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Cleavable Peptide Linkers for ADCs & PDCs

Protease-cleavable, pH-labile, disulfide (redox), photocleavable, and reagent-cleavable linker peptides—site-defined synthesis with QC & COA.

Build stable conjugates that release on cue. Engineer linker performance for circulation stability, intracellular release, and reproducible analytics.

Request a Quote Overview Linker types ADC/PDC literature
Overview Cleavable linker types ADC & PDC use cases Design guide Quote specs QC & deliverables FAQ Contact Recommended reading

Overview: Cleavable Peptide Linkers

What are cleavable peptide linkers?

Cleavable peptide linkers (also called cleavable linker peptides) are designed connectors between a targeting module (antibody or peptide) and a payload (drug, fluorophore, affinity tag). The linker is engineered to remain stable during synthesis, purification, and (when relevant) systemic circulation, then release the payload under a defined trigger—often after cellular internalization (lysosome), in an acidic compartment, under reducing conditions, via light, or by a specific reagent.

In antibody–drug conjugates (ADCs), protease-cleavable peptide linkers are frequently used to couple stability in plasma with intracellular release. In peptide–drug conjugates (PDCs), linker choice and placement must preserve peptide function while tuning release kinetics and solubility.

Protease-cleavable linkers pH-cleavable linkers Disulfide (redox) cleavage Photocleavable Site-defined conjugation 45+ Years of Expertise U.S. Facilities - Texas
Why choose Bio-Synthesis
  • Design-first quoting: match trigger (enzyme/pH/redox/photo) to your biology and payload.
  • Site-defined builds: N-terminus/C-terminus or defined side-chain handles (Lys/Cys).
  • Spacer tuning: PEG/spacer options to improve accessibility and solubility.
  • Fit-for-purpose QC: HPLC purity + LC-MS identity; optional cleavage verification.
What “cleavable” means in practice

Most projects define (1) trigger, (2) compartment, (3) cleavage rate window, and (4) whether traceless release is required.

  • Trigger: protease, pH, redox, light, or reagent
  • Compartment: lysosome, endosome, cytosol, tumor microenvironment, in vitro
  • Release: traceless vs small residual linker fragment (“scar”)

Related: Peptide Modifications, Click Chemistry Peptides, Isotope-Labeled Peptides. If your sequence is challenging, see difficult peptide synthesis.

Cleavable linker options we provide

Expand each category to see representative cleavable peptide linker motifs, common chemical groups, and best-fit use cases for ADCs and PDCs.

Protease-cleavable peptide linkers lysosomal / tumor proteases
Best fit: ADC Also used: PDC Lysosomal release

Enzyme-responsive peptide motifs engineered for systemic stability and intracellular cleavage (commonly in lysosomes). Spacer length and motif accessibility strongly influence cleavage rate.

  • Val–Cit (often used with self-immolative spacers)
  • Val–Ala
  • Gly–Phe–Leu–Gly (GFLG)
  • PLGLAG (MMP-responsive; tumor microenvironment)

Typical attachment handles: N-terminus, Lys (amine), or staged assembly via azide/alkyne.

pH-cleavable (acid-labile) linkers endosomal / lysosomal pH
Best fit: PDC Also used: ADC Acidic compartments

Chemically labile groups designed to cleave at mildly acidic pH while remaining more stable at physiological pH. Release-rate tuning is a primary design variable.

  • Hydrazone linkers
  • Acetal / ketal motifs
  • Cis-aconityl linkers

Typical attachment handles: N-terminus / Lys (amine) with post-SPPS conjugation when appropriate.

Redox-cleavable linkers disulfide-based
Best fit: PDC Cytosolic release Cys-selective

Disulfide linkers can be cleaved in reducing intracellular environments with elevated glutathione (GSH). Steric tuning (hindered vs unhindered disulfides) can modulate cleavage rate.

  • Disulfide (–S–S–) linkers
  • Hindered disulfides (slower cleavage; stability tuning)

Typical attachment handle: Cys (thiol) for controlled, site-defined conjugation.

Photocleavable linkers light-triggered release
Best fit: Tool compounds Arrays / surfaces Spatiotemporal control

Light-triggered cleavage enables precise spatial and temporal control over payload release. Light protection is recommended during synthesis, handling, and storage.

  • o-Nitrobenzyl derivatives
  • Coumarin-based photocleavable groups

Typical attachment handles: N-terminus / Lys (amine); wavelength and matrix effects should be specified.

Self-immolative spacer systems clean payload release
Best fit: ADC Traceless-leaning Payload-first design

Self-immolative spacers undergo spontaneous fragmentation after an initial trigger cleavage, helping release the active payload cleanly (often used downstream of protease-cleavable motifs).

