Bispecific Antibodies in the Treatment of Hematologic Malignancies

Duell, Johannes; Lammers, Philip E.; Djuretic, Ivana; Chunyk, Allison G.; Alekar, Shilpa; Jacobs, Ira; Gill, Saar

doi:10.1002/cpt.1396

Cited by 60 publications

(64 citation statements)

References 75 publications

(163 reference statements)

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“…Hallmarks of tumor immune evasion, such as heterogenous expression and down-regulation of antigen levels, present obstacles to both T cell and NK cell redirecting BsAbs (79). New constructs, such as multivalent and tri-specific BsAbs, are under investigation as possible responses to these concerns (81)(82)(83). These new designs may also be pivotal in reducing toxicity.…”

Section: Bispecific Antibodies: Overview Designs and Potential For MMmentioning

confidence: 99%

“…Down-regulation of the target antigen is a classic mechanism of tumor resistance, and multivalent BsAb constructs that increase target avidity, as well as trispecific antibodies that target more than one tumor antigen, may be methods to overcome this obstacle (82). Targeting multiple tumor antigens in one antibody may also prove useful in addressing the heterogeneity of target expression on malignant cells.…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

“…Independent T cell activation, a feature displayed by some but not all BsAbs, is an important area of further development. In some MM cases, inhibition of co-stimulation in the tumor microenvironment via expression of co-inhibitory molecules aids tumor evasion by neutralizing T cell activity (82). BsAb designs that induce biological synergies, resulting in independent T cell activation without the need for costimulatory molecules (e.g., the designs of anti-BCMA BsAb AMG420, anti-CD38 BsAb AMG424, and anti-FcRL5 BsAb BFCR4350A), are thus important for further development (18,125,188).…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

“…Combinations of BsAbs with therapeutic Treg depletion may also assist in fighting against immunosuppression. A potential concern about BsAb treatment is that independent T cell activation may also activate unwanted Tregs (82). In MM, Treg numbers are abnormally high, aiding immunosuppression of effector cells in the BM microenvironment (42).…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Bispecific Antibodies: Overview Designs and Potential For MMmentioning

confidence: 99%

Section: Future Directions and Conclusionmentioning

confidence: 99%

Section: Future Directions and Conclusionmentioning

confidence: 99%

Section: Future Directions and Conclusionmentioning

confidence: 99%

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

et al. 2020

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“…A bispecific antibody has two different light chains and two different heavy chains pair via engineered interchain interactions. Furthermore, bispecific antibodies have high efficacy for cytotoxicity, high affinity and small in size (easily penetrable to tissues) [64][65].…”

Section: Naked Antibodies Bispecific Antibodies and Conjugated Antibmentioning

confidence: 99%

Development of Therapeutic Antibody Technology And Recent Perspectives For Leukemia-Lymphoma Treatment

Yirga¹,

Lin²,

Huang³

et al. 2019

J Leuk

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Advancement of monoclonal antibodies (Mabs) to be accepted as a therapy has long history. This article describes the dramatic developmental trend of therapeutic antibody technology and their significant role for treatment of leukemia-lymphoma at the current time. The therapeutic Mab technology development from murine (mouse origin) to fully human resulted in low immunogenicity and high quality Mabs. Chemotherapy is standard care for leukemialymphoma treatments. However, it is associated with high toxicities (side effects), painful and relatively ineffective against certain leukemia-lymphoma subtypes. The remarkable contribution of Von Behring, Paul Ehrlich and the discovery of hybridoma technology marked the beginning of antibodies for therapeutic applications. Rituximab is the first Mab approved by Food and Drug Administration against B-cell malignancies. Today, a number of effective Mabs targeting leukemia and lymphoma were approved and successfully developed. The Mab therapeutic phenomena in the body (also called war in the blood) has various mechanism of actions. In recent years, Mab against leukemialymphoma achieved significantly therapeutic outcomes, eventually this led to traditional chemotherapy treatment free era. We also reviewed that, the therapeutic efficacy of Mabs against leukemia-lymphoma as compared antibody alone and antibody conjugated with potent chemotherapy or cytotoxic drugs. This article extends our understanding of advancements in therapeutic Mabs technology and provides new insights of Mab leukemia-lymphomas therapy. We also encourage further more studies for Mab based diagnostics, treatments of leukemia and lymphomas.

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Pharmacokinetics of Biologics

McLachlan¹,

Adiwidjaja²

2020

Biologics, Biosimilars, and Biobetters

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Bispecific Antibodies in the Treatment of Hematologic Malignancies

Cited by 60 publications

References 75 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

Development of Therapeutic Antibody Technology And Recent Perspectives For Leukemia-Lymphoma Treatment

Pharmacokinetics of Biologics

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