Crystal structure of a<i>Staphylococcus aureus</i>protein A domain complexed with the Fab fragment of a human IgM antibody: Structural basis for recognition of B-cell receptors and superantigen activity

Graille, Marc; Stura, E.A.; Corper, Adam L.; Sutton, Brian J.; Taussig, Michael J.; Charbonnier, Jean‐Baptiste; Silverman, Gregg J.

doi:10.1073/pnas.97.10.5399

Cited by 449 publications

(449 citation statements)

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“…[85][86][87] Superposition of crystal structures of Fc or Fab domains in complex with subdomains of protein A on CODV-Ig models constructed with the type 1 crystal structure of CODV-Fab IL4 x IL13 show that these binding sites are unobstructed in CODV-Ig except for steric interferences observed at the site of Fv1. 81,[88][89][90] Superposition of the Fab/protein A complexes on the initial type 4 model suggests unobstructed protein A binding sites on both Fv1 and Fv2. Thus, choice of linker lengths may influence purification of CODV-Igs, in particular when Fv domains with HC of subgroup III are employed.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The virulence factor, protein A of Staphylococcus aureus (SpA), 3 can impair host B cell-mediated defenses through specific binding interactions with a V H framework site conserved in many BCR (1), and this superantigen (SAg)-mediated depletion of large supraclonal B cell sets is a T cell-independent process (2-4 and reviewed in Ref. 5).…”

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confidence: 99%

Cutting Edge: Bim Is Required for Superantigen-Mediated B Cell Death

Goodyear

Corr

Sugiyama

et al. 2007

The Journal of Immunology

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To impair B cell clonal regulation, the microbial virulence factor, protein A of Staphylococcus aureus, can interact with evolutionarily conserved BCR-binding sites to induce a form of Fas-independent activation-associated B cell death that results in selective immune tolerance. We now show that this in vivo death pathway is associated with induction of increased transcript and protein levels of Bim, a BH3-only proapoptotic Bcl-2 family protein, which is inhibited by excess B cell-activating factor. An absolute requirement for Bim was documented, since Bim-deficient B cells were protected from in vivo superantigen-induced death and instead underwent persistent massive supraclonal expansion without functional impairment. These studies characterize a BCR-dependent negative clonal selection pathway that has been co-opted by a common bacterial pathogen to induce selective defects in host immune defenses.

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“…36 The above experiments show that antibody fragments are capable of refolding or partially refolding on the membrane after protein gel blotting. This is in line with what has previously been reported about the folding characteristics of the Hel4 antibody and V H 3 gene family containing scFv.…”

Section: Discussionmentioning

confidence: 99%

Degradation of C-terminal tag sequences on domain antibodies purified fromE. colisupernatant

Lykkemark

Mandrup

Friis

et al. 2014

mAbs

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Crystal structure of aStaphylococcus aureusprotein A domain complexed with the Fab fragment of a human IgM antibody: Structural basis for recognition of B-cell receptors and superantigen activity

Cited by 449 publications

References 50 publications

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

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

Cutting Edge: Bim Is Required for Superantigen-Mediated B Cell Death

Degradation of C-terminal tag sequences on domain antibodies purified fromE. colisupernatant

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