From bench to bedside: translating ADCs into the clinic

• Managing atypical toxicity profiles and response timelines to optimize dosing strategies for safety and efficacy 

• Selecting clinical endpoints aligned with new payload mechanisms to demonstrate value 

• Using biomarker-guided patient selection to improve trial outcomes and success rates 

• IND-ready analytical packages to expedite submission timelines 

• Ensuring scalability and scale-up readiness as conjugates advance to late-stage development 

• Bridging into GMP to meet regulatory standards for clinical trial materials 

• Leveraging imaging-based early endpoints for clinical trial acceleration

Linker design and payload innovation 

• Engineering hydrophilic polymers or PEGylated linkers to improve aggregation and clearance issues while improving circulation time 

• Developing extracellular or environment-responsive cleavable linkers to improve targeted payload release 

• Explore dual payload integration and their synergistic release profiles to achieve synergistic therapeutic effects 

• Incorporating PROTAC-based payloads for improved targeted protein degradation 

• Utilizing AI tools to predict linker aggregation and cleavage performance  

• Backbone engineering to fine-tune payload exposure 

• Investigating RNA payload conjugation for gene modulation and silencing 

Manufacturing strategies to move the bioconjugate field forward

• Controlling DAR variability in conjugation techniques to improve consistency

• Applying enzymatic conjugation methods to achieve uniformity and reduce heterogeneity 

• Incorporating hydrophobic masking strategies to reduce aggregation and improve stability

• Translating academic ‘ideas’ into scalable, robust manufacturing processes suitable for industry 

• Considering conjugated vaccine manufacturing to expand bioconjugate applications beyond oncology therapeutic

• Applying QbD principles and early regulatory engagement to streamline approvals for novel modalities

• Considering diagnostic bioconjugates alongside therapeutic modalities to support platform scalability

Tackling site-specificity in ADCs

• Implementing site-specific approaches to reduce DAR heterogeneity and improve conjugate predictability 

• Scaling enzymatic conjugation techniques without compromising precision to enable viability

  • Balancing chemical and enzymatic approaches to achieve both stability and targeted placement of payloads
    
    

• Using AI modeling to predict optimal conjugation sites and improve efficiency

• Validating conjugation sites functionally to confirm that modifications do not compromise activity 

• Predicting immunogenicity and clearance risks from conjugation location

• Standardizing protocols for cross-platform comparability and regulatory alignment

Building the ideal bioconjugate scaffold through antibody discovery and engineering 

• Engineering Fc regions for enhanced half-life and reduced immunogenicity 

• AI-driven epitope mapping for novel antibody scaffolds 

• Incorporation of engineered cysteine or unnatural amino acids for site-specific conjugation 

• Bi- and multi-specific antibody engineering to expand targeting breadth 

• Tailoring affinity and avidity to match payload characteristics 

• Leveraging phage display and synthetic libraries for antibody candidate discovery 

• Humanization strategies to broaden patient compatibility 
  

Enabling controlled and sustained release

• Balancing payload stability in circulation with rapid activation at the target site to optimize therapeutic windows 

• Advancing click-cleavable and redox-sensitive linker technologies for precision release 

• Designing dual-trigger mechanisms (e.g., pH and enzyme) for selective payload delivery to refine selectivity

• Assessing real-time in vitro and in vivo assays to model linker cleavage under physiological conditions 

  - Managing immunogenicity risks with cleavable vs non-cleavable linker designs

• Controlled release for chronic diseases requiring long-term, low-dose exposure 

• Exploring multimodal release platforms to achieve spatial and temporal control of payload delivery 

   

Beyond antibodies: the new frontiers of bioconjugation

• Enhancing intracellular delivery of oligonucleotides and peptides through innovative carries such as nanoparticles, fusogenic peptides, and cell-penetrating tags 

• Engineering backbone modifications (e.g., phosphorothioates) to stabilize oligonucleotides and reduce immune response 

• Reducing immunogenicity in oligos via sequence engineering and immune profiling 

• Developing peptide conjugates with improved stability via cyclization and stapling techniques 

• Designing modular linkers to enable flexible payload pairing across modalities 

• Addressing synthesis and purification complexity in mixed-modality conjugates 

• Creating targeted peptide-drug conjugates to achieve tissue-specific delivery with minimal toxicity 

Measuring what matters: analytics for bioconjugate characterization 

• Addressing inconsistent DAR and its PK/PD implications to assess efficacy 

• Integrating multi-attribute methods for comprehensive conjugate characterization 

• Pinpointing off-target conjugation with LC-MS mapping to improve safety profiles 

• Monitoring aggregation and degradation in real-time with SEC, light scattering, and LC-MS tools to ensure conjugate stability 

• Implementing cell-based potency assays to confirm functional consistency 

• Integrating radioconjugates as part of analytical workflows for functional readouts to explore diagnostics and theranostic opportunities 

Innovations in targeting and precision delivery 

• Navigating tumor heterogeneity and ensuring sufficient antigen expression across patient populations 

• Enhancing binding specificity to minimize off-target effects in healthy tissues 

• Leveraging AI/ML for antigen selection and target validation 

• Fine-tuning internalization kinetics to optimize payload release timing 

• Incorporating non-traditional moieties such as small molecule ligands or aptamers for intracellular targets 

• Utilizing targeted nanoparticles and modular conjugation systems for receptor-mediated endocytosis to broaden delivery options 

Overcoming ADC manufacturing bottlenecks

• Achieving batch-to-batch consistency in DAR to ensure reliable ADC performance
• Avoiding aggregation during conjugation and purification to maintain conjugate quality
• Addressing limitations of chromatography in large-scale manufacturing for improved scalability
• Managing supply chain fragility for payloads, linkers, and antibodies to ensure uninterrupted production
• Utilizing advanced bioassays for predictive quality and functional equivalence in early development 

Future directions in bioconjugation: designing next-generation therapies

• Expanding applications beyond oncology to include autoimmune, infectious, and neurological diseases
• Designing conditionally active constructs to minimize systemic exposure and enhance safety
• Developing bi- and multi-specific scaffolds to improve targeting breadth and therapeutic potential
• Creating long-circulating conjugates with reduced clearance for chronic conditions
• Establishing new regulatory endpoints tailored to non-oncology indications
• Incorporating companion diagnostics and theranostics to guide treatment and validate targets