Synthesis of site-specific antibody-drug conjugates using unnatural amino acids

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Antibody-drug conjugates (ADCs) allow selective targeting of cytotoxic drugs to cancer cells presenting tumor-associated surface markers, thereby minimizing systemic toxicity. Traditionally, the drug is conjugated nonselectively to cysteine or lysine residues in the antibody. However, these strategies often lead to heterogeneous products, which make optimization of the biological, physical, and pharmacological properties of an ADC challenging. Here we demonstrate the use of genetically encoded unnatural amino acids with orthogonal chemical reactivity to synthesize homogeneous ADCs with precise control of conjugation site and stoichiometry. p-Acetylphenylalanine was site-specifically incorporated into an anti-Her2 antibody Fab fragment and full-length IgG in Escherichia coli and mammalian cells, respectively. The mutant protein was selectively and efficiently conjugated to an auristatin derivative through a stable oxime linkage. The resulting conjugates demonstrated excellent pharmacokinetics, potent in vitro cytotoxic activity against Her2(+) cancer cells, and complete tumor regression in rodent xenograft treatment models. The synthesis and characterization of homogeneous ADCs with medicinal chemistry-like control over macromolecular structure should facilitate the optimization of ADCs for a host of therapeutic uses.
Publisher
NATL ACAD SCIENCES
Issue Date
2012-10
Language
English
Article Type
Article
Keywords

AURISTATIN-E CONJUGATE; BREAST-CANCER; IN-VIVO; ANTITUMOR-ACTIVITY; THERAPEUTIC INDEX; ARMING ANTIBODIES; ESCHERICHIA-COLI; CYTOTOXIC DRUG; GENETIC-CODE; POTENT

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.109, no.40, pp.16101 - 16106

ISSN
0027-8424
DOI
10.1073/pnas.1211023109
URI
http://hdl.handle.net/10203/209139
Appears in Collection
BS-Journal Papers(저널논문)
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