ADC Linker-Payload Design & Optimization

Home ServicesADC & Bioconjugate DesignADC Linker-Payload Design & Optimization

Overview

An antibody–drug conjugate is a system, and its therapeutic index is set by how its parts interact rather than by any one of them. We model that system: conjugation site selection and its effect on stability and homogeneity, cleavable versus non-cleavable linker choice against the target biology, payload hydrophobicity and its consequences for aggregation and clearance, drug-to-antibody ratio distribution, and the bystander behaviour that follows from payload permeability. The result is a reasoned design space rather than a single proposed construct.

Schematic: conjugation site, linker chemistry and payload are modelled as one system, because the therapeutic index comes from how they interact.

Key Advantages

Conjugation Sites Assessed Structurally

Candidate sites are evaluated for solvent accessibility, local stability, proximity to the antigen-binding site and effect on Fc function, which site-specific conjugation makes a genuine design decision.

Linker Chemistry Matched To Biology

Protease-cleavable, acid-labile, glutathione-sensitive and non-cleavable options are compared against target internalisation, trafficking and the intended bystander behaviour.

Hydrophobicity Managed Explicitly

Payload and linker hydrophobicity drive aggregation and accelerate clearance; we predict the effect across DAR values and identify hydrophilic mitigations such as PEG or sulfonate spacers.

DAR Distribution Considered

Average DAR hides a distribution, and the high-DAR species disproportionately affect clearance and tolerability. Designs address the distribution rather than the mean alone.

Where This Service Is Used

Selecting linker and payload combinations for a new ADC programme

Choosing and engineering conjugation sites for site-specific conjugation

Diagnosing aggregation, instability or rapid clearance in an existing conjugate

Assessing whether bystander killing is achievable and desirable for a given target

Comparing candidate designs before committing to conjugation chemistry development

Methods and Techniques Applied

Antibody structural modelling with surface accessibility and local stability analysis at candidate sites

Conjugation site assessment including effects on antigen binding, Fc function and thermal stability

Linker and payload property modelling: hydrophobicity, stability, release chemistry and predicted kinetics

Aggregation propensity prediction across the DAR range with hydrophilic mitigation design

Payload permeability modelling to assess bystander potential

Comparative assessment of candidate designs against the target biology and the therapeutic objective

What We Need From You

Antibody sequence and, where available, structure or format details

Target biology: expression level, internalisation rate, trafficking behaviour, tumour heterogeneity

Payload class and mechanism, with any existing conjugate data

Conjugation chemistry available to you and the intended DAR range

What You Receive

Ranked conjugation site recommendations with structural rationale per site

Linker and payload combination assessment against the target biology

Predicted stability, aggregation and hydrophobicity profiles across the DAR range

Bystander effect assessment with the payload properties that drive it

Design comparison table with the trade-offs stated for each candidate construct

What We Compute and Report

Solvent accessibility, local stability and functional proximity for every candidate conjugation site

Predicted aggregation propensity across the drug-to-antibody ratio range

Hydrophobicity metrics for each linker-payload combination assessed

Payload permeability estimate, which governs whether bystander activity is achievable

Comparative ranking of candidate designs with the trade-offs stated explicitly

Interpretation and Limitations

Computational predictions prioritise hypotheses; they do not independently establish binding, biological activity, therapeutic efficacy, safety or clinical validity. Performance depends on input quality, target class, the structural evidence available and the applicability domain of the selected methods. Scores used for ranking are comparative devices and should not be read as measured quantities. All deliverables are for research use only and are not intended for diagnostic or therapeutic use.

Specifications

Item	Specification	Notes
Designs compared	5–30 combinations	Across sites, linkers and payload classes
Typical turnaround	4–8 weeks	Including structural modelling and simulation
Conjugation	Stochastic and site-specific	Cysteine, lysine, glycan and engineered sites
Output	Models, tables, report	With site-level structural analysis

Service Workflow

Step 01

Scientific Consultation

We discuss the objective, the decision it supports and the data you hold. Nothing is quoted before we understand what the result has to answer.

Step 02

Feasibility Review

We check that the data, target class and available structural evidence can support the proposed approach, and say plainly where they cannot.

Step 03

Technical Proposal

Scope, methods, deliverables, timeline and price are confirmed in writing, together with the limitations we expect to report.

Step 04

Computation and QC

The analysis runs on pinned tool versions in a containerised environment, with quality checkpoints and method comparison where that is informative.

Step 05

Report and Follow-Up

You receive the ranked results, the documented methods, the limitations and a proposed validation plan, plus support in interpreting them.

Is This the Right Service for You?

Choose this service when

Conjugation chemistry must be chosen before development resources are committed

An existing conjugate aggregates, clears too fast or is heterogeneous

Site-specific conjugation is being adopted in place of stochastic chemistry

Consider another service when

The carrier is a peptide rather than an antibody

Peptide-Drug Conjugate Design

The antibody itself still needs engineering

Full-Length IgG Antibody Design

What Goes Wrong, and How We Handle It

The failure modes that produce confident-looking results which do not survive the next experiment. Each one is designed against rather than discovered afterwards.

Accessibility, local stability, proximity to the paratope and effect on Fc function are assessed for every candidate site.

Case Studies

The situation

The conjugate aggregated above DAR 4 and cleared far faster than the naked antibody.

What the work involved

The conjugated model was analysed for surface hydrophobic patches, hydrophobicity was accounted across the DAR distribution, and alternative sites away from the implicated region were compared.

What came back

Two of the stochastically modified lysines sat inside an existing hydrophobic patch. Site-specific alternatives were ranked, with a hydrophilic spacer option quantified for its predicted effect.

Illustrative of the shape this work takes. Details are generalised, no client or target is identified, and scope and outcome vary with the system in question.

Questions We Are Asked Before Scoping

Note: ICDMO delivers computational (in silico) services. Results prioritise hypotheses for testing; they do not by themselves establish binding, biological activity, efficacy or safety. All deliverables are for research use only and are not intended for diagnostic or therapeutic use. Downstream experimental work is scoped separately and executed through qualified partners.

Get in Touch
about ADC Linker-Payload Design & Optimization

Tell us about the target, the data you hold and the decision the result needs to support. A scientist reviews every enquiry and replies within one business day.

Feasibility reviewed before any scope or price is fixed

Methods, parameters, confidence and limitations in every report

Confidentiality agreement available before data is shared