Dawn of a new era of antibody-drug conjugates and bispecific T-cell engagers for treatment of multiple myeloma: a systematic review of literature

Khattak, Zoia Ehsan; Hashmi, Hamza; Khan, Sana Irfan; Aamir, Sobia; Arif, Uroosa; Khan, Atif Irfan; Darwin, Alicia; Singh, Arun D.; Khouri, Jack; Anwer, Faiz

doi:10.1007/s00277-021-04599-5

Cited by 6 publications

(5 citation statements)

References 38 publications

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“…Their specificity is determined by the antibody, while the antitumor effect is associated with the presence of a cytotoxic drug acting on cytoskeleton components or inhibiting enzymes involved in DNA metabolism [35][36][37][38]. Also, other ADCs are composed of an antibody linked to an immune-stimulating cytokine and, for this reason, can show an antitumor effect by triggering killer effector lymphocytes together with tumor-homing [39][40][41][42][43]. In this context, the maytansinoid DM1 microtubular inhibitors have been linked to antibodies against fibronectin domains expressed preferentially in tumors together with IL2 pro-inflammatory cytokine [38].…”

Section: Discussionmentioning

confidence: 99%

Antibody–Drug Conjugate Made of Zoledronic Acid and the Anti-CD30 Brentuximab–Vedotin Exert Anti-Lymphoma and Immunostimulating Effects

Morelli,

Matis,

Benelli

et al. 2024

Cells

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Relevant advances have been made in the management of relapsed/refractory (r/r) Hodgkin Lymphomas (HL) with the use of the anti-CD30 antibody–drug conjugate (ADC) brentuximab–vedotin (Bre–Ved). Unfortunately, most patients eventually progress despite the excellent response rates and tolerability. In this report, we describe an ADC composed of the aminobisphosphonate zoledronic acid (ZA) conjugated to Bre–Ved by binding the free amino groups of this antibody with the phosphoric group of ZA. Liquid chromatography–mass spectrometry, inductively coupled plasma–mass spectrometry, and matrix-assisted laser desorption ionization–mass spectrometry analyses confirmed the covalent linkage between the antibody and ZA. The novel ADC has been tested for its reactivity with the HL/CD30+ lymphoblastoid cell lines (KMH2, L428, L540, HS445, and RPMI6666), showing a better titration than native Bre–Ved. Once the HL-cells are entered, the ADC co-localizes with the lysosomal LAMP1 in the intracellular vesicles. Also, this ADC exerted a stronger anti-proliferative and pro-apoptotic (about one log fold) effect on HL-cell proliferation compared to the native antibody Bre–Ved. Eventually, Bre–Ved–ZA ADC, in contrast with the native antibody, can trigger the proliferation and activation of cytolytic activity of effector-memory Vδ2 T-lymphocytes against HL-cell lines. These findings may support the potential use of this ADC in the management of r/r HL.

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Section: Discussionmentioning

confidence: 99%

Antibody–Drug Conjugate Made of Zoledronic Acid and the Anti-CD30 Brentuximab–Vedotin Exert Anti-Lymphoma and Immunostimulating Effects

Morelli,

Matis,

Benelli

et al. 2024

Cells

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“…[38][39][40] Peculiar ADC are the immunocytokine-drug conjugates (IDC), which combine a tumor-homing antibody, a cytotoxic drug and a cytokine in the same molecular entity. 41 As an example, a trifunctional ADC carrying IL-12, capable of inducing activation and proliferation of T and natural killer lymphocytes, has been reported. 42 In any case, none of these ADC or IDC is aimed to select an effector cell population and drive it directly to the tumor.…”

