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Investigation of Hydrophilic Auristatin Derivatives for Use in Antibody Drug Conjugates.
- Source :
-
Bioconjugate chemistry [Bioconjug Chem] 2017 Feb 15; Vol. 28 (2), pp. 371-381. Date of Electronic Publication: 2017 Jan 06. - Publication Year :
- 2017
-
Abstract
- Antibody drug conjugates offer a targeted cancer treatment for the delivery of potent cytotoxic drugs. Derivatives of the natural product dolastatin 10 containing pyridines and other basic amines were examined with the objective of determining if a more hydrophilic auristatin derivative would be potent enough for use as part of an ADC. This may be advantageous if a less hydrophobic drug makes a better ADC. A pyridine derivative, monomethyl auristatin PYE, showed the greatest potency when tested in vivo. While only a modest tumor growth inhibition was observed when the HCC1954 human breast cancer xenografts were treated with"non-cleavable" linker ADCs, tumor regression was seen when treated with an enzymatically degradable "cleavable" linker ADC when conjugated to trastuzumab. Based on these studies, monomethyl auristatin PYE shows promise for use as an ADC payload.
- Subjects :
- Amides chemistry
Animals
Cell Line, Tumor
Humans
Immunoconjugates pharmacology
Mice
Protein Multimerization drug effects
Protein Structure, Quaternary
Tubulin chemistry
Xenograft Model Antitumor Assays
Aminobenzoates chemistry
Hydrophobic and Hydrophilic Interactions
Immunoconjugates chemistry
Oligopeptides chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4812
- Volume :
- 28
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Bioconjugate chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28060485
- Full Text :
- https://doi.org/10.1021/acs.bioconjchem.6b00530