Monoclonal Antibodies: The Greatest Resource to Treat Multiple Myeloma

Luca, Fabiola De; Allegra, Alessandro; Chio, Carla Di; Previti, Santo; Zappalà, Maria; Ettari, Roberta

doi:10.3390/ijms24043136

Cited by 10 publications

(6 citation statements)

References 81 publications

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“…CD38 is a prime target in MM, with two anti-CD38 mAbs (Daratumumab and Isatuximab) currently approved for use in the United States. These immunotherapeutic agents have transformed the treatment of MM, with a diverse mechanism of action composed of antibody-dependent, cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity [53][54][55][56]. While CD38 has exhibited susceptibility to immunoediting as a consequence of selective pressure imposed by immunotherapeutic agents [57], we have deliberately chosen to target it.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells

Edri,

Ben-Haim,

Hailu

et al. 2023

IJMS

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Natural killer (NK) cells are a vital component of cancer immune surveillance. They provide a rapid and potent immune response, including direct cytotoxicity and mobilization of the immune system, without the need for antigen processing and presentation. NK cells may also be better tolerated than T cell therapy approaches and are susceptible to various gene manipulations. Therefore, NK cells have become the focus of extensive translational research. Gamida Cell’s nicotinamide (NAM) platform for cultured NK cells provides an opportunity to enhance the therapeutic potential of NK cells. CD38 is an ectoenzyme ubiquitously expressed on the surface of various hematologic cells, including multiple myeloma (MM). It has been selected as a lead target for numerous monoclonal therapeutic antibodies against MM. Monoclonal antibodies target CD38, resulting in the lysis of MM plasma cells through various antibody-mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, significantly improving the outcomes of patients with relapsed or refractory MM. However, this therapeutic strategy has inherent limitations, such as the anti-CD38-induced depletion of CD38-expressing NK cells, thus hindering ADCC. We have developed genetically engineered NK cells tailored to treat MM, in which CD38 was knocked-out using CRISPR-Cas9 technology and an enhanced chimeric antigen receptor (CAR) targeting CD38 was introduced using mRNA electroporation. This combined genetic approach allows for an improved cytotoxic activity directed against CD38-expressing MM cells without self-inflicted NK-cell-mediated fratricide. Preliminary results show near-complete abolition of fratricide with a 24-fold reduction in self-lysis from 19% in mock-transfected and untreated NK cells to 0.8% of self-lysis in CD38 knock-out CAR NK cells. Furthermore, we have observed significant enhancements in CD38-mediated activity in vitro, resulting in increased lysis of MM target cell lines. CD38 knock-out CAR NK cells also demonstrated significantly higher levels of NK activation markers in co-cultures with both untreated and αCD38-treated MM cell lines. These NAM-cultured NK cells with the combined genetic approach of CD38 knockout and addition of CD38 CAR represent a promising immunotherapeutic tool to target MM.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells

Edri,

Ben-Haim,

Hailu

et al. 2023

IJMS

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“…LT1100; Fenton, MO). [N- (3,11,14,22,25,10,15,21,26,32-hexaaza-10,21,32-trihydroxytetratriacontane)]-maleimide (deferoxamine-maleimide) was sourced from Macrocyclics (Dallas, TX). Finally, phorbol 12-myristate 13acetate and Tris(2-carboxyethyl) phosphine hydrochloride (TCEP) were sourced from Sigma-Aldrich (St. Louis, MO).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…In MM, the ability of bortezomib (BTZ) to overcome CAM-DR was in part due to VLA4 downregulation. 9 A more practical approach to disable VLA4 in hematopoietic malignancies is to induce target-specific immune responses with antibody (Ab) therapeutics, 10 which offer added strengths of low toxicity and off-the-shelf availability. The application of Ab therapeutics against VLA-4 for leukemia and MM is highly plausible due to its participation in chemotherapy resistance.…”

Section: ■ Introductionmentioning

confidence: 99%

Imaging Very Late Antigen-4 on MOLT4 Leukemia Tumors with Cysteine Site-Specific ⁸⁹Zr-Labeled Natalizumab Immuno-Positron Emission Tomography

