Conjugation site modulates the in vivo stability and therapeutic activity of antibody-drug conjugates
| Autor: | Helga Raab, Richard H. Scheller, Reina N. Fuji, Suzie J. Scales, Ola Saad, Darshana Ramesh Patel, Leslie A. Khawli, Willy Solis, Allen J. Ebens, Charles Eigenbrot, Dongwei Li, Janet Tien, Mark X. Sliwkowski, Elaine Mai, Luna Liu, Paul Polakis, Paul J. Mcdonald, Susan D. Spencer, Surinder Kaur, Shang-Fan Yu, Margaret Kenrick, Wai Lee Wong, Jay Tibbitts, Trung Nguyen, Philip E. Hass, Sunil Bhakta, Jakub Baudys, Richard Vandlen, Kelly Flagella, Jagath Reddy Junutula, Kathryn L Parsons-Reponte, Keyang Xu, Ben-Quan Shen |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Immunoconjugates Cell Survival Protein Conformation Biomedical Engineering Mice Nude Bioengineering Antibodies Monoclonal Humanized Protein Engineering Applied Microbiology and Biotechnology Antibodies Maleimides chemistry.chemical_compound Mice Structure-Activity Relationship Succinimide Cell Line Tumor Structure–activity relationship Animals Humans Aminobenzoates Maytansine Cysteine Sulfhydryl Compounds Binding site Maleimide Mammary Neoplasms Experimental Glutathione Trastuzumab Rats Macaca fascicularis Biochemistry chemistry Immunoglobulin G Biophysics Molecular Medicine Binding Sites Antibody Linker Oligopeptides Biotechnology Conjugate |
| Zdroj: | Nature biotechnology. 30(2) |
| ISSN: | 1546-1696 |
| Popis: | The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated thiol-reactive linkers in plasma owing to maleimide exchange with reactive thiols in albumin, free cysteine or glutathione. In contrast, a partially accessible site with a positively charged environment promoted hydrolysis of the succinimide ring in the linker, thereby preventing this exchange reaction. The site with partial solvent-accessibility and neutral charge displayed both properties. In a mouse mammary tumor model, the stability and therapeutic activity of the antibody conjugate were affected positively by succinimide ring hydrolysis and negatively by maleimide exchange with thiol-reactive constituents in plasma. Thus, the chemical and structural dynamics of the conjugation site can influence antibody conjugate performance by modulating the stability of the antibody-linker interface. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|