Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates
The synthesis and biological evaluation of hydrophilic heterobifunctional cross-linkers for conjugation of antibodies with highly cytotoxic agents are described. These linkers contain either a negatively charged sulfonate group or a hydrophilic, noncharged PEG group in addition to an amine-reactive N-hydroxysuccinimide (NHS) ester and sulfhydryl reactive termini. These hydrophilic linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher drug/antibody ratio (DAR) than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. Antibody-maytansinoid conjugates (AMCs) bearing these sulfonate- or PEG-containing hydrophilic linkers were, depending on the nature of the targeted cells, equally to more cytotoxic to antigen-positive cells and equally to less cytotoxic to antigen-negative cells than conjugates made with SPDB or SMCC linkers and thus typically displayed a wider selectivity window, particularly against multidrug resistant (MDR) cancer cell lines in vitro and tumor xenograft models in vivo.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2011 |
|---|---|
| Erschienen: |
2011 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:54 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 54(2011), 10 vom: 26. Mai, Seite 3606-23 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhao, Robert Y [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
14083FR882 |
|---|
| Anmerkungen: |
Date Completed 01.08.2011 Date Revised 03.01.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/jm2002958 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM207702713 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM207702713 | ||
| 003 | DE-627 | ||
| 005 | 20231224002635.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2011 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/jm2002958 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0692.xml |
| 035 | |a (DE-627)NLM207702713 | ||
| 035 | |a (NLM)21517041 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhao, Robert Y |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Synthesis and evaluation of hydrophilic linkers for antibody-maytansinoid conjugates |
| 264 | 1 | |c 2011 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 01.08.2011 | ||
| 500 | |a Date Revised 03.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a The synthesis and biological evaluation of hydrophilic heterobifunctional cross-linkers for conjugation of antibodies with highly cytotoxic agents are described. These linkers contain either a negatively charged sulfonate group or a hydrophilic, noncharged PEG group in addition to an amine-reactive N-hydroxysuccinimide (NHS) ester and sulfhydryl reactive termini. These hydrophilic linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher drug/antibody ratio (DAR) than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. Antibody-maytansinoid conjugates (AMCs) bearing these sulfonate- or PEG-containing hydrophilic linkers were, depending on the nature of the targeted cells, equally to more cytotoxic to antigen-positive cells and equally to less cytotoxic to antigen-negative cells than conjugates made with SPDB or SMCC linkers and thus typically displayed a wider selectivity window, particularly against multidrug resistant (MDR) cancer cell lines in vitro and tumor xenograft models in vivo | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Antibodies |2 NLM | |
| 650 | 7 | |a Immunoconjugates |2 NLM | |
| 650 | 7 | |a Succinimides |2 NLM | |
| 650 | 7 | |a Sulfones |2 NLM | |
| 650 | 7 | |a Maytansine |2 NLM | |
| 650 | 7 | |a 14083FR882 |2 NLM | |
| 650 | 7 | |a Polyethylene Glycols |2 NLM | |
| 650 | 7 | |a 3WJQ0SDW1A |2 NLM | |
| 650 | 7 | |a N-hydroxysuccinimide |2 NLM | |
| 650 | 7 | |a MJE3791M4T |2 NLM | |
| 700 | 1 | |a Wilhelm, Sharon D |e verfasserin |4 aut | |
| 700 | 1 | |a Audette, Charlene |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Gregory |e verfasserin |4 aut | |
| 700 | 1 | |a Leece, Barbara A |e verfasserin |4 aut | |
| 700 | 1 | |a Lazar, Alexandru C |e verfasserin |4 aut | |
| 700 | 1 | |a Goldmacher, Victor S |e verfasserin |4 aut | |
| 700 | 1 | |a Singh, Rajeeva |e verfasserin |4 aut | |
| 700 | 1 | |a Kovtun, Yelena |e verfasserin |4 aut | |
| 700 | 1 | |a Widdison, Wayne C |e verfasserin |4 aut | |
| 700 | 1 | |a Lambert, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Chari, Ravi V J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 54(2011), 10 vom: 26. Mai, Seite 3606-23 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:54 |g year:2011 |g number:10 |g day:26 |g month:05 |g pages:3606-23 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/jm2002958 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 54 |j 2011 |e 10 |b 26 |c 05 |h 3606-23 | ||