Kim,

Jung,

Kim

et al. 2024

Mol. Pharmaceutics

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Very late antigen-4 (VLA4; CD49d) is a promising immune therapy target in treatment-resistant leukemia and multiple myeloma, and there is growing interest in repurposing the humanized monoclonal antibody (Ab), natalizumab, for this purpose. Positron emission tomography with radiolabeled Abs (immuno-PET) could facilitate this effort by providing information on natalizumab's in vivo pharmacokinetic and target delivery properties. In this study, we labeled natalizumab with 89 Zr specifically on sulfhydryl moieties via maleimide−deferoxamine conjugation. High VLA4-expressing MOLT4 human T cell acute lymphoblastic leukemia cells showed specific 89 Zr−natalizumab binding that was markedly blocked by excess Ab. In nude mice bearing MOLT4 tumors, 89 Zr−natalizumab PET showed high-contrast tumor uptake at 7 days postinjection. Biodistribution studies confirmed that uptake was the highest in MOLT4 tumors (2.22 ± 0.41%ID/g) and the liver (2.33 ± 0.76%ID/g), followed by the spleen (1.51 ± 0.42%ID/g), while blood activity was lower at 1.12 ± 0.21%ID/g. VLA4-specific targeting in vivo was confirmed by a 58.1% suppression of tumor uptake (0.93 ± 0.15%ID/g) when excess Ab was injected 1 h earlier. In cultured MOLT4 cells, short-term 3 day exposure to the proteasome inhibitor bortezomib (BTZ) did not affect the α4 integrin level, but BTZ-resistant cells that survived the treatment showed increased α4 integrin expression. When the effects of BTZ treatment were tested in mice, there was no change of the α4 integrin level or 89 Zr−natalizumab uptake in MOLT4 leukemia tumors, which underscores the complexity of tumor VLA4 regulation in vivo. In conclusion, 89 Zr−natalizumab PET may be useful for noninvasive monitoring of tumor VLA4 and may assist in a more rational application of Ab-based therapies for hematologic malignancies.

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“…In vitro models showed that sBCMA reduces the cytotoxic effects of BCMA-directed CARs in a dose-dependent manner; notably, no cell lysis occurred at sBCMA levels of 2343 ng/mL [27]. Given the importance of BCMA in MM physiology and its almost unique expression on malignant PCs, numerous therapies have been introduced targeting this specific molecule, including conjugate antibodies (Belantamab mafodotin) and bispecific antibodies (Teclistamab and Elranatamab) [28].…”

Section: Bcma-targeting Car-tmentioning

confidence: 99%

CAR-T Therapy in Multiple Myeloma: Looking Beyond

Maiorana,

Antolino,

La Verde

et al. 2024

Hemato

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Multiple Myeloma is a hematological neoplasm that, over the recent few years, has benefited from numerous therapeutic options. Among the latter, CAR-T stands out as the most recent and one of the most promising treatments currently available. Despite its recent introduction, multiple CAR-T products have already been approved, and research regarding cellular therapy is rapidly increasing. We conducted a comprehensive search and review of the available literature, including published studies and abstracts from recent meetings (ASH, ASCO, ASTCT, IMS), regarding Multiple Myeloma and CAR-T therapy. We describe the discovery and research regarding promising targets like the B-Cell Maturation Antigen (BCMA) and others, the origin and nature of CAR-T cells, and the recent introduction of anti-BCMA CAR-Ts Idecabtagene-vicleucel and Ciltacabtagene-autoleucel, which are currently the only approved CAR-T products for MM. Additionally, we discuss non-BCMA-targeting CAR-Ts and their clinical implications. Given the significant impact of cellular therapy, we provide an overview of its limitations and possible adverse implications, as well as related resistance mechanisms. Finally, we describe the current research aimed at improving CAR-T therapy in MM, including structural innovations and new therapeutic approaches, such as in the earlier lines of treatment and maintenance therapy.

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Monoclonal Antibodies: The Greatest Resource to Treat Multiple Myeloma

Cited by 10 publications

References 81 publications

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells

Imaging Very Late Antigen-4 on MOLT4 Leukemia Tumors with Cysteine Site-Specific ⁸⁹Zr-Labeled Natalizumab Immuno-Positron Emission Tomography

CAR-T Therapy in Multiple Myeloma: Looking Beyond

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Monoclonal Antibodies: The Greatest Resource to Treat Multiple Myeloma

Cited by 10 publications

References 81 publications

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells

Imaging Very Late Antigen-4 on MOLT4 Leukemia Tumors with Cysteine Site-Specific 89Zr-Labeled Natalizumab Immuno-Positron Emission Tomography

CAR-T Therapy in Multiple Myeloma: Looking Beyond

Contact Info

Product

Resources

About

Imaging Very Late Antigen-4 on MOLT4 Leukemia Tumors with Cysteine Site-Specific ⁸⁹Zr-Labeled Natalizumab Immuno-Positron Emission Tomography