Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin

Wu, Chengbin; Hua, Ying; Grinnell, Christine; Bryant, Shaughn; Miller, Renee; Clabbers, Anca; Bose, Sahana; McCarthy, Donna; Zhu, Rongrong; Santora, Ling; Davis-Taber, Rachel; Kunes, Yune Z.; Fung, Emma; Schwartz, Arthur G.; Sakorafas, Paul; Gu, Jijie; Tarcsa, Edit; Murtaza, Anwar; Ghayur, Tariq

doi:10.1038/nbt1345

Cited by 314 publications

(272 citation statements)

References 33 publications

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“…Bispecific agents, such as dual variable‐domain immunoglobulins (DVD‐Ig) 17, could theoretically deliver higher local concentrations with lower systemic exposure. In this format, the variable domains of 2 distinct monoclonal antibodies are linked, creating a tetravalent, dual‐targeting single agent.…”

mentioning

confidence: 99%

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Onuoha

Ferrari

Sblattero

et al. 2015

Arthritis & Rheumatology

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ObjectiveBiologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies.MethodsActivatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets.ResultsIntact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules.ConclusionThe design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases.

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mentioning

confidence: 99%

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Onuoha

Ferrari

Sblattero

et al. 2015

Arthritis & Rheumatology

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“…2). 23 However, some DVD-Igs show a positional effect; thus, they maintain antigenaffinity at the level of the parental antibody only at the outer, N-terminal Fv (Fv1). Antigen affinity at the inner Fv (Fv2) is significantly reduced.…”

Section: Introductionmentioning

confidence: 99%

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications

Steinmetz

Vallée

Beil

et al. 2016

mAbs

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Bispecific immunoglobulins (Igs) typically contain at least two distinct variable domains (Fv) that bind to two different target proteins. They are conceived to facilitate clinical development of biotherapeutic agents for diseases where improved clinical outcome is obtained or expected by combination therapy compared to treatment by single agents. Almost all existing formats are linear in their concept and differ widely in drug-like and manufacture-related properties. To overcome their major limitations, we designed cross-over dual variable Ig-like proteins (CODV-Ig). Their design is akin to the design of circularly closed repeat architectures. Indeed, initial results showed that the traditional approach of utilizing (G4S) x linkers for biotherapeutics design does not identify functional CODV-Igs. Therefore, we applied an unprecedented molecular modeling strategy for linker design that consistently results in CODV-Igs with excellent biochemical and biophysical properties. CODV architecture results in a circular self-contained structure functioning as a self-supporting truss that maintains the parental antibody affinities for both antigens without positional effects. The format is universally suitable for therapeutic applications targeting both circulating and membrane-localized proteins. Due to the full functionality of the Fc domains, serum half-life extension as well as antibody-or complement-dependent cytotoxicity may support biological efficiency of CODV-Igs. We show that judicious choice in combination of epitopes and paratope orientations of bispecific biotherapeutics is anticipated to be critical for clinical outcome. Uniting the major advantages of alternative bispecific biotherapeutics, CODV-Igs are applicable in a wide range of disease areas for fast-track multi-parametric drug optimization.

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“…[1][2][3][4][5][6][7][8][9][10][11][12] Bispecific molecules described thus far can be divided into five classes based on their molecular format: 1) BsAb with IgG1-like structure, which are monovalent for each antigen; 2) BsAb prepared by appending binding domains to the IgG, which are bivalent for each antigen; 3) BsAb prepared using antibody fragments, which are monovalent for each antigen and often lack the Fc region; 4) bispecific fusion proteins, which are formed of an antibody fragment genetically linked to a protein to add additional functionality or specificity; and 5) bispecific conjugates, which are prepared by chemical conjugation of antibody fragments. While some such bispecific molecules have demonstrated manufacturing robustness, in vivo drug-like properties, suitable pharmacokinetics (PK) and efficacy have been achieved, platforms that yield multifunctional bispecific antibodies with different spatial configurations and flexibility suitable for a variety of target and disease applications are still needed.…”

Section: Introductionmentioning

confidence: 99%

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

Bezabeh¹,

Fleming²,

Fazenbaker³

et al. 2016

mAbs

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By simultaneous binding two disease mediators, bispecific antibodies offer the opportunity to broaden the utility of antibody-based therapies. Herein, we describe the design and characterization of Bs4Ab, an innovative and generic bispecific tetravalent antibody platform. The Bs4Ab format comprises a full-length IgG1 monoclonal antibody with a scFv inserted into the hinge domain. The Bs4Ab design demonstrates robust manufacturability as evidenced by MEDI3902, which is currently in clinical development. To further demonstrate the applicability of the Bs4Ab technology, we describe the molecular engineering, biochemical, biophysical, and in vivo characterization of a bispecific tetravalent Bs4Ab that, by simultaneously binding vascular endothelial growth factor and angiopoietin-2, inhibits their function. We also demonstrate that the Bs4Ab platform allows Fc-engineering similar to that achieved with IgG1 antibodies, such as mutations to extend half-life or modulate effector functions.

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Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin

Cited by 314 publications

References 33 publications

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

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