A T-cell–redirecting bispecific G-protein–coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma

Pillarisetti, Kodandaram; Edavettal, Suzanne C.; Mendonca, Mark; Li, Yingzhe; Tornetta, Mark A.; Babich, Alexander; Majewski, Nate; Husovsky, Matt; Reeves, Dara; Walsh, Eileen S.; Chin, Diana; Luistro, Leopoldo; Joseph, Jocelin; Chu, Gerald C.; Packman, Kathryn; Shetty, Shoba; Elsayed, Yusri; Attar, Ricardo M.; Gaudet, François

doi:10.1182/blood.2019003342

Cited by 94 publications

(48 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…JNJ-64407564 is an anti-GPRC5D × anti-CD3 BsAb with an IgG1 Fc region (198,199). A preclinical study tested JNJ-64407564 in a co-culture of MM cell lines and healthy human T cells (E:T, 5:1), a co-culture of healthy human whole blood and MM cell lines, and a co-culture of BMMCs from MM patients and exogenous healthy human T cells (200). JNJ-64407564 induced MM cell directed cytotoxicity in all co-cultures and dose-dependent T cell proliferation in the MM cell line and healthy human T cell co-culture.…”

Section: Clinical Trials Of Gprc5d-targeting Bsabs Jnj-64407564mentioning

confidence: 99%

“…JNJ-64407564 was then tested in two NSG mice models with human MM xenografts and human PBMCs; the drug led to significant anti-tumor activity and 100% complete responses in both groups. Testing of the drug in cynomolgus monkeys showed no adverse effects (200). A phase 1 doseescalation and expansion trial (NCT03399799) in patients with R/R MM began in 2017, with JNJ-64407564 administered by intravenous or subcutaneous injection.…”

Section: Clinical Trials Of Gprc5d-targeting Bsabs Jnj-64407564mentioning

confidence: 99%

See 1 more Smart Citation

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

et al. 2020

View full text Add to dashboard Cite

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ∼30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter-and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. Highrisk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.

show abstract

Section: Clinical Trials Of Gprc5d-targeting Bsabs Jnj-64407564mentioning

confidence: 99%

Section: Clinical Trials Of Gprc5d-targeting Bsabs Jnj-64407564mentioning

confidence: 99%

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Moreover, bispecifics based on myeloma surface antigens other than BCMA have been developed as alternative CD3 epitope binding partners. In addition to the aforementioned talquetamab (NCT03399799) [77], these include the CD3xCD38 construct found in GBR 1342 (NCT03309111) [78] and the CD3xFcRH5 design incorporated into BFCR4350A (NCT03275103) [79].…”

Section: T-cell-engaging Bispecific Antibodiesmentioning

confidence: 99%

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

Abramson¹

2021

Monoclonal Antibodies

View full text Add to dashboard Cite

Therapeutic measures designed to treat multiple myeloma (MM) have undergone a fundamental shift over the past two decades as a number of small molecules that attack this cancer by different mechanisms, including proteasome blockade, immunomodulation, and histone deacetylase (HDAC) inhibition, have been introduced. The insertion of monoclonal antibodies (mAbs) into the mix began in 2015 with the U.S. Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, which target CD38 and SLAMF7, respectively. In 2020, they were joined by another anti-CD38 mAb, isatuximab, and the bispecific antibody-drug conjugate (ADC) belantamab mafodotin, which targets the B-cell maturation antigen (BCMA). This review focuses on additional mAbs currently under clinical study for MM. These include several BCMAxCD3-directed bispecifics (AMG 420, AMG 701, REGN5458, REGN5459, teclistamab, and TNB-383B), the ADCs indatuximab ravtansine and STRO-001, and checkpoint inhibitors, although the future status of the latter is in a state of flux due to toxicity issues that arose in trials in which these drugs, especially PD-1 or PD-L1 blockers, were combined with immunomodulators.

show abstract

“…GPRC5D is a novel surface receptor on myeloma cells, whose overexpression is associated with a poor prognosis of patients [ 43 ]. In in vitro and in murine models, the GPRC5D/CD3 DuoBody JNJ-64407564 can induce the T-cell mediated killing of GPRC5D positive plasma cells [ 44 ]. These findings provide a proof of concept for targeting GPRC5D with bsAb in MM.…”

Section: Rationale and Potential Targets Of Bsabs In MMmentioning

confidence: 99%

Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma

Zhou

Einsele

Danhof

2020

JCM

View full text Add to dashboard Cite

Despite the introduction of novel agents such as proteasome inhibitors, immunomodulatory drugs, and autologous stem cell transplant, multiple myeloma (MM) largely remains an incurable disease. In recent years, monoclonal antibody-based treatment strategies have been developed to target specific surface antigens on MM cells. Treatment with bispecific antibodies (bsAbs) is an immunotherapeutic strategy that leads to an enhanced interaction between MM cells and immune effector cells, e.g., T-cells and natural killer cells. With the immune synapse built by bsAbs, the elimination of MM cells can be facilitated. To date, bsAbs have demonstrated encouraging results in preclinical studies, and clinical trials evaluating bsAbs in patients with MM are ongoing. Early clinical data show the promising efficacy of bsAbs in relapsed/refractory MM. Together with chimeric antigen receptor-modified (CAR)-T-cells, bsAbs represent a new dimension of precision medicine. In this review, we provide an overview of rationale, current clinical development, resistance mechanisms, and future directions of bsAbs in MM.

show abstract

A T-cell–redirecting bispecific G-protein–coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma

Cited by 94 publications

References 25 publications

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma

Contact Info

Product

Resources

About