Peptide Linkers

Peptides linkers belong to enzymatically cleavable linkers which are gaining significant attention in ADC development due to superior plasma stability and release mechanism. With state-of-art equipments and advanced techniques, Creative Biolabs has established the platform of peptide-based linker technology for ADC generation. Peptide linkers have expected stability and provide better control of drug release.

Peptide linkers
Figure: Structure of brentuximab vedotin (Discov Med. 2010)

The scission of peptidic bonds relies on lysosomal proteolytic enzymes, which have very low activities in blood. So, peptidic bonds have excellent serum stability. And the action of lysosomal proteases in cytosol leads to drugs release. Early peptides linkers used in ADCs such as Gly-Phe-Leu-Gly and Ala-Leu-Ala-Leu have limitations that the drug release was relatively slow and the linkage with many cytotoxic drugs may lead to aggregation. For recent years, the most widely used peptide linkers are Val-Cit and Phe-Lys, which are optimized dipeptide-based linkers and can be cleaved by lysosomal extracts and purified human cathepsin B. Val-Cit (vc) has been utilized in several ADCs development especially for auristatin-based payloads, such as MMAE/MMAF. Auristatins are highly potent, totally synthetic, and stable and are amenable to chemical modification strategies allowing for linker attachment. In order to separate the drugs from the site of enzymatic cleavage, some self-immolative spacers are designed, such as bifunctional p-aminobenzyl alcohol group (PAB), avoiding influencing drug structure and cytotoxic activity. Including auristatins/auristatin family members, successfully cases for peptide linkers in antibody-drug conjugates are comprised of drugs such as doxorubicin, mitomycin C, camptothecin, tallysomycin. With more updated, several other ADCs containing peptide linkages are in clinical trials, such as Brentuximab vedotin, Glembatumumab vedotin, MDX-1203, SGN-75, PSMA-ADC (PSMA-ADC-1301), etc. Moreover Brentuximab vedotin has been launched with the trade name Adcetris.

Cleavable peptide linkers take advantage of the antibody-drug conjugate targeting mechanism which involves sequential binding of the antibody-drug conjugate to its cognate antigen on the surface of the target cancer cells, and internalization of the ADC-antigen complexes through the endosomal- lysosomal pathway. Creative Biolabs have successfully produced a series of peptide linkers, such as Fmoc-Gly3-Val-Cit-PAB, Fmoc-Phe-Lys(Trt)-PAB, Fmoc-Ala-Ala-Asn-PAB-PNP, Ala-Ala-Asn-PAB TFA salt, etc. Creative Biolabs also provides customized-design services for peptide linkers depending on the antibody, drug and tumor target, we will design and select the most suited linker evaluated based on efficacy and toxicity of an individual ADC construct with best quality in a highly productive and cost-effective way.

We are offering different strategies of linkers in ADC development:

Jan Anderl, et al. Linker Technologies for Antibody–Drug Conjugates. Antibody-Drug Conjugates, 2013:77-80.
Beck A, et al. The next generation of antibody-drug conjugates comes of age. Discov Med. 2010 Oct; 10(53):329-39.

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