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Dual-Variable Domain Immunoglobulin (DVD-Ig™) Technology: A Versatile, Novel Format for the Next Generation of Dual-Targeting Biologics

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Bispecific Antibodies

Abstract

Human diseases are complex and heterogeneous. Distinct and redundant mechanisms often determine clinical outcome. Therefore, single therapeutic agents that can block two or more key disease mediators with high specificity would provide substantial benefit to patients. The dual-variable domain immunoglobulin (DVD-Ig™) design represents a novel dual-specific antibody format. With this format, the target-binding domains (i.e., variable domains) of two pre-existing monoclonal antibodies can be combined in tandem via naturally occurring linkers to create a tetravalent, dual-targeting single agent. A well-constructed DVD-Ig™ molecule has many desirable properties of a stable monoclonal antibody: it expresses well in mammalian cells, can be purified to homogeneity using standard approaches, displays good drug-like physicochemical and pharmacokinetic properties, and is amenable to large-scale manufacturing. Several DVD-Ig™ molecules have been constructed and characterized recently. In this chapter, we summarize the design considerations as well as functional, biophysical/biochemical, and pharmacokinetic properties of DVD-Ig™ molecules. As examples, we provide details from our previously published study of the DVD-Ig™ molecule directed against human interleukin-12 and interleukin-18, a target pair with distinct functions, and also provide a brief summary of our experience with more than 100 DVD-Ig™ molecules.

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Abbreviations

bsAb:

Bispecific antibody

CHO:

Chinese hamster ovary cell line

CL:

Clearance

C max :

Observed maximum plasma concentration

DLL4:

Delta-like protein 4

DSC:

Differential scanning calorimetry

DVD-Ig™:

Dual-variable domain immunoglobulin

EGFR:

Epidermal growth factor receptor

F:

Bioavailability

HEK293:

Human embryonic kidney 293

hIL:

Human interleukin

IC50 :

Half maximal inhibitory concentration

IEC:

Ion exchange chromatography

IL:

Interleukin

IV:

Intravenous

K D :

Equilibrium dissociation constant

mAb:

Monoclonal antibody

MS:

Mass spectrometry

MTX:

Methotrexate

PEG:

Polyethylene glycol

PGE2 :

Prostaglandin E2

SC:

Subcutaneous

scFv:

Single-chain variable fragment

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SEC:

Size-exclusion chromatography

T ½ :

Half-life

T m :

Thermal unfolding

T max :

Time to reach C max

TNF:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

VH/VL:

Heavy/light chain variable domain

V ss :

Volume of distribution at steady state

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Acknowledgements

We acknowledge the significant contributions by Chengbin Wu, Rong Rong Zhu, and Jerry Carson. Editorial support was provided by Robin Stromberg, of Arbor Communications, Inc. (Ann Arbor, MI, USA) and funded by Abbott Laboratories.

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Authors and Affiliations

  1. Department of Drug Metabolism and Pharmacokinetics, Abbott Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA

    Edit Tarcsa

  2. Global Pharmaceutical Sciences, Abbott Laboratories, Abbott Park, North Chicago, IL, 60064, USA

    Wolfgang Fraunhofer

  3. Department of Biologics, Abbott Bioresearch Center, 100 Research Drive, Worcester, MA, 01605, USA

    Tariq Ghayur, Jochen Salfeld & Jijie Gu

Authors
  1. Edit Tarcsa
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  2. Wolfgang Fraunhofer
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  3. Tariq Ghayur
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  4. Jochen Salfeld
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  5. Jijie Gu
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Corresponding author

Correspondence to Jijie Gu .

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Editors and Affiliations

  1. Inst. Zellbiologie und Immunologie, Universität Stuttgart, Allmandring 31, Stuttgart, 70569, Germany

    Roland E. Kontermann

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Tarcsa, E., Fraunhofer, W., Ghayur, T., Salfeld, J., Gu, J. (2011). Dual-Variable Domain Immunoglobulin (DVD-Ig™) Technology: A Versatile, Novel Format for the Next Generation of Dual-Targeting Biologics. In: Kontermann, R. (eds) Bispecific Antibodies. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-20910-9_10

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