HDP-101: Preclinical evaluation of a novel anti-BCMA antibody drug conjugates in multiple myeloma.

Pahl, Andreas; Ko, Jonathan; Breunig, Christian; Figueroa-Vazquez, Vianihuini; Lehners, Nicola; Baumann, Anja; Pálfí, Anikó; Mueller, Christoph; Lutz, Christian; Hechler, Torsten; Kulke, Michael; Müller-Tidow, Carsten; Goldschmidt, Hartmut; Raab, Marc S.

doi:10.1200/jco.2018.36.15_suppl.e14527

Cited by 14 publications

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“…It appears to be superior to microtubule inhibitors which mainly target proliferating cells [89]. Preclinical study discovered that when administrated at pico-to nanomolar concentrations, HDP-101 exhibited profound cytotoxicity to BCMA + myeloma cell lines and non-proliferating primary MM cells isolated from patients with R/R MM irrespective of BCMA expression level [90,91]. Dose-dependent tumor regression after HDP-101 treatment was also observed in mouse xenograft models with both subcutaneous and systemic MM.…”

Section: Hdp-101mentioning

confidence: 99%

BCMA-targeted immunotherapy for multiple myeloma

2020

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B cell maturation antigen (BCMA) is a novel treatment target for multiple myeloma (MM) due to its highly selective expression in malignant plasma cells (PCs). Multiple BCMA-targeted therapeutics, including antibody-drug conjugates (ADC), chimeric antigen receptor (CAR)-T cells, and bispecific T cell engagers (BiTE), have achieved remarkable clinical response in patients with relapsed and refractory MM. Belantamab mafodotin-blmf (GSK2857916), a BCMA-targeted ADC, has just been approved for highly refractory MM. In this article, we summarized the molecular and physiological properties of BCMA as well as BCMA-targeted immunotherapeutic agents in different stages of clinical development.

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Section: Hdp-101mentioning

confidence: 99%

BCMA-targeted immunotherapy for multiple myeloma

2020

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“…Increasing concentrations of the BCMA-targeted ADC HDP-101 were then added to cells to obtain a dose response curve. HDP-101 was produced as described previously (27,28). 96 hrs post treatment, cell viability was measured using CellTiter-Glo 2.0 reagent (#G9241, Promega) following manufacturer's protocol.…”

Section: Antibody Drug Conjugate Dose Response Assaysmentioning

confidence: 99%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

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Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell-surface expression of the multiple myeloma immunotherapy antigen - B cell maturation antigen, BCMA. We discovered that pharmacological inhibition of HDAC7 and the Sec61 complex increased cell-surface BCMA, including in primary patient cells. Importantly, pharmacological Sec61 inhibition enhanced the anti-myeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference CAR-T coculture screen enabled us to identify both antigen-dependent and -independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study demonstrates the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.Key PointsUsing CRISPR screens, we systematically identify mechanisms increasing expression of the immunotherapy target BCMA and ADC efficacy.We also identify antigen-independent mechanisms regulating response of cancer cells to BCMA-CAR-T cells.

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“…[31,61]. GSK2857916 was administered via 1-h infusions once every 3 weeks, and the ORR in the dose-Antibody-drug conjugates bind to tumor-associated antigens on target cells, which leads to subsequent internalization and release of the toxic payload to induce selective cell death.Other anti-BCMA ADCs in clinical development include HDP-101 (an anti-BCMA antibody conjugated to the RNA polymerase II inhibitor amanitin), which may provide potent antitumor activity in patients with 17p deletions due to reduced RNA polymerase II subunit A expression in these patients, and MEDI2228, an anti-BCMA mAb conjugated to the PBD tesirine via a cleavable linker[39,60,63].…”

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confidence: 99%

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

et al. 2020

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Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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HDP-101: Preclinical evaluation of a novel anti-BCMA antibody drug conjugates in multiple myeloma.

Cited by 14 publications

References 0 publications

BCMA-targeted immunotherapy for multiple myeloma

BCMA-targeted immunotherapy for multiple myeloma

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

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