Abstract 77: Preclinical evaluation of HDP-101, an anti-BCMA antibody-drug conjugate

Hechler, Torsten; Pálfí, Anikó; Müller, Christoph; Lutz, Christian; Pahl, Andreas; Kulke, Michael

doi:10.1158/1538-7445.am2017-77

Cited by 6 publications

(6 citation statements)

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“…Mild-to-moderate elevation of liver enzymes and lactic dehydrogenase were noted, but these abnormalities were transient. HDP-101 has a long half-life in serum (about 12 days) ( 81 , 82 ).…”

Section: Antibody–drug Conjugatesmentioning

confidence: 99%

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

2018

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The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody–drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.

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“…Mild-to-moderate elevation of liver enzymes and lactic dehydrogenase were noted, but these abnormalities were transient. HDP-101 has a long half-life in serum (about 12 days) ( 81 , 82 ).…”

Section: Antibody–drug Conjugatesmentioning

confidence: 99%

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

2018

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“…118 No other anti-BCMA ADCs are currently in clinical testing for hematologic malignancies; however, a preclinical ADC targeted to enter the clinic in late 2018 has been reported. 119 HDP-101 is an anti-BCMA mAb site-specifically conjugated to a derivative of amanitin, the toxic component of death cap mushrooms, through a noncleavable linker. It has been reported to induce complete remission after a single injection in xenograft models of MM, and the compound was well tolerated in cynomolgus monkeys.…”

Section: Anti-cd269 (B-cell Maturation Agent) Adcsmentioning

confidence: 99%

Investigational Antibody–Drug Conjugates for Treatment of B-lineage Malignancies

Herrera

Molina

2018

Clinical Lymphoma Myeloma and Leukemia

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Antibody-drug conjugates (ADCs) are tripartite molecules consisting of a monoclonal antibody, a covalent linker, and a cytotoxic payload. ADC development has aimed to target the specificity inherent in antigen-antibody interactions to deliver potent cytotoxins preferentially to tumor cells and maximize antitumor activity and simultaneously minimize off-target toxicity. The earliest ADCs provided disappointing results in the clinic; however, the lessons learned regarding the need for human or humanized antibodies, more stable linkers, and greater potency payloads led to improved ADCs. Three ADCs, gemtuzumab ozogamicin, brentuximab vedotin (BV), and inotuzumab ozogamicin, have been approved for hematologic malignancies. Site-specific conjugation methods have now resulted in a new generation of more uniform, molecularly defined ADCs. These are expected to display improved in vivo properties and have recently entered the clinic. We reviewed investigational ADCs currently in clinical testing for the treatment of B-cell lineage malignancies, including leukemias, lymphomas, and multiple myeloma. The rationales for antigen targeting, data reported to date, current trial status, and preclinical results for several newer ADCs expected to enter first-in-human studies are presented. Owing to the large number of ongoing and reported BV clinical studies, only the studies of BV for diffuse large B-cell lymphoma and those combining BV with checkpoint inhibitors in B-lineage malignancies have been reviewed. With > 40 ongoing clinical trials and 7 investigational ADCs already having advanced to phase II studies, the role of ADCs in the armamentarium for the treatment of B-lineage malignancies continues to be elucidated.

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“…BCMA has emerged as a very selective target of choice for the treatment of multiple myeloma [95]. In vitro, HDP-101 was tested on various multiple myeloma cells taken from patients, including non-dividing cells or cells with a low concentration of BCMA antigens (down to 270 copies per cell) [96]. In all cases, the observed IC 50 of the ATAC HDP-101 was in the picomolar range.…”

Section: New Cytotoxic Agentsmentioning

confidence: 99%

Antibody–Drug Conjugates: The Last Decade

et al. 2020

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An armed antibody (antibody–drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of.

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Abstract 77: Preclinical evaluation of HDP-101, an anti-BCMA antibody-drug conjugate

Cited by 6 publications

References 0 publications

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

Investigational Antibody–Drug Conjugates for Treatment of B-lineage Malignancies

Antibody–Drug Conjugates: The Last Decade

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