# Site-specific conjugation & linker chemistry

Source: https://onco.cc/technologies/site-specific-conjugation/  
OnCo record `site-specific-conjugation` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Site-specific conjugation and linker chemistry decide exactly where and how many payloads attach to the antibody, which determines how safe and effective an ADC is.

## Summary

Random lysine or cysteine conjugation (T-DM1, brentuximab) gives heterogeneous mixtures. Engineered cysteines (THIOMAB), glycan remodelling (Synaffix GlycoConnect), enzymatic (sortase, transglutaminase), and non-natural amino acids (Ambrx, Sutro) yield homogeneous DAR. Hydrophilic linkers (Mersana Dolaflexin, Zymeworks ZD06519 platform, MediLink TMALIN) allow DAR 8 without aggregation; cleavable tetrapeptide GGFG (DXd) versus non-cleavable SMCC (T-DM1) governs bystander effect.

## Fields

- Kind: Technology
- Status: established
- Last checked: 2026-09-04
- Principle: Defined attachment sites and linker hydrophilicity control pharmacokinetics, aggregation, and payload release.
- Strengths: Homogeneous product, better PK; Enables high DAR and dual payloads
- Limitations: Manufacturing complexity

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Bioconjugation
- Wikipedia: https://en.wikipedia.org/wiki/Bioconjugation

## Connected records

- fronts: [Antibody-Drug Conjugates](https://onco.cc/fronts/adcs/), [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/)
- technologies: [ADC bioconjugation manufacturing (CDMOs)](https://onco.cc/technologies/adc-cdmo-manufacturing/), [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Antibody-oligonucleotide conjugates](https://onco.cc/technologies/antibody-oligonucleotide-conjugates/), [Dual-payload ADC](https://onco.cc/technologies/dual-payload-adc/), [The ADC supply chain (antibody, payload-linker, conjugation, fill)](https://onco.cc/technologies/adc-supply-chain/)
- companies: [Abzena](https://onco.cc/companies/abzena/), [Araris Biotech (Taiho)](https://onco.cc/companies/araris/), [Enlaza Therapeutics](https://onco.cc/companies/enlaza-therapeutics/), [Sutro Biopharma](https://onco.cc/companies/sutro-biopharma/), [Synaffix (Lonza)](https://onco.cc/companies/synaffix/), [Tubulis (Gilead)](https://onco.cc/companies/tubulis/)
- terms: [Drug-to-antibody ratio (DAR)](https://onco.cc/terms/dar/), [Linker (ADC)](https://onco.cc/terms/linker/)
- cancers: [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/)
- trials: [ACE-Breast-02](https://onco.cc/trials/ace-breast-02/), [ARX788 in HER2-positive, Metastatic Breast Cancer Subjects (ACE-Breast-03)](https://onco.cc/trials/nct04829604/)
- drugs: [ARX788](https://onco.cc/drugs/arx788/), [Luveltamab tazevibulin](https://onco.cc/drugs/luveltamab-tazevibulin/)
- roadmaps: [ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs](https://onco.cc/roadmaps/adc-generations/)
- ideas: [An open engineering platform for academic ADCs and bispecifics](https://onco.cc/ideas/idea-fund-academic-adc-bispecific-platform/), [Dual-payload ADCs in first line to prevent resistance](https://onco.cc/ideas/idea-dual-payload-first/), [Platform designation for ADC linker-payloads so manufacturing data carry across](https://onco.cc/ideas/idea-reg-adc-platform-designation/)

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