A review of bispecific antibodies and antibody constructs in oncology and clinical challenges

Suurs, Frans V.; Hooge, Marjolijn N. Lub-de; Vries, Elisabeth G.E. de; Groot, Derk Jan A. de

doi:10.1016/j.pharmthera.2019.04.006

Cited by 225 publications

(170 citation statements)

References 144 publications

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“…The development of bsAbs has received considerable attention in the past 20 years [35,36]. For treatment in oncology, one bsAb has received marketing approval, and more than 50 other bsAbs are undergoing clinical trials.…”

Section: Discussionmentioning

confidence: 99%

A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors

Yoon¹,

Lee²,

Lee³

et al. 2020

Biomolecules

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As mesothelin is overexpressed in various types of cancer, it is an attractive target for therapeutic antibodies. T-cell bispecific antibodies bind to target cells and engage T cells via binding to CD3, resulting in target cell killing by T-cell activation. However, the affinity of the CD3-binding arm may influence CD3-mediated plasma clearance or antibody trapping in T-cell-containing tissues. This may then affect the biodistribution of bispecific antibodies. In this study, we used scFab and knob-into-hole technologies to construct novel IgG-based 1 + 1 MG1122-A and 2 + 1 MG1122-B bispecific antibodies against mesothelin and CD3ε. MG1122-B was designed to be bivalent to mesothelin and monovalent to CD3ε, using a 2 + 1 head-to-tail format. Activities of the two antibodies were evaluated in mesothelin-positive tumor cells in vitro and xenograft models in vivo. Although both antibodies exhibited target cell killing efficacy and produced regression of xenograft tumors with CD8+ T-cell infiltration, the antitumor efficacy of MG1122-B was significantly higher. MG1122-B may improve tumor targeting because of its bivalency for tumor antigen. It may also reduce systemic toxicity by limiting the activation of circulating T cells. Thus, MG1122-B may be useful for treating mesothelin-positive solid tumors.

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Section: Discussionmentioning

confidence: 99%

A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors

Yoon¹,

Lee²,

Lee³

et al. 2020

Biomolecules

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“…At present, blinatumomab, a CD19 × CD3 antibody-based bispecific molecule, is the only example of an immune cellengaging bispecific drug that has FDA approval for the treatment of disease-B cell acute lymphoblastic leukemia (69,70). However, there are dozens of bispecific antibody-based molecules in various stages of development, and clinical testing, against multiple types of cancers (71,72). This includes several DART molecules being evaluated for potential use in treatment of leukemias and lymphomas (73,74), colorectal cancer (55), and solid tumors (75).…”

Section: Discussionmentioning

confidence: 99%

Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules

et al. 2020

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Mother-to-child transmission of HIV-1 remains a major global health challenge. Currently, HIV-1-infected infants require strict lifelong adherence to antiretroviral therapy to prevent replication of virus from reservoirs of infected cells, and to halt progression of disease. There is a critical need for immune interventions that can be deployed shortly after infection to eliminate HIV-1-infected cells in order to promote long-term remission of viremia, or to potentially cure pediatric HIV-1-infection. Bispecific HIV × CD3 DART ® molecules able to co-engage the HIV-1 envelope protein on the surface of infected cells and CD3 on cytolytic T cells have been previously shown to eliminate HIV-1 infected cells in vitro and are candidates for passive immunotherapy to reduce the virus reservoir. However, their potential utility as therapy for infant HIV-1 infection is unclear as the ability of these novel antibody-based molecules to work in concert with cells of the infant immune system had not been assessed. Here, we use human umbilical cord blood as a model of the naïve neonatal immune system to evaluate the ability of HIV x CD3 DART molecules to recruit and redirect neonatal effector cells for elimination of autologous CD4 + T cells infected with HIV-1 encoding an envelope gene sequenced from a motherto-child transmission event. We found that HIV × CD3 DART molecules can redirect T cells present in cord blood for elimination of HIV-infected CD4 + T cells. However, we observed reduced killing by T cells isolated from cord blood when compared to cells isolated from adult peripheral blood-likely due to the absence of the memory and effector CD8 + T cells that are most cytolytic when redirected by bispecific DART molecules. We also found that newly developed HIV × CD16 DART molecules were able to recruit CD16-expressing natural killer cells from cord blood to eliminate HIV-infected cells, and the activity of cord blood natural killer cells could be substantially increased Pollara et al. DART-Molecule Recruitment of Neonatal Cells by priming with IL-15. Our results support continued development of HIV-specific DART molecules using relevant preclinical animal models to optimize strategies for effective use of this immune therapy to reduce HIV-1 infection in pediatric populations.

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“…Redirection of immune cells towards diseased cells are termed as effector cells that can comprise other cells beyond T cells and include NK cells, macrophages, neutrophils, monocytes, and granulocytes [396,543] to facilitate specific killing of tumor cells. Each of the effector cells express different types of activating receptors, and a specific population can be recruited by carefully selecting the targeted trigger receptor [544,545].…”

Section: Considerations For Selectionmentioning

confidence: 99%

Antibody Structure and Function: The Basis for Engineering Therapeutics

et al. 2019

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Antibodies and antibody-derived macromolecules have established themselves as the mainstay in protein-based therapeutic molecules (biologics). Our knowledge of the structure–function relationships of antibodies provides a platform for protein engineering that has been exploited to generate a wide range of biologics for a host of therapeutic indications. In this review, our basic understanding of the antibody structure is described along with how that knowledge has leveraged the engineering of antibody and antibody-related therapeutics having the appropriate antigen affinity, effector function, and biophysical properties. The platforms examined include the development of antibodies, antibody fragments, bispecific antibody, and antibody fusion products, whose efficacy and manufacturability can be improved via humanization, affinity modulation, and stability enhancement. We also review the design and selection of binding arms, and avidity modulation. Different strategies of preparing bispecific and multispecific molecules for an array of therapeutic applications are included.

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A review of bispecific antibodies and antibody constructs in oncology and clinical challenges

Cited by 225 publications

References 144 publications

A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors

A Novel T Cell-Engaging Bispecific Antibody for Treating Mesothelin-Positive Solid Tumors

Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules

Antibody Structure and Function: The Basis for Engineering Therapeutics

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