Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of hematologic malignancies. Most of these ADCs are based on only a few toxic compounds, largely limited to microtubule- or DNA-targeting toxins that mainly impact proliferating cells and have limited efficacy in diseases with a low proliferative fraction such as indolent lymphomas or multiple myeloma. Thus, new compounds with alternative toxicity mechanisms and the ability to actively induce cell death in non-proliferating tumor cells could enhance the therapeutic potential of ADCs. We are currently developing amanitin based ADCs. Amanitin specifically inhibits RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell. Subsequently tumor cells enter apoptosis and are eliminated.
Del(17p) is a frequent deletion in tumor cells, identifying high-risk patients with poor prognosis. TP53, a well-known tumor suppressor gene, is located on the short arm of chromosome 17. The major subunit of the RNA Polymerase II POLR2A is frequently co-deleted with TP53 in del(17p) human cancers, which renders these tumors more vulnerable to amanitin-ADC treatment compared to wild-type tumor and healthy cells.
HDP-101 is a new ADC targeting BCMA (B cell maturation antigen) carrying a synthetic version of amanitin as a payload. In vitro cytotoxic potency of HDP-101 was demonstrated on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from patients with refractory myeloma. Furthermore, the cytotoxic effects of HDP-101 were seen even in non-proliferating myeloma cells with low BCMA density. Toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In murine xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single dose in subcutaneous and as well as in disseminated models. Safety profiling in Cynomolgus monkeys revealed a good therapeutic index after repeated dosing. On safe doses, hematology and clinical chemistry parameters were mainly unaffected except for a mild to moderate and transient increase of liver enzymes and lactate dehydrogenase predominantly after the first dose. Free payload was detectable at levels close to the lower limit of quantification only.
GLP toxicity studies of the released payload in rodents revealed a NOAEL, which is well above concentrations observed in non-human primate studies after ADC administration as well as above the toxin doses administered by the ADC. This may be attributed to the hydrophilicity of the toxin, which cannot passively enter any antigen-negative cell and is rapidly cleared without further drug metabolism.
Our non-clinical studies concluded that this amanitin-based ADC is a novel promising approach in the therapy of multiple myeloma to overcome drug resistance and improve patient outcome. Patients whose myeloma cells harbor 17p deletion may have a specific therapeutic sensitivity towards HDP-101.
HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial in setup phase with HDP-101 in patients with multiple myeloma whose disease has progressed. The aim of the Phase 1 dose escalation part is to determine the Maximum Tolerated Dose and/or establish the Recommended phase 2 Dose. The primary objective of the phase 2 dose expansion phase is to assess the preliminary anti-tumor activity of HDP-101. Patients in phase 2a will be stratified based on del(17p) status. An adaptive Bayesian logistic regression model with overdose control principle will be used to guide the dose escalation steps. The design of the study ensures a safe dose escalation to reach a potential clinical benefit in a patient who have limited or no therapeutic options. The study is expected to enroll patients in early 2021.
Strassz:Heidelberg Pharma: Current Employment. Raab:Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Orlowski:STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kulke:Heidelberg Pharma: Current Employment, Current equity holder in publicly-traded company. Schiedner:Heidelberg Pharma: Current Employment. Pahl:Heidelberg Pharma: Current Employment, Current equity holder in publicly-traded company.
Author notes
Asterisk with author names denotes non-ASH members.
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