Toxicity & Efficacy in ADCs: How to Get it Right

Antibody-Drug Conjugates (ADCs) still face significant challenges related to patient tolerability and therapeutic window, and ADCs often fail to significantly reduce toxicity compared to traditional cytotoxic agents, highlighting the ongoing struggle to improve specificity and safety. 

Selective Targeting and Payload Design (‘Selectivity Squared’) 

Traditional ADC payloads typically fall into three main classes, each designed to disrupt cancer cell survival through distinct mechanisms. Microtubule inhibitors, such as MMAE and DM1, interfere with spindle formation in mitosis. Auristatins such as MMAE bind to the side of forming spindles causing kinks which results in improper alignment, whilst maytansinoids bind to the spindle terminus directly inhibiting its growth. Topoisomerase I inhibitors, including DXd and SN-38, inhibit the topo 1 enzyme which helps to regulate DNA under- and over-winding to remove knots and tangles from the genetic material, topo1 functions by creating single-stranded breaks in DNA which is key to cell regulation. Meanwhile, DNA-damaging/chelating agents—often highly potent—directly compromise DNA by binding into the minor groove and covalently bonding. 

A common trait with all the mechanisms employed by conventional ADC cytotoxic payload is that each is present in both healthy and disease state cells, thus limiting selectivity and substantially increasing the prevalence of systemic payload mediated toxicity.  

Increasing the therapeutic window may involve enhancing both the selectivity of the antibody and the specificity of the payload. Modifying linker chemistry and optimizing payload conjugation are crucial, as even minor changes can drastically affect the balance between efficacy and toxicity. This is where the concept of a biologic/ chemical bispecific molecule comes into play. The combination of a highly specific antibody with a targeted small molecule therapeutic can maximize targeted action, an approach we informally refer to as “selectivity squared”. Rather than relying solely on the antibody for specificity, we’re now integrating selectivity at multiple levels—the antibody, the small molecule payload, and even the linker. 

Multidisciplinary Approach to ADC Development 

Achieving this selectivity requires a multidisciplinary approach, bringing together chemistry, bioscience, DMPK, and both in vivo efficacy and ex vivo PK to understand how subtle changes can have a significant impact the overall therapeutic profile. We’re used to developing small molecules and we’re used to small changes having significant effects on PK and toxicity and overall therapeutic profile. 

It’s no different in this emerging ADC paradigm. Every single atom change, linker adjustment, or payload modification can dramatically shift an ADC from a highly selective therapeutic to an ineffective or less selective compound. By embracing a holistic perspective—one that sees ADCs as hybrid molecules rather than just targeted delivery vehicles—we can unlock new potential and rethink how selectivity is built from the ground up. 

Catch up on the previous parts in our ADC development blog series:

Part 1: Exploring new paths in ADC development

Part 2: What’s the Evolving Role of Medicinal Chemistry in ADC Development?

Part 3: Linker Technologies in ADCs: How They Impact Efficacy & Stability

About the Authors

Allan Jordan is Vice President Oncology Drug Discovery at Sygnature Discovery and Josh Greally is ADC Lead at Sygnature Discovery. Follow their ADC development series on YouTube to hear all their insights.