Antibody-drug conjugates (ADCs) continue to gain traction as a cornerstone of targeted oncology, offering the ability to selectively deliver potent cytotoxins to tumor cells while sparing healthy tissue. Recent advancements have focused on optimizing each ADC component—antibody, linker, and payload—to expand therapeutic windows, enhance efficacy, and address resistance mechanisms.

Precision Conjugation: From Heterogeneity to Homogeneity

Traditional conjugation approaches often led to heterogeneous drug-to-antibody ratios (DAR), impacting both safety and efficacy. Modern site-specific conjugation techniques now allow for precise payload attachment at defined sites on the antibody backbone. Strategies such as cysteine re-bridging, engineered lysine tagging, and enzymatic ligation have resulted in ADCs with improved pharmacokinetic profiles, lower immunogenicity, and enhanced manufacturability.

Expanding the Payload Toolbox

The field is moving beyond traditional microtubule inhibitors like auristatins and maytansinoids. New payload classes are addressing resistance and expanding ADC utility:

• DNA-damaging agents, such as pyrrolobenzodiazepines (PBDs), introduce irreversible DNA cross-links with high potency and sustained efficacy (source).
• RNA polymerase II inhibitors, particularly amanitin derivatives, are demonstrating potential in tumors that are resistant to conventional therapies (source).
• Microtubule destabilizers like tubulysins and eribulin offer alternative mechanisms for mitotic arrest with favorable efficacy profiles (source).

Smart Linkers for Controlled Release

The linker plays a crucial role in determining ADC safety and efficacy. Innovations in cleavable linkers—triggered by intracellular pH shifts or lysosomal proteases—enable selective drug release within cancer cells. Non-cleavable linkers, which release payloads through complete proteolytic degradation of the antibody, have also shown promise for their stability in circulation (overview).

Clinical Pipeline Highlights

Several next-gen ADCs are showing promise in late-stage clinical development:

• Datopotamab Deruxtecan (Dato-DXd), developed by AstraZeneca and Daiichi Sankyo, targets TROP2 but fell short in overall survival in late-stage breast cancer. However, it succeeded in delaying disease progression, a key secondary endpoint.
• Patritumab Deruxtecan has demonstrated extended progression-free survival in patients with EGFR-mutated non-small cell lung cancer (NSCLC) who previously failed TKIs.
• ZL-1310, Zai Lab’s novel ADC, delivered a remarkable 74% response rate in patients with small cell lung cancer, representing a breakthrough in an area with limited treatment options.

Industry Strategy and Expansion

The competitive landscape is driving strategic deals and diversification:

• AstraZeneca’s acquisition of EsoBiotec for up to $1 billion underscores its focus on next-gen cell and ADC platforms.
• AbbVie’s acquisition of ImmunoGen has bolstered its ADC pipeline, including Teliso-V, aimed at multiple solid tumors.
• Emerging players are also pushing boundaries, including ADCs with immune-modulating payloads and those designed for non-oncology indications.

The Road Ahead

The evolution of ADCs is poised to accelerate, driven by integrated approaches across discovery, development, and manufacturing. Precision engineering of antibodies, exploration of novel cytotoxins, and smarter linker technologies are enabling a new wave of ADCs with broader therapeutic indices and expanded indications. There’s also increasing interest in bispecific ADCs, ADCs for autoimmune diseases, and combinations with immunotherapies.

As the field moves forward, partnerships, regulatory guidance, and robust translational strategies will be essential to unlock the full clinical potential of ADCs.