Section: Discussionmentioning

confidence: 99%

Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab

Benelli

Costa

Salvini

et al. 2022

J Immunother Cancer

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BackgroundAntibody-drug conjugates (ADC) are essential therapeutic options to treat solid and hematological cancers. The anti-epidermal growth factor-receptor (EGFR) antibody cetuximab (Cet) is used for the therapy of colorectal carcinoma (CRC). Anti-CRC Vδ2 cytolytic T lymphocytes can be elicited by the priming of tumor cells with the aminobisphosphonate zoledronic acid (ZA) and consequent presentation of isopentenyl pyrophosphates through butyrophilin (BTN) family members such as BTN3A1 and BTN2A1. A major drawback that impairs the targeting of ZA to CRC is the bone tropism of aminobisphosphonates.MethodsThe phosphoric group of ZA was linked to free amino groups of Cet in the presence of imidazole following the labeling of phosphoric groups of DNA to amino groups of proteins. The generation of Cet-ZA ADC was confirmed by matrix assisted laser desorption ionization mass spectrometry and inductively coupled plasma-mass spectrometry analysis. Thirteen CRC organoids were obtained with a chemically defined serum-free medium in Geltrex domes. Proliferation and activation of cytolytic activity against CRC organoids by Vδ2 T cells was detected with flow cytometry, crystal violet and cytotoxic probe assays and image analysis. Immunohistochemistry and quantification of BTN3A1 or BTN2A1 expression and the number of tumor infiltrating Vδ2 T cells in CRC were performed by automatic immunostaining, whole slide scanning and computerized analysis of digital pathology imaging.ResultsThe novel ADC Cet-ZA was generated with a drug antibody ratio of 4.3 and displayed a reactivity similar to the unconjugated antibody. More importantly, patient-derived CRC organoids, or CRC tumor cell suspensions, could trigger the expansion of Vδ2 T cells from peripheral blood and tumor infiltrating lymphocytes when primed with Cet-ZA. Furthermore, Cet-ZA triggered Vδ2 T cell-mediated killing of CRC organoids. The expression of BTN3A1 and BTN2A1 was detected not only in CRC organoids but also in CRC specimens, together with a considerable amount of tumor infiltrating Vδ2 T cells.ConclusionsThese findings are proof of concept that the Cet-ZA ADC can be used to target specifically CRC organoids and may suggest a new experimental approach to deliver aminobisphosphonates to EGFR+solid tumors.

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“…Multiple myeloma is the second most common hematological malignancy in adults, and has seen significant improvement in outcomes recently due to a steady widening of therapeutic armamentarium, including the recent approval of B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy. 8,9 The current estimated incidence of therapy-related myeloid neoplasms (t-MDS, t-AML, and t-CMML) has been estimated to range between 0.9 and 8.5% across studies. 10,11 treatment, suggesting the role of intrinsic disease biology in the development of these neoplasms.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic hematopoietic stem cell transplantation in patients with therapy‐related hematologic malignancies developing after multiple myeloma

Nampoothiri

Pašić

Law

et al. 2022

European J of Haematology

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Introduction Increasing survival of patients with multiple myeloma (MM) has resulted in an increased recognition of therapy‐related hematological malignancies (t‐MDS/AML, t‐ALL, and t‐CMML). There are limited data on the role of allogeneic hematopoietic stem cell transplantation (HCT) in this patient population. Patients and Methods We retrospectively reviewed patients who underwent HCT for t‐MDS/AML, t‐ALL, and t‐CMML developing after receiving treatment for MM at our center. Patients were analyzed for myeloma characteristics and therapy, time to diagnosis of therapy‐related hematological neoplasms, clinical, laboratory characteristics, transplant details, relapse‐free survival (RFS), and overall survival (OS). Results Twenty patients underwent HCT for therapy‐related hematological malignancies after MM (t‐MDS/AML = 13, t‐ALL = 6, t‐CMML = 1). Median(range) age at time of transplant was 62.5 (49–73) years and 70% (n = 14) were male. The most common cytogenetic abnormality was complex/monosomal karyotype in 30% (n = 6) followed by monosomy/deletion of chromosome 5 or 7 in 15% (n = 3) of patients each. Donors were human leukocyte antigen matched (10/10 or 6/6) siblings in 30% (n = 6), unrelated in 60% (n = 12) and haploidentical in 10% (n = 2) patients. Estimated 2‐year OS and RFS for the whole cohort were 53.1% and 47.2% respectively. There was a trend toward better survival in patients with t‐ALL when compared to t‐MDS/AML; however, the difference was not statistically significant. We did not find any pre‐transplant or post‐transplant factors that were predictive of survival outcomes after multivariate analysis. Conclusions Allogeneic HCT provides substantial long‐term disease‐free survival in a proportion of patients with MM‐associated therapy‐related hematological malignancies. Multicenter studies with more patients and longer follow‐up may provide additional information about factors affecting outcomes.

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Dawn of a new era of antibody-drug conjugates and bispecific T-cell engagers for treatment of multiple myeloma: a systematic review of literature

Cited by 6 publications

References 38 publications

Antibody–Drug Conjugate Made of Zoledronic Acid and the Anti-CD30 Brentuximab–Vedotin Exert Anti-Lymphoma and Immunostimulating Effects

Antibody–Drug Conjugate Made of Zoledronic Acid and the Anti-CD30 Brentuximab–Vedotin Exert Anti-Lymphoma and Immunostimulating Effects

Targeting of colorectal cancer organoids with zoledronic acid conjugated to the anti-EGFR antibody cetuximab

Allogeneic hematopoietic stem cell transplantation in patients with therapy‐related hematologic malignancies developing after multiple myeloma

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