On-target restoration of a split T cell-engaging antibody for precision immunotherapy

Banaszek, Agnes; Bumm, Thomas G.P.; Nowotny, Boris; Geis, Maria; Kim, Jacob; Wölfl, Matthias; Trebing, Johannes; Kucka, Kirstin; Kouhestani, Dina; Gogishvili, Tea; Krenz, Bastian; Lutz, Justina; Rasche, Leo; Hönemann, Dirk; Neuweiler, Hannes; Heiby, Julia C.; Bargou, Ralf C.; Wajant, Harald; Einsele, Hermann; Riethmüller, Gert; Stuhler, Gernot

doi:10.1038/s41467-019-13196-0

Cited by 47 publications

(40 citation statements)

References 37 publications

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“…Each half contains a TAA binding scFv fused to either the variable light (VL) or variable heavy (VH) chain domain of an anti-CD3 antibody. When the two complementary halves simultaneously bind their respective antigens on the same cell, they reconstitute the original CD3-binding site to engage T cells (Banaszek et al 2019 ).…”

Section: Increased Tumor Selectivitymentioning

confidence: 99%

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Huang

Duijnhoven²,

Sijts

et al. 2020

J Cancer Res Clin Oncol

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Purpose Bispecific antibodies (BsAbs) have emerged as a leading drug class for cancer therapy and are becoming increasingly of interest for therapeutic applications. As of April 2020, over 123 BsAbs are under clinical evaluation for use in oncology (including the two marketed BsAbs Blinatumomab and Catumaxomab). The majority (82 of 123) of BsAbs under clinical evaluation can be categorized as bispecific immune cell engager whereas a second less well-discussed subclass of BsAbs targets two tumor-associated antigens (TAAs). In this review, we summarize the clinical development of dual TAAs targeting BsAbs and provide an overview of critical considerations when designing dual TAA targeting BsAbs. Methods Herein the relevant literature and clinical trials published in English until April 1st 2020 were searched using PubMed and ClinicalTrials.gov database. BsAbs were considered to be active in clinic if their clinical trials were not terminated, withdrawn or completed before 2018 without reporting results. Data missed by searching ClinicalTrials.gov was manually curated. Results Dual TAAs targeting BsAbs offer several advantages including increased tumor selectivity, potential to concurrently modulate two functional pathways in the tumor cell and may yield improved payload delivery. Conclusions Dual TAAs targeting BsAbs represent a valuable class of biologics and early stage clinical studies have demonstrated promising anti-tumor efficacy in both hematologic malignancies and solid tumors.

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Section: Increased Tumor Selectivitymentioning

confidence: 99%

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Huang

Duijnhoven²,

Sijts

et al. 2020

J Cancer Res Clin Oncol

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“…Furthermore, Banaszek et al reported on hemibodies consisting of two different antigen-specific scFvs fused to the variable light or variable heavy chain domains of a CD3 antibody. If both hemibodies simultaneously bind their respective antigens on a single cell, a T-cell engaging CD3 binding domain is generated [ 97 ]. In preclinical models, hemibodies can preferentially induce the cellular lysis of double-positive cells and spare single-positive cells [ 97 ].…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma

Zhou

Einsele

Danhof

2020

JCM

Self Cite

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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.

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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%

“…Emerging BsAb technologies may prevent against unnecessary B and plasma cell depletion by increasing their specificity. A promising example of such technology is the "split" trispecific antibody, which is divided into two scFv halves, both connected to the same anti-CD3 antibody (83). The CD3-binding site only becomes functional when both scFvs have attached to their target antigen, ensuring that effector cell lysis is only directed at cells expressing both antigens.…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

“…The CD3-binding site only becomes functional when both scFvs have attached to their target antigen, ensuring that effector cell lysis is only directed at cells expressing both antigens. Thus, antigen combinations uniquely expressed by the cancer cells can be targeted, without accompanying B cell and plasma cell depletion (83).…”

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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On-target restoration of a split T cell-engaging antibody for precision immunotherapy

Cited by 47 publications

References 37 publications

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy

Bispecific Antibodies: A New Era of Treatment for Multiple Myeloma

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

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