At CPHI 2025, experts reported that innovations in linker chemistry are enabling more stable and selective ADCs and expanding payload options beyond traditional cytotoxics. Improved cleavage-site design and the use of non-natural amino acids enhance targeted payload release and fidelity. Companies such as Sutro and Lotte Biologics have reported regulatory filings and provisional patents for new linker approaches. Challenges include fragmented supply chains and geopolitical trade tensions, but speakers expect a wave of new ADCs and growing exploration of non-cytotoxic payloads.
Linker Breakthroughs at CPHI 2025 Unlock Greater Stability and New Payloads for ADCs
At CPHI 2025, experts reported that innovations in linker chemistry are enabling more stable and selective ADCs and expanding payload options beyond traditional cytotoxics. Improved cleavage-site design and the use of non-natural amino acids enhance targeted payload release and fidelity. Companies such as Sutro and Lotte Biologics have reported regulatory filings and provisional patents for new linker approaches. Challenges include fragmented supply chains and geopolitical trade tensions, but speakers expect a wave of new ADCs and growing exploration of non-cytotoxic payloads.
06:01 AM, 11/21/2025Health
At CPHI 2025 in Frankfurt, experts highlighted a wave of innovations in linker chemistry that are expanding the capabilities of antibody-drug conjugates (ADCs). By redesigning the molecular connectors between antibodies and their therapeutic payloads, developers are achieving improved stability, more precise payload release and the ability to carry novel drug types beyond traditional cytotoxics.
Advances in linker design
Panelists explained that modern linker engineering focuses on three key areas: selective cleavage, payload compatibility and overall conjugate stability. Improved cleavage-site designs allow enzymes or tumor-specific conditions to trigger drug release at the intended location and time, reducing off-target effects and systemic toxicity.
Venkatesh Srinivasan, CTO of Sutro Biopharma, described linkers that incorporate non-natural amino acids to achieve very high release fidelity within the tumor microenvironment. He also noted that conjugation stoichiometry can be tuned so a single antibody carries two distinct payloads, offering opportunities for combination mechanisms on one scaffold.
Kern Chang, PhD, CTO at Lotte Biologics, emphasized that many payloads are hydrophobic, which can destabilize ADCs. Lotte is developing hydrophilic linker chemistries to improve solubility and reduce aggregation; the company filed a provisional patent this year and plans further filings in 2026.
Challenges and development bottlenecks
Despite technical progress, panelists warned of supply-chain and development challenges. ADC manufacture involves multiple components—antibody, linker and payload—often produced by different suppliers and in different countries, complicating coordination and quality control. Panelists also cited recent US tariff measures and broader geopolitical tensions as additional obstacles for global biopharma supply chains.
"The linker has been neglected for years. Especially for first-generation ADCs, not many people really paid attention to linkers,"
Outlook
ADCs remain an emerging therapeutic class, with fewer than 20 approvals worldwide, but speakers predicted a new wave of oncologic ADCs as linker technology matures. Beyond cytotoxic payloads, developers are actively exploring non-cytotoxic options—such as steroidal and antibiotic payloads—which could broaden ADC applications into inflammatory disease and infectious disease settings.
Overall, advances in linker chemistry are positioning ADCs for greater functional diversity and improved clinical performance, provided industry players can align manufacturing, regulatory and commercial strategies.