  • PABC (para-aminobenzyl carbamate)
  • Peptide–PABC systems (e.g., Val–Cit–PABC architectures)

Useful when residual linker fragments may reduce payload activity or complicate analytics.

Reagent-cleavable / platform linkers capture-and-release workflows
Best fit: Screening Purification platforms Chemical cleavage

Linkers designed for controlled chemical cleavage during purification, screening, or analytical workflows. Best when a biological trigger is not required.

  • Base-labile motifs
  • Nucleophile-sensitive motifs
  • “Safety-catch” linkers (activated on demand)

Tell us your trigger reagent and compatibility constraints; we’ll propose an SPPS-compatible build.

Conjugation interfaces & payload compatibility

Common attachment handles we build
  • N-terminus / C-terminus for straightforward, robust architectures
  • Lys (amine) for controlled site-defined attachment (orthogonal protection supported)
  • Cys (thiol) for redox-cleavable designs and thiol-selective conjugation
  • Azide / alkyne for click-compatible staged assembly (e.g., CuAAC / SPAAC workflows)

If you have a specific antibody or payload handle (e.g., maleimide/NHS/DBCO), include it in your request—this accelerates feasibility.

Optional: cleavage verification. If you need proof-of-release, request LC–MS verification pre/post trigger (enzyme, pH, redox, light, or reagent) using application-aligned conditions.
Typical payload functional groups (examples)
Payload handle Best matched peptide handle Notes
Maleimide Cys (thiol) Site-defined conjugation; control free-thiol count to avoid heterogeneity.
NHS ester N-terminus / Lys (amine) Fast coupling; plan for selective protection if multiple amines present.
Azide / alkyne Alkyne / azide Click chemistry supports staged builds and complex architectures.
DBCO / BCN Azide SPAAC (copper-free) click for sensitive payloads/bioconjugates.
Carboxyl / amine Amine / carboxyl EDC/NHS-style approaches for certain workflows; discuss selectivity requirements.

Need a specific interface (e.g., aldehyde/oxime, hydrazide, sulfonyl fluoride)? Share your chemistry goal and we’ll propose a compatible build.

ADC & PDC use cases

ADCs: intracellular payload release

Design focus: plasma stability + lysosomal cleavage + clean payload release.

  • Protease-cleavable peptide linkers
  • Spacer engineering for enzyme access
  • Optional cleavage verification plan
PDCs: targeted delivery & tuning

Design focus: maintain peptide binding/uptake while optimizing PK, solubility, and release.

  • Site-defined conjugation (N/C/Lys/Cys)
  • PEG/spacer options for solubility
  • Redox or pH triggers when appropriate
Tool compounds & imaging

Design focus: trigger control, rapid release, and clean analytical readout.

  • Photocleavable or reagent-cleavable options
  • LC-MS-friendly architectures
  • Capture-and-release workflows

Design guide (fast decisions)

1) Choose trigger + compartment
  • Lysosome/protease: protease-cleavable peptide linker
  • Acidic endosome/lysosome: pH-cleavable linker
  • Reducing cytosol: disulfide (redox-cleavable) linker
  • On-demand: photocleavable linker
  • Workflow platform: reagent-cleavable linker
2) Choose attachment handle (site-defined)

These options align well with SPPS and controlled conjugation.

  • N-terminus / C-terminus: simplest for robust synthesis
  • Lys (amine): controlled site-specific attachment
  • Cys (thiol): ideal for disulfide/thiol-reactive conjugation
  • Azide/alkyne: click-compatible staged assembly

Tip: if cleavage is slow, accessibility is often the culprit—spacer length can fix it.

3) Define release outcome (traceless vs residual)

Clarify whether a residual linker fragment is acceptable. This single decision narrows chemistry options fast and reduces redesign cycles.

Requirement What it means Best when
Traceless Release produces the native payload (or native peptide) with minimal residual atoms from the linker. Activity depends on native structure; tight SAR; clean analytics required.
Residual OK Release leaves a small linker “scar” but meets performance and analytical goals. Broader chemistry options; faster development; many tool workflows.

Quote specifications (copy/paste)

For the fastest quote, send the items below. We’ll respond with feasibility notes, a recommended chemistry plan, QC options, and pricing.

Required
  • Sequence (antibody handle or peptide sequence) + any PTMs
  • Conjugation site (N/C/Lys/Cys/handle)
  • Trigger (enzyme, pH range, redox, light, reagent)
  • Payload functional group or structure
Recommended
  • Traceless vs residual release preference
  • Spacer/PEG preference (if any)
  • Purity target and quantity
  • Optional cleavage verification request (LC–MS pre/post trigger)

QC & typical deliverables

Standard QC
  • Analytical HPLC/UPLC purity profile
  • Identity confirmation (LC-MS when feasible)
  • Certificate of Analysis (COA)
Conjugation control
  • Site-defined attachment strategy (N/C/Lys/Cys/handle)
  • Optional spacer tuning for accessibility
  • Documentation aligned to your workflow
Optional add-ons

Project-dependent add-ons can be aligned to your regulatory and analytical context.

