Guiding bispecific monovalent antibody formation through proteolysis of IgG1 single-chain.
MAbs
; 9(3): 438-454, 2017 04.
Article
em En
| MEDLINE
| ID: mdl-28055299
ABSTRACT
We developed an IgG1 domain-tethering approach to guide the correct assembly of 2 light and 2 heavy chains, derived from 2 different antibodies, to form bispecific monovalent antibodies in IgG1 format. We show here that assembling 2 different light and heavy chains by sequentially connecting them with protease-cleavable polypeptide linkers results in the generation of monovalent bispecific antibodies that have IgG1 sequence, structure and functional properties. This approach was used to generate a bispecific monovalent antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor that 1) can be produced and purified using standard IgG1 techniques; 2) exhibits stability and structural features comparable to IgG1; 3) binds both targets simultaneously; and 4) has potent anti-tumor activity. Our strategy provides new engineering opportunities for bispecific antibody applications, and, most importantly, overcomes some of the limitations (e.g., half-antibody and homodimer formation, light chains mispairing, multi-step purification), inherent with some of the previously described IgG1-based bispecific monovalent antibodies.
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MEDLINE
Assunto principal:
Imunoglobulina G
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Engenharia de Proteínas
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Anticorpos Biespecíficos
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Anticorpos de Cadeia Única
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article