In antibody–drug conjugate (ADC) development, the traditional mindset has long been: “the more potent, the better.” Cytotoxic payloads such as MMAE or Exatecan dominate the field, designed to be so powerful that just a handful of molecules per cell are enough to induce cell death.

When toxicity poses challenges, the common workaround has been simple: reduce the drug-to-antibody ratio (DAR).

But here’s the question: does an ADC payload always need to be cytotoxic?

The Case for Non-Cytotoxic Payloads

A growing movement is exploring non-cytotoxic payloads—molecules that modulate biological pathways instead of directly killing cells. This shift is not limited to oncology and is opening doors to new therapeutic strategies.

These ADCs come with several advantages:

• Easier to handle and safer in the lab

• Less expensive to develop

• Broader range of biological applications

Examples of Non-Cytotoxic Payloads

Some notable payload classes already under investigation include:

• Glucocorticoid receptor modulators (e.g., ABBV-3373) for chronic inflammation

• LXR agonists targeting lipid metabolism

• TLR/STING agonists to trigger immune responses in the tumor microenvironment

• PROTACs, oligonucleotides, and photosensitizers with novel mechanisms of action

And these are not just theoretical concepts. Several non-cytotoxic ADCs are already in clinical trials, including:

• ABBV-3373 and ABBV-154 for rheumatoid arthritis and polymyalgia rheumatica

• BDC-1001 in HER2+ and HER2-low breast cancer

Why Chemists Should Be Excited

For chemists, this trend offers practical and strategic advantages:

• ✔ Simpler laboratory setups (no isolators, fewer hazards) → lower synthesis costs

• ✔ Broader target space, extending far beyond oncology

• ✔ New mechanisms of action that allow for more innovative therapeutic strategies

In short: the future of ADCs may not be about stronger payloads, but smarter ones.

How SigutLabs Can Help

At SigutLabs, we support ADC innovation through the custom design and synthesis of payload-linker systems, including emerging non-cytotoxic scaffolds.

If you’re exploring non-cytotoxic ADCs or want to push beyond traditional cytotoxic payloads, we’d be excited to collaborate with you.

Contact us to start building the next generation of ADCs together.