Antibody-drug conjugates (ADCs) are like “smart missiles” in cancer treatment. They combine a targeting antibody (which finds cancer cells) with a strong cancer-killing drug. But how do these two parts stay connected until they reach the tumor? The answer lies in ADC linkers—the tiny but crucial “bridges” that hold everything together. Let’s break down what ADC linkers do, their types, and why they matter.

What Do ADC Linkers Do?

ADC linkers have three main jobs:

1.Keep the drug attached during blood circulation to avoid harming healthy cells.

2.Release the drug only at the tumor, ensuring it works where needed.

3.Stay strong during manufacturing, storage, and travel in the bloodstream.

If the linker breaks too early, the drug might spill into the body, causing side effects. If it’s too stable, the drug won’t release properly at the tumor.

Two Types of ADC Linkers

Linkers fall into two categories d on how they release the drug:

1. Cleavable Linkers (Breakable)

These linkers “snap” under specific conditions inside or near cancer cells:

·Enzyme-sensitive: Broken by enzymes (like cathepsin B) inside cancer cells. Example: Valine-citrulline (VC) linkers.

·Acid-sensitive: Dissolve in the acidic environment of tumors (like vinegar-like conditions).

·Glutathione-sensitive: Cut by high levels of glutathione, a molecule abundant in cancer cells.

Why use them? They release drugs precisely and may create a “bystander effect”—where the drug leaks out and kills nearby cancer cells, even those not tagged by the antibody.

2. Non-Cleavable Linkers (Unbreakable)

These linkers stay intact until the entire ADC is broken down inside cancer cells.

Why use them? They’re ultra-stable, minimizing drug leaks into the bloodstream. However, they rely on the cancer cell fully digesting the ADC, which might not always happen.

The Bystander Effect: Helpful or Harmful?

The bystander effect can be both good and risky:

·Good: It kills mixed groups of cancer cells, even those hiding from the antibody.

·Risky: If the drug leaks too much, it might damage healthy tissues.

Recent studies show this effect depends on the drug and linker type. For example, small drugs (like MMAE) work better with cleavable linkers, while larger drugs may need non-cleavable ones for safety.

PEG Technology: Making Linkers Work Better

Linkers sometimes clump together or dissolve poorly. Scientists solve this by adding polyethylene glycol (PEG)—a “shield” that:

·Boosts solubility: Prevents clumping and helps linkers mix well in liquids.

·Extends lifespan: Keeps ADCs circulating longer in the blood.

FDA-approved ADCs like Trodelvy® (for breast cancer) and Zynlonta® (for lymphoma) use PEGylated linkers, proving their effectiveness.

What’s Next for ADC Linkers?

Researchers are working on smarter linkers, such as:

·Site-specific linkers: Attaching linkers to precise spots on antibodies for consistent performance.

·Dual-action linkers: Responding to both acidity and enzymes for better control.

·Non-toxic payloads: Linking drugs that boost immunity instead of just killing cells.