The purpose is to conjugate a drug via its hydroxyl group to an antibody. Following linker cleavage, it is important for the linker to self-immolate in order to restore the drug to its original structure.
Hydroxyl groups are not very reactive and therefore are difficult to conjugate. Depending on your drug, you may derivatize it with succinic anhydride to get a carboxylic acid, which subsequently can be conjugated either directly with EDC or by conversion to an NHS ester. The succinic semi-ester should be not very stable in the long term and might release the drug.
@Alexander
Is the hydroxyl group on your drug compound aliphatic (alkyl), tautomeric (enol), or aromatic (phenoxy)? The type of hydroxyl will determine which self-immolating linker may be amenable in constructing your antibody-drug conjugate (ADC). A priori, three types of cleavable linker may be feasible: disulfide, para-amino-benzyl, β-glucuronide. Your hydroxyl-containing drugs may be attached by a carbonate or carbamate on one side of the linker, leaving the other side attachable to the antibody (typically as an NHS ester). Carbonates and carbmates can be formed using carbonyl diimidazole (CDI) or N,N′-Disuccinimidyl carbonate (DSC) as more convenient and "safer" alternatives to phosgene. Below are some publicly accessible reviews on ADC synthetic chemistry. Common linker structures are included to facilitate your retrosynthetic analysis. NOTE: The initiating mechanism of self-immolation is typically enzymatic (may require a specific built-in peptide sequence or substrate) or physiological (pH or redox state). Hope this information helps!
• Review: See Structures in Section 3 and cited references therein
"Linkers Having a Crucial Role in Antibody–Drug Conjugates" (Int J Mol Sci, 2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849017/
• Review: Copy made available by authors at Lonza corporation in Switzerland
"Antibody−Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies" (Bioconjug Chem, 2010)
http://bio.lonza.com/uploads/tx_mwaxmarketingmaterial/Lonza_ProductDataSheets_Antibody-Drug_Conjugates_Linking_Cytotoxic_Payloads_to_Monoclonal_Antibodies.pdf
• Research article: Copy made available on ResearchGate by corresponding authors at Seattle Genetics corporation & U Texas Southwestern Med Ctr:
Expanded Utility of the β-Glucuronide Linker: ADCs That Deliver Phenolic Cytotoxic Agents
https://www.researchgate.net/publication/244866147_Expanded_Utility_of_the_b-Glucuronide_Linker_ADCs_That_Deliver_Phenolic_Cytotoxic_Agents
Article Expanded Utility of the ??-Glucuronide Linker: ADCs That Del...
Hi Lael, thank you so much for your detailed response. To answer your question, the hydroxyl group is aliphatic. I will read through the papers you suggested and look into the CDI and DSC as drug conjugation options. Many thanks
@ Michael,
Vielen dank fuer Ihre Antwort! I have looked into the reactions you have mentioned and it looks like a good way of conjugating my drug. I am concerned though that making any changes could affect its activity. The challenge for me therefore is to find a self-immolating linker that could be conjugated to it. If I assume that the conversion of hydroxyl does not drastically change drug activity, are you aware of any self immolating linkers with a free amine that could be used in the EDC/NHS reaction? Noch mal vielen Dank fuer Ihre Zeit und Hilfe.
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