  • Cleavage verification by LC–MS
  • Aliquoting/formulation preferences
  • Stability/handling recommendations

FAQ

Which keyword should I target: “cleavable peptide linkers” or “cleavable linker peptides”?

Use cleavable peptide linkers as the primary keyword (title/H1) for ADC/PDC audiences, and include cleavable linker peptides as a secondary keyword in headings and FAQs.

How do protease-cleavable peptide linkers work in ADCs?

They’re designed to stay stable during circulation and then cleave after cellular uptake (often in lysosomes) to release the payload. Motif choice and spacer design strongly influence stability and cleavage rate.

Can you provide site-defined conjugates?

Yes. Site-defined builds are commonly done at the N-terminus/C-terminus or on defined side chains (Lys/Cys). Orthogonal handles (azide/alkyne) can also be used for staged assembly.

Can you verify cleavage performance?

Yes. We can support LC–MS verification pre/post trigger (enzyme, pH, redox, or light), depending on your workflow needs.

Do you support pH-cleavable and redox-cleavable systems?

Yes. We support pH-labile architectures (acidic endosome/lysosome) and disulfide-based redox-cleavable designs (reducing intracellular environments), subject to payload and sequence compatibility.

What information do you need to quote?

Sequence/handle + conjugation site, trigger and compartment, payload functional group, traceless vs residual preference, quantity/purity, and whether you want cleavage verification.

More FAQ'sAll FAQ's

Contact & quote request

For the fastest quote, send your sequence/handle, trigger, payload functional group, target release outcome (traceless vs residual), quantity/purity, and whether you want cleavage verification by LC–MS.

Fastest path
Request a Quote Copy quote specs

What happens next: Our technical team reviews your request and replies with a recommended linker architecture, synthesis/QC plan, and delivery options aligned to your ADC or PDC workflow.

Fast quote checklist
  • Sequence/handle + modifications (if any)
  • Conjugation site (N/C/Lys/Cys/handle)
  • Trigger + compartment (lysosome/endosome/cytosol/in vitro)
  • Payload functional group + release preference
  • Quantity/purity + any documentation requirements

Recommended reading (ADC & PDC linkers)

High-signal reviews on cleavable linker mechanisms, stability vs release trade-offs, and conjugate design for ADCs and PDCs.

  • Chemical Society Reviews (2019): Cleavable linkers in antibody–drug conjugates.
    Foundational review of cleavable linker technologies in ADCs.
    Publisher page (RSC)
  • Pharmaceutics (2022): Linkers—assurance for controlled delivery of antibody–drug conjugate.
    Classification of cleavable vs non-cleavable linkers; design considerations for stability and release.
    Full text (MDPI) • DOI: 10.3390/pharmaceutics14020396
  • ScienceDirect (2021): Antibody–drug conjugates—recent advances in linker chemistry.
    Review of chemical trigger mechanisms and attachment strategies affecting PK and efficacy.
    Article page
  • ScienceDirect (2023): Research advances in peptide–drug conjugates.
    PDC architecture and how cleavable linker choice drives release and performance.
    Article page
  • Frontiers in Pharmacology (2025): Trends in peptide drug conjugate R&D.
    Current PDC trends including linker choices and next-gen engineering approaches.
    Full text • DOI: 10.3389/fphar.2025.1553853
  • Bioengineering (2025): Peptide–drug conjugates as next-generation therapeutics.
    Broad PDC platform review including linker engineering and payload optimization.
    Full text (MDPI) • DOI: 10.3390/bioengineering12050481
  • Journal of Nanobiotechnology (2025): Current progress and remaining challenges of peptide–drug conjugates.
    Positions PDCs relative to ADCs; discusses linker stability and translational challenges.
    Full text (Springer) • DOI: 10.1186/s12951-025-03277-2
  • J. Med. Chem. (2024): Peptide–drug conjugates—an emerging direction for the next generation of bioconjugates.
    Medicinal chemistry perspective on PDCs including linker and conjugation architectures.
    Publisher page (ACS) • DOI: 10.1021/acs.jmedchem.3c01835
  • ScienceDirect (2025): Linkers for effective peptide–drug conjugates.
    Linker-focused PDC review; how linker choice affects PK and synthetic methods.
    Article page

Related: Peptide Modifications, Click Chemistry Peptides, Isotope-Labeled Peptides.

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