Affinity enhancement of bispecific antibody against two different epitopes in the same antigen

Cheong, Hong Seok; Chang, Jin Soo; Park, Jong Myun; Byun, Sun‐Sig

doi:10.1016/s0006-291x(05)80857-5

Cited by 28 publications

(7 citation statements)

References 13 publications

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“…For monomeric alternative scaffold proteins and fragment antibodies, generation of biparatopic proteins is an extremely efficient way of increasing avidity. Thus, a large number of these proteins have been developed as biparatopic agents [12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29], which is not as important with conventional antibodies because they are already bivalent [5,7,8,10,[30][31][32][33][34][35][36][37].…”

Section: Increased Binding Avidity Of Biparatopic Proteinsmentioning

confidence: 99%

“…Biparatopic proteins contain two antigen-binding domains (i.e., paratopes) that bind to different antigen epitopes. Biparatopic antibodies (BpAbs) have been known for almost 30 years [5], but it was not until recently that technological advances [6] allowed the development of biparatopic antibodies with sufficient quality for development into drugs. Currently, two BpAbs against human epidermal growth factor receptor 2 (HER2) are undergoing clinical trial, with one being developed as an antibody-drug conjugate [8,9] and the other being developed as both a naked antibody and an antibody-drug conjugate [10,11].…”

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confidence: 99%

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Development and activities, including immunocomplex formation, of biparatopic antibodies and alternative scaffold proteins

Akiba

Tsumoto

2020

Translational and Regulatory Sciences

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Biparatopic antibodies and biparatopic alternative scaffolds are proteins that can simultaneously bind two distinct epitopes, and as such are promising formats for the development of next-generation antibody therapeutics. By design, biparatopic proteins have high avidity and can bridge between epitopes in an intra-or intermolecular manner to form diverse immunocomplexes. Some biparatopic proteins can be efficiently internalized into cells, which may be useful for the targeted delivery of therapeutic molecules into cells. In addition, biparatopic proteins can also lock the conformation of membrane proteins to exert an agonist or antagonist effect. Here, we review the development and characteristics of biparatopic proteins and examine how they differ in terms of antigen-binding efficiency, immunocomplex formation and biological activity compared with conventional monoparatopic proteins.

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Section: Increased Binding Avidity Of Biparatopic Proteinsmentioning

confidence: 99%

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confidence: 99%

Development and activities, including immunocomplex formation, of biparatopic antibodies and alternative scaffold proteins

Akiba

Tsumoto

2020

Translational and Regulatory Sciences

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“…Although this enhancement in binding affinity as measured by SPR is modest, it is possible that the dimerization may be more important for the function of YLDV-IL18BP during infection of the host, perhaps by increasing the half-life of the protein in the infected tissue or by increasing the avidity of binding to IL18 at low protein concentration. In fact, divalent or multivalent binding is an important, inherent feature of many biological systems to enhance the effectiveness of binding of ligands to receptors and of antibodies to antigens [24]–[28]. More specifically, this has been a feature for quite a few poxvirus cytokine binding proteins.…”

Section: Discussionmentioning

confidence: 99%

A Unique Bivalent Binding and Inhibition Mechanism by the Yatapoxvirus Interleukin 18 Binding Protein

