Clinical Pharmacology and Translational Aspects of Bispecific Antibodies

Trivedi, Ashit; Stienen, Sabine; Zhu, Min; Li, H; Yuraszeck, Theresa; Gibbs, John P.; Heath, Timothy D.; Loberg, Robert D.; Kasichayanula, Sreeneeranj

doi:10.1111/cts.12459

Cited by 65 publications

(52 citation statements)

References 77 publications

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“…However, in the wake of the TGN1412 incident, which led to the introduction of the minimal anticipated biological effect level (MABEL)‐ or minimum effective dose (MED)‐based approach, additional precautions have been taken for molecules of novel pathways or for immune modulators. The MABEL approach was used more frequently in recent years, reflecting the increasing repertoire of immune modulators and the recognition of translational insufficiency for this family of molecules . While the MABEL‐based approach is the most conservative approach leading to a lower starting dose, it could achieve the desired objectives of FIH clinical trials effectively with a more aggressive dose escalation …”

Section: Frequently Asked Questions On Pk Related Activities During Ementioning

confidence: 99%

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Ovacik¹,

Lin

2018

Clinical Translational Sci

207

154

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The tutorial introduces the readers to the fundamentals of antibody pharmacokinetics (PK) in the context of drug development. Topics covered include an overview of antibody development, PK characteristics, and the application of antibody PK/pharmacodynamics (PD) in research and development decision‐making. We also discuss the general considerations for planning a nonclinical PK program and describe the types of PK studies that should be performed during early development of monoclonal antibodies.

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Section: Frequently Asked Questions On Pk Related Activities During Ementioning

confidence: 99%

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Ovacik¹,

Lin

2018

Clinical Translational Sci

207

154

View full text Add to dashboard Cite

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“…A sufficient amount of these complexes would induce the formation of a transient cytolytic synapse between the engaged effector cells and the target cells, which activates the engaged effector cell (e.g., cytotoxic T cells) in a T cell receptor-independent manner to induce membrane perforation and then granzyme-mediated apoptotic death of the engaged target cells (e.g., tumor cells) (Figure 1). 4–6 The clinical success of blinatumomab (Blincyto®), a bispecific T-cell engager (BiTE®) directed against CD19 for B cell malignancies, has led to a substantial increase in the number of BiTEs and other T-cell redirecting bsAbs in clinical development to treat both hematological malignancies and solid tumors. 4,5 Currently, there are more than 40 others in clinical development and hundreds more in discovery and preclinical development.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 Currently, there are more than 40 others in clinical development and hundreds more in discovery and preclinical development. 6 …”

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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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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“…[4,5] These differences stem from intrinsic features in their structures such as binding-site specificity and hinge flexibility (Figure 1a). [7] IgG is by far the most commonly exploited isotype for biotherapeutics, [1] including bispecific antibodies [8,9] and antibody-drug conjugates (ADCs). [7] IgG is by far the most commonly exploited isotype for biotherapeutics, [1] including bispecific antibodies [8,9] and antibody-drug conjugates (ADCs).…”

mentioning

confidence: 99%

A Mass‐Spectrometry‐Based Modelling Workflow for Accurate Prediction of IgG Antibody Conformations in the Gas Phase

et al. 2018

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Immunoglobulins are biomolecules involved in defence against foreign substances. Flexibility is key to their functional properties in relation to antigen binding and receptor interactions. We have developed an integrative strategy combining ion mobility mass spectrometry (IM‐MS) with molecular modelling to study the conformational dynamics of human IgG antibodies. Predictive models of all four human IgG subclasses were assembled and their dynamics sampled in the transition from extended to collapsed state during IM‐MS. Our data imply that this collapse of IgG antibodies is related to their intrinsic structural features, including Fab arm flexibility, collapse towards the Fc region, and the length of their hinge regions. The workflow presented here provides an accurate structural representation in good agreement with the observed collision cross section for these flexible IgG molecules. These results have implications for studying other nonglobular flexible proteins.

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Clinical Pharmacology and Translational Aspects of Bispecific Antibodies

Cited by 65 publications

References 77 publications

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

Tutorial on Monoclonal Antibody Pharmacokinetics and Its Considerations in Early Development

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

A Mass‐Spectrometry‐Based Modelling Workflow for Accurate Prediction of IgG Antibody Conformations in the Gas Phase

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