oncogenic HPV types. It is estimated that L1-VLP vaccines, which require a fairly complex production system and are still quite costly, fail to cover 20-30% of HPV cervical cancers worldwide, especially in low-resource countries. Alternative antigens relying on the N-terminal region of minor capsid protein L2 are intrinsically less immunogenic but capable of eliciting broadly neutralizing responses. We previously demonstrated the enhanced immunogenicity and cross-neutralization potential of an easily produced recombinant L2 antigen bearing the HPV16 L2(20-38) peptide epitope internally fused to bacterial thioredoxin (Trx). However, antibodies induced by Trx-HPV16 L2(20-38) failed to cross-neutralize notable high-risk HPV types such as HPV31. In the present work, the Trx-L2 design was modified to include L2 sequence information from the highly divergent HPV31 and HPV51 types in addition to HPV16, with the aim of extending cross-neutralization. Multivalent antigens comprising L2(20-38) peptides from all three HPV types on a single Trx scaffold molecule were compared to a mixture of the three type-specific monovalent Trx-L2 antigens. While multivalent antigens as well as the mixed antigens elicited similar anti-HPV16 neutralization titers, cross-reactive responses against HPV31 and HPV51 were of higher magnitude and more robust for the latter formulation. A mixture of monovalent Trx-L2 antigens thus represents a candidate lead for the development of a broadly cross-protective, low-cost second-generation anti-HPV vaccine.