| RRC ID |
51971
|
| 著者 |
Sellmann C, Doerner A, Knuehl C, Rasche N, Sood V, Krah S, Rhiel L, Messemer A, Wesolowski J, Schuette M, Becker S, Toleikis L, Kolmar H, Hock B.
|
| タイトル |
Balancing Selectivity and Efficacy of Bispecific Epidermal Growth Factor Receptor (EGFR) × c-MET Antibodies and Antibody-Drug Conjugates.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
Bispecific antibodies (bsAbs) and antibody-drug conjugates (ADCs) have already demonstrated benefits for the treatment of cancer in several clinical studies, showing improved drug selectivity and efficacy. In particular, simultaneous targeting of prominent cancer antigens, such as EGF receptor (EGFR) and c-MET, by bsAbs has raised increasing interest for potentially circumventing receptor cross-talk and c-MET-mediated acquired resistance during anti-EGFR monotherapy. In this study, we combined the selectivity of EGFR × c-MET bsAbs with the potency of cytotoxic agents via bispecific antibody-toxin conjugation. Affinity-attenuated bispecific EGFR × c-MET antibody-drug conjugates demonstrated high in vitro selectivity toward tumor cells overexpressing both antigens and potent anti-tumor efficacy. Due to basal EGFR expression in the skin, ADCs targeting EGFR in general warrant early safety assessments. Reduction in EGFR affinity led to decreased toxicity in keratinocytes. Thus, the combination of bsAb affinity engineering with the concept of toxin conjugation may be a viable route to improve the safety profile of ADCs targeting ubiquitously expressed antigens.
|
| 巻・号 |
291(48)
|
| ページ |
25106-25119
|
| 公開日 |
2016-11-25
|
| DOI |
10.1074/jbc.M116.753491
|
| PII |
S0021-9258(20)34592-0
|
| PMID |
27694443
|
| PMC |
PMC5122778
|
| MeSH |
A549 Cells
Antibodies, Bispecific / immunology*
Antibodies, Bispecific / therapeutic use
ErbB Receptors / immunology*
Hep G2 Cells
Humans
Immunotoxins / immunology*
Immunotoxins / therapeutic use
Neoplasms / drug therapy
Neoplasms / immunology
Proto-Oncogene Proteins c-met / immunology*
|
| IF |
4.238
|
| 引用数 |
15
|
| リソース情報 |
| ヒト・動物細胞 |
KP4(RCB1005)
EBC-1(RCB1965) |