et al. 2012

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Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which contribute to virulence. Previous structural and functional studies on IL18 and IL18BPs revealed an essential binding hot spot involving a lysine on IL18 and two aromatic residues on IL18BPs. The aromatic residues are conserved among the very diverse mammalian and poxviruses IL18BPs with the notable exception of yatapoxvirus IL18BPs, which lack a critical phenylalanine residue. To understand the mechanism by which yatapoxvirus IL18BPs neutralize IL18, we solved the crystal structure of the Yaba-Like Disease Virus (YLDV) IL18BP and IL18 complex at 1.75 Å resolution. YLDV-IL18BP forms a disulfide bonded homo-dimer engaging IL18 in a 2∶2 stoichiometry, in contrast to the 1∶1 complex of ectromelia virus (ECTV) IL18BP and IL18. Disruption of the dimer interface resulted in a functional monomer, however with a 3-fold decrease in binding affinity. The overall architecture of the YLDV-IL18BP:IL18 complex is similar to that observed in the ECTV-IL18BP:IL18 complex, despite lacking the critical lysine-phenylalanine interaction. Through structural and mutagenesis studies, contact residues that are unique to the YLDV-IL18BP:IL18 binding interface were identified, including Q67, P116 of YLDV-IL18BP and Y1, S105 and D110 of IL18. Overall, our studies show that YLDV-IL18BP is unique among the diverse family of mammalian and poxvirus IL-18BPs in that it uses a bivalent binding mode and a unique set of interacting residues for binding IL18. However, despite this extensive divergence, YLDV-IL18BP binds to the same surface of IL18 used by other IL18BPs, suggesting that all IL18BPs use a conserved inhibitory mechanism by blocking a putative receptor-binding site on IL18.

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“…Because of the closely linked antigenic epitopes in LpAng II, the polyclonal antibodies may possess cooperative characteristics similar to those of a monoclonal antibody mixture ( Ehrlich & Moyle 1984). Furthermore, cooperativity increased the specificity and sensitivity of the RIA, as non-specific bindings are less likely to possess such cooperativity characteristics (Cheong et al 1990). The RIA developed for LpAng II was highly specific, as the cross reactivities to other fish-type Ang IIs were low (!1%).…”

Section: Discussionmentioning

confidence: 99%

Characterization of a native angiotensin from an anciently diverged serine protease inhibitor in lamprey

Wong

Takei²

2011

Journal of Endocrinology

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Angiotensinogen belongs to family A serine protease inhibitors (SERPIN family) and we have cloned and characterized SERPIN genes in two lamprey species, which possess all the properties of angiotensinogen. The putative angiotensinogens in lampreys can be considered as an evolutionary link between SERPIN and other angiotensinogen according to the phylogenetic analyses. The inferred sea lamprey angiotensinogen gene was expressed abundantly in liver and to a lesser extent in other tissues. The predicted lamprey angiotensin I (Ang I) sequence was unique and different from the teleost-type Ang I identified previously by the incubation of lamprey plasma with its kidney extract. Therefore, we characterized and compared the biochemical and physiological properties of this native lamprey Ang II (LpAng II) (EEDYDERPYMQPF) with teleost-type Ang II (NRVYVHPF). Using a newly developed RIA for LpAng II, plasma levels in Japanese lamprey were measured (157 . 4G35 . 2 fmol/ml, nZ6), but teleost-type Ang II was undetectable. In conscious cannulated lamprey, LpAng II at 100 pmol/kg elicited a transient vasodepressor effect. At doses higher than 300 pmol/kg, a biphasic cardiovascular response with an initial vasodepressor effect followed by a transient rebound vasopressor effect was observed in a dose-dependent manner. However, teleosttype Ang II was not vasoactive up to 1 nmol/kg. In Japanese eel, LpAng II injection up to 3 nmol/kg did not alter the cardiovascular parameters. Our results suggested that the renin-angiotensin system first appeared in cyclostomes, and LpAng II could be important for the regulation of cardiovascular dynamics in lampreys because of its potent and acute vasoactive effect.

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Affinity enhancement of bispecific antibody against two different epitopes in the same antigen

Cited by 28 publications

References 13 publications

Development and activities, including immunocomplex formation, of biparatopic antibodies and alternative scaffold proteins

Development and activities, including immunocomplex formation, of biparatopic antibodies and alternative scaffold proteins

A Unique Bivalent Binding and Inhibition Mechanism by the Yatapoxvirus Interleukin 18 Binding Protein

Characterization of a native angiotensin from an anciently diverged serine protease inhibitor in lamprey

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