Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck, Theresa; Kasichayanula, Sreeneeranj; Benjamin, Jonathan

doi:10.1002/cpt.651

Cited by 75 publications

(75 citation statements)

References 79 publications

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“…10 In addition, the disposition of bsAbs at tumor sites of action, the numbers of tumor infiltrating T cells, the heterogeneous distribution of effector and target cells, and the possible immunosuppressive tumor microenvironment should all be taken into account when designing T-cell redirecting bsAbs, especially when treating solid tumors. 11 …”

Section: Introductionmentioning

confidence: 99%

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Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

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T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure–response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs.

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Section: Introductionmentioning

confidence: 99%

“…A holistic approach must consider all of the above factors, as well as the in vivo pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the bsAbs. 11 …”

Section: Introductionmentioning

confidence: 99%

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Jiang

Chen

Carpenter

et al. 2018

mAbs

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show abstract

“…A key determinant of the success of any new drug lies in the ability to accurately translate preclinical data to the clinic to inform both the clinical starting dose as well as the predicted human effective dose. For T‐cell–engaging CD3 bispecifics, a minimum anticipated biologic effect level (MABEL) has been used to estimate starting dose due to their immune agonistic properties . A widely applied method for calculating the MABEL‐based starting dose is based on the in vitro potency threshold, for example effective concentration (EC) 20 or EC 50 , estimated from various human assays for assessing bispecific activity, including but not limited to cytokine release, cytotoxicity, and T‐cell activation/proliferation.…”

Section: Translational Strategies For Cd3‐bispecific Antibodiesmentioning

confidence: 99%

Bispecific Antibodies in the Treatment of Hematologic Malignancies

Duell

Lammers

Djuretic

et al. 2019

Clin Pharma and Therapeutics

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Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single‐agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single‐agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients.

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“…Currently, many bispecific antibodies are being developed for cancer immunotherapy. Yuraszeck et al 8. described unique challenges and experiences in the preclinical and the clinical development of blinatumomab, a bispecific T‐cell engaging antibody, pointing out the critical need to optimize dose and schedule of combination therapy and the potential utility of quantitative systems pharmacology and other pharmacometric tools (e.g., physiologically based pharmacokinetic modeling).…”

Section: Emerging Drug Development Paradigm and Regulatory Review Andmentioning

confidence: 99%

Cancer Therapy: Shooting for the Moon

Lee

Blumenthal

Hohl

et al. 2017

Clin Pharma and Therapeutics

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Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Cited by 75 publications

References 79 publications

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

Bispecific Antibodies in the Treatment of Hematologic Malignancies

Cancer Therapy: Shooting for the Moon

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