Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Radocha, Jakub; Donk, Niels W.C.J. van de; Weisel, Katja

doi:10.3390/cancers13071571

Cited by 22 publications

(20 citation statements)

References 132 publications

(134 reference statements)

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“… 25 , 53 Monoclonal anti-CD38 antibody daratumumab works through promoting antimyeloma immune responses by various mechanism involving lymphocytes. 54 Thus, by stimulating lymphocyte infiltration into the tumor, as observed in this study, melflufen may build an effective combination with daratumumab. Indeed, RRMM patients recruited to the daratumumab/melflufen/dexamethasone arm of the ANCHOR study have shown ORR of 76% and clinical benefit rate of 79%, with 2 patients (6%) having achieved complete response.…”

Section: Discussionsupporting

confidence: 52%

Novel Peptide-drug Conjugate Melflufen Efficiently Eradicates Bortezomib-resistant Multiple Myeloma Cells Including Tumor-initiating Myeloma Progenitor Cells

et al. 2021

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Introduction of the proteasome inhibitor bortezomib has dramatically improved clinical outcomes in multiple myeloma. However, most patients become refractory to bortezomib-based therapies. On the molecular level, development of resistance to bortezomib in myeloma cells is accompanied by complex metabolic changes resulting in increased protein folding capacity, and less dependency on the proteasome. In this study, we show that aminopeptidase B, encoded by the RNPEP gene, is upregulated in bortezomib-resistant myeloma cell lines, and in a murine in vivo model. Moreover, increased RNPEP expression is associated with shorter survival in multiple myeloma patients previously treated with bortezomib-containing regimens. Additionally, expression is increased in plasma cell precursors, a B-lymphoid compartment previously associated with myeloma stem cells. We hypothesized that increased aminopeptidase B expression in aggressive myeloma clones may be used therapeutically toward elimination of the cells via the use of a novel peptide-drug conjugate, melphalan flufenamide (melflufen). Melflufen, a substrate of aminopeptidase B, efficiently eliminates bortezomib-resistant myeloma cells in vitro and in vivo, and completely suppresses clonogenic myeloma growth in vitro at subphysiological concentrations. Thus, melflufen represents a novel treatment option that is able to eradicate drug-resistant myeloma clones characterized by elevated aminopeptidase B expression.

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Section: Discussionsupporting

confidence: 52%

Novel Peptide-drug Conjugate Melflufen Efficiently Eradicates Bortezomib-resistant Multiple Myeloma Cells Including Tumor-initiating Myeloma Progenitor Cells

et al. 2021

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“…A graft vs. myeloma effect has been shown by the differences in post-allogeneic stem cell transplant relapse rates based on the inherited repertoire of KIR genes expressed by donor NK cells, indicating a role for NK cell-mediated suppression of relapse [22,24]. Lastly, NK cells mediate ADCC against myeloma cells in vitro and in vivo, thus enhancing the anti-MM activity of current therapies, which includes mAbs such as the anti-CD38 daratumumab and isatuximab [45] and the anti-SLAMF7 elotuzumab (Figure 2) [70,71].…”

Section: Nkmentioning

confidence: 99%

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Botta

Mendicino

Martino

et al. 2021

Cancers

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Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.

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“…The CD38-targeting antibodies generally represent a safe treatment. Indeed, the most reported toxicity is infusion related reactions which remain successfully controlled by premedication and infusion rate management with low frequency of recurrence during subsequent injections ( 62 ). A higher rate of viral infections in patients treated with daratumumab has been reported in some studies leading to a recommended administration of valaciclovir during the administration of anti-CD38 antibodies ( 62 ).…”

Section: Cd38-targeting Strategiesmentioning

confidence: 99%

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

2021

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The presence of anti-human leucocyte antigen (HLA) antibodies in the potential solid organ transplant recipient’s blood is one of the main barriers to access to a transplantation. The HLA sensitization is associated with longer waitlist time, antibody mediated rejection and transplant lost leading to increased recipient’s morbidity and mortality. However, solid organ transplantation across the HLA immunological barriers have been reported in recipients who were highly sensitized to HLA using desensitization protocols. These desensitization regimens are focused on the reduction of circulating HLA antibodies. Despite those strategies improve rates of transplantation, it remains several limitations including persistent high rejection rate and worse long-term outcomes when compare with non-sensitized recipient population. Currently, interest is growing in the development of new desensitization approaches which, beyond targeting antibodies, would be based on the modulation of alloimmune pathways. Plasma cells appears as an interesting target given their critical role in antibody production. In the last decade, CD38-targeting immunotherapies, such as daratumumab, have been recognized as a key component in the treatment of myeloma by inducing an important plasma cell depletion. This review focuses on an emerging concept based on targeting CD38 to desensitize in the field of transplantation.

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Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

Cited by 22 publications

References 132 publications

Novel Peptide-drug Conjugate Melflufen Efficiently Eradicates Bortezomib-resistant Multiple Myeloma Cells Including Tumor-initiating Myeloma Progenitor Cells

Novel Peptide-drug Conjugate Melflufen Efficiently Eradicates Bortezomib-resistant Multiple Myeloma Cells Including Tumor-initiating Myeloma Progenitor Cells

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

HLA Desensitization in Solid Organ Transplantation: Anti-CD38 to Across the Immunological Barriers

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