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Antibody–Drug Conjugates (ADCs): A Beginner-Friendly Deep Dive into Design, Linkers, Internalization, and Platform Strategy


Diagram of ADC drug delivery: antibody, linker, and cytotoxic payload attach to and penetrate cancer cell, releasing drug inside.

This long-form article is written for readers without prior ADC expertise who want to understand why antibody–drug conjugates have become one of the most important oncology drug platforms of the 2020s. Starting from first principles, it gradually builds toward engineering trade-offs and industry strategy.

Executive Summary


  • Antibody–drug conjugates (ADCs) are designed to deliver extremely potent drugs directly into cancer cells using antibodies as targeting vehicles.

  • ADC success depends not on a single component, but on system-level integration of antibody, linker, payload, and cellular internalization.

  • After years of trial and error, ADC technology matured rapidly after 2020 due to better conjugation chemistry, new payload classes, and strategic shifts by large pharmaceutical companies.

  • ADCs are no longer viewed as single drugs, but as scalable therapeutic platforms.



1. What Is an ADC — and Why Is It More Than “An Antibody Plus a Toxin”?


At first glance, ADCs sound deceptively simple:


Use an antibody as a GPS device to deliver a highly toxic drug specifically into cancer cells.

Traditional chemotherapy circulates throughout the body and damages any rapidly dividing cells, leading to well-known side effects. ADCs attempt to solve this problem by restricting highly potent drugs to tumor cells.

However, in practice, ADCs are not simple combinations. Many early ADC programs failed because developers underestimated what actually happens inside the body after injection.



2. The Three Fundamental Building Blocks of ADCs


Every ADC is composed of three core elements:


  1. Monoclonal antibody – identifies and binds a specific antigen on cancer cells

  2. Linker – the chemical bridge connecting the antibody and the drug

  3. Payload – the cytotoxic small-molecule drug that ultimately kills the cell


The key insight is that these components are not independent design choices. Decisions made for one component constrain the others.



3. Internalization: Why ADCs Must Enter the Cell



For ADCs, binding to the cell surface is only the beginning. If the ADC is not efficiently internalized, its payload may never be released.


A typical ADC pathway involves:


  1. Antigen binding on the cell surface

  2. Receptor-mediated endocytosis

  3. Trafficking through endosomes and lysosomes

  4. Linker cleavage or antibody degradation

  5. Payload release and cell death


This is why antigen internalization behavior is often more important than antigen expression level.



4. Linkers: The Most Underrated Engineering Challenge



Linkers solve a difficult spatiotemporal problem:

  • Remain stable in circulation

  • Release payload reliably inside cancer cells


Cleavable linkers


These exploit tumor-specific conditions such as acidic pH, proteases, or reducing environments. They can enable bystander effects, killing nearby cancer cells, but must be carefully engineered for stability.


Non-cleavable linkers


These require complete lysosomal degradation of the antibody before payload release. They are more stable systemically but limit bystander killing.



5. Payloads: From “More Toxic” to “More Functional”



Early ADCs relied heavily on microtubule inhibitors. While potent, they struggled in many solid tumors.


Newer payloads introduce:


  • Mechanistic diversity (e.g., topoisomerase I inhibitors)

  • Functional expansion (immune modulation, targeted protein degradation)

  • Linker–payload co-design influencing bystander effects


Payloads have become functional modules rather than simple toxins.



6. Drug-to-Antibody Ratio (DAR) and Conjugation Strategy



DAR determines how many payload molecules are attached to each antibody.

  • Too low: insufficient efficacy

  • Too high: aggregation, rapid clearance, toxicity


To improve consistency and scalability, the industry is shifting from random conjugation toward site-specific conjugation technologies.



7. Why ADCs Took Off After 2020



Three factors converged:

  1. Improved linker stability and conjugation control

  2. Clinical success of next-generation payloads in solid tumors

  3. Strategic movement by Big Pharma toward platform-based oncology assets

ADCs transitioned from high-risk experiments to mainstream development programs.



8. Next-Generation ADCs: Beyond Single Payloads



To address tumor heterogeneity and resistance, newer ADC formats include:

  • Dual-payload ADCs

  • Bispecific ADCs

  • Immune-activating ADCs (iADCs)

These designs signal a shift from delivery tools to systems-level therapies.



From Understanding ADCs to Making Better Decisions | LuTra Studio Consulting


For many teams, the hardest part of ADC development is not execution, but early-stage decision-making:

  • Is this target truly suitable for an ADC approach?

  • Are the linker, payload, and conjugation strategy aligned as a system?

  • Is the program a one-off asset or a scalable platform?


LuTra Studio works with biotech teams to integrate biology, chemistry, engineering, and strategy early—before costly structural mistakes are locked in.

If you are evaluating ADCs as a platform or want a second perspective on early design assumptions, we are happy to explore the conversation.



Selective References


  • Beck A. et al., Nature Reviews Drug Discovery – ADC evolution and perspectives

  • Lambert JM & Morris CQ, Advanced Therapy – foundational ADC concepts

  • Springer Review: Antibody–drug conjugates: current and future biopharmaceuticals

  • ADC Review (2024–2025) – next-generation ADC formats

  • FDA CDER – Approved ADC summaries

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