Preclinical Evaluation of Hdp-101, a Novel Anti-BCMA Antibody-Drug Conjugate, in Multiple Myeloma

Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of hematologic malignancies. Surprisingly, most ADCs are based on only few toxic compounds, largely limited to microtubuli- or DNA-targeting toxins (auristatins and maytansines or duocarmycins and pyrrolobenzodiazepines, PBDs). These payloads are mainly targeting proliferating cells potentially leading to limited efficacy in diseases with a low proliferation rates such as indolent lymphomas or multiple myeloma. Thus, new compounds with alternative toxicity mechanisms could enhance the therapeutic potential of ADCs. We therefore focus on amanitin based ADCs, so called ATACs (antibody-targeted Amanitin conjugates) comprising a new class of antibody-drug conjugates with amanitin as toxic payload. Amanitin is the most well-known toxin of the amatoxin family and binds to the eukaryotic RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell.

In the current study, we have assessed in vitro and in vivo specificity andefficacy of HDP-101, an ATAC targeting BCMA (B cell maturation antigen). BCMA (also known as CD269) is expressed on cells of the B cell lineage, predominantly on plasma blasts and plasma cells. It is not expressed on naïve, germinal center, and memory B cells. BCMA is highly expressed on malignant plasma cells and therefore considered an ideal target in multiple myeloma.

In vitro cytotoxic potency of HDP-101 was tested on several BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from triple and quadruple refractory myeloma patients. Profound cytotoxic effects were seen at pico- to nanomolar concentrations of HDP-101 even in myeloma cells with low epitope density. Importantly, toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In mouse xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single i.v. dose of 2.0 mg/kg and 4.0 mg/kg in subcutaneous xenografts and after single i.v. doses from 0.1 mg/kg to 2.0 mg/kg in disseminating xenografts.

Safety profiling in Cynomolgus monkeys revealed a good tolerability and therapeutic index after sequentially applied doses of 0.3 mg/kg, 1.0 mg/kg, and multiple dose applications of 4 x 3.0 mg/kg. Hematology and clinical chemistry parameters were unaffected except for a mild to moderate and transient increase of liver enzymes and lactate dehydrogenase. The half-life of the HDP-101 in serum was ~12 days; the free toxin was detectable at levels close to the lower limit of quantification only.

In conclusion, targeted cytotoxic drug delivery to BCMA positive myeloma cell lines was achieved by using HDP-101, an anti-BCMA-ATAC. The mode of action of the payload amanitin led to an efficient anti-tumor response in vitro and in vivo with good tolerability in non-human primate studies yielding a very favorable therapeutic index. Amanitin-based ADCs in the therapy of multiple myeloma is a novel promising approach with a distinct mode of action to overcome drug resistance and improve patient outcome. A First-in-human trial with HDP-101 is expected to start in 2018.