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CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin
format for medical applications
#MMPMID26984268
Steinmetz A
; Vallée F
; Beil C
; Lange C
; Baurin N
; Beninga J
; Capdevila C
; Corvey C
; Dupuy A
; Ferrari P
; Rak A
; Wonerow P
; Kruip J
; Mikol V
; Rao E
MAbs
2016[Jul]; 8
(5
): 867-78
PMID26984268
show ga
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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