Antibody-drug conjugates (ADCs) represent a transformative class of cancer therapeutics that combine the high specificity of monoclonal antibodies with the potent cytotoxicity of chemotherapeutic agents. This dual-function design enables targeted drug delivery to tumor cells while minimizing damage to healthy tissue. Despite the clinical success of several FDA-approved ADCs, challenges such as tumor heterogeneity, acquired resistance, and dose-limiting toxicities remain. These issues underscore the need for next-generation ADC platforms that offer improved selectivity, broader efficacy, and better safety profiles. Recent innovations – including protein degrader-based conjugates (DACs), bispecific ADCs, conditionally activated probodies, immune-stimulating antibody conjugates (ISACs) and dual-drug ADCs – have emerged to address these limitations. This article highlights several of these next-generation formats and key design strategies.
1. Protein-Degrader ADCs (DACs)
In DACs, the traditional cytotoxic payload is displaced by a proteolysis-targeting chimera (PROTAC). PROTACs are bifunctional molecules that recruit an E3 ubiquitin ligase to selectively degrade disease-related proteins. This design is capable of targeting “undruggable” cancer proteins. Key targets such as BRD4 and GSPT1 have demonstrated promising results in preclinical and early clinical studies, with DACs like ORM-5029 and ORM-6151 (Orum Therapeutics) achieving potent antitumor activity. Beyond BRD4, DACs have also been explored against a wide range of intracellular targets including Erα, TGFβR2, SMARCA2 and GSPT1. Meanwhile, antibody-directed modalities such as AbTACs, PROTABs and LYTACs have expanded the degradable target landscape to include cell-surface proteins like PD-L1 and HER2. Despite their potential, DACs require careful optimization of drug-to-antibody ratio (DAR), hydrophobicity, and linker stability to ensure safe and effective clinical application. Innovations in linker chemistry and degrader structure will be crucial to fully realize the clinical potential of these next-generation ADCs.
2. Immune-Stimulating ADCs (ISACs)
Immune-Stimulating ADCs (ISACs) are a novel class of ADCs that incorporate immune-stimulatory payloads such as toll-like receptor (TLR) or STING agonists, instead of traditional cytotoxic drugs to activate innate immune responses within the tumor microenvironment. By selectively delivering these immune-stimulatory molecules to tumors, ISACs aim to stimulate antigen-presenting cells (APCs), enhance T and NK cell activation, and establish immunological memory, thereby offering durable antitumor responses. Among TLR-based ISACs, agents like BDC-1001 (Bolt Biotherapeutics) showed encouraging early clinical results with a favorable safety profile. STING-based ISACs, for example, XMT-2056 (Mersana Therapeutics), have shown potent preclinical activity and synergy with other immunotherapies. While ISACs offer a promising immunotherapy with the potential to overcome resistance and provide long-lasting tumor control, their clinical development requires careful management of safety concerns, particularly related to immune overstimulation and anti-drug antibody (ADA) formation. Continued optimization of payload potency, conjugation strategies and patient selection will be essential to fully realize the therapeutic potential of this emerging ADC format.
3. Bispecific ADCs
Tumor heterogeneity and the emergence of resistance often limit the effectiveness of conventional ADCs targeting a single antigen. To solve this problem, bispecific ADCs have been developed to simultaneously recognize two distinct epitopes or two separate antigens. This dual-targeting strategy aims to enhance tumor specificity, broaden the range of targetable cancer cells and improve intracellular payload delivery. Biparatopic ADCs, which bind to different epitopes of the same antigen, can promote receptor clustering and accelerate internalization and lysosomal trafficking. Notable examples in clinical trials include MEDI4276 (AstraZeneca) and ZW49 (Zymeworks/BeiGene). Dual-antigen bispecific ADCs further expand the therapeutic potential by engaging two different tumor-associated antigens. This design can effectively target heterogeneous tumor populations and may reduce off-tumor toxicity by requiring co-expression of both antigens. Promising examples include AZD9592 (AstraZeneca) and M1231 (Merck). Despite promising clinical progress, bispecific ADCs pose unique challenges such as potential agonistic activity, complex pharmacokinetics and variability in target antigen co-expression among patients. Therefore, careful epitope selection, affinity tuning and deep understanding of tumor biology are essential to maximize the therapeutic index of this promising ADC format.
4. Probody Drug Conjugates (PDCs)
Probody-drug conjugates (PDCs) are a novel class of ADCs that incorporate conditionally active antibodies. This design is to reduce on-target off-tumor toxicity by restricting antibody binding to the tumor microenvironment (TME). This concept is analogous to prodrugs, where activation occurs only under specific biological conditions. To date, there are two types of mechanisms of activation. The first type is protease-sensitive masking domains, such as CX-2029 (CytomX/AbbVie), which utilized cleavable peptide spacers that are degraded by tumor-associated enzymes, thereby unmasking the antibody and enabling selective payload delivery. The second strategy relies on pH-responsive antigen-binding domains, where conformational changes triggered by the acidic TME restore antibody binding, such as HTI-1151 (Halozyme). While PDCs offer a compelling strategy for targeting antigens with broad normal tissue expression, their development requires careful optimization of masking domains and an in-depth understanding of the TME to ensure precise activation and therapeutic efficacy.
5. Dual-drug ADCs
Dual-drug ADCs are an innovative format designed to overcome tumor heterogeneity and acquired drug resistance by delivering two distinct cytotoxic agents within a single antibody framework. By combining payloads with complementary mechanisms of action, dual-drug ADCs aim to improve therapeutic efficacy, broaden tumor coverage, and minimize the emergence of resistant subclones. Recent advances in conjugation techniques, such as using branched linkers and precise enzyme-based attachment, have made it possible to create dual-drug ADCs that are uniform in structure and carry precisely-defined drug to antibody ratios (DARs) of each drug. One representative example is an anti-CD30 ADC that delivers both MMAE and MMAF, which was particularly effective in drug-resistant lymphoma models. Similarly, dual-drug ADCs targeting HER2 demonstrated superior antitumor activity in HER2-low, drug-resistant breast cancer models compared to single-drug ADCs and 1:1 ADC cocktails. While some dual-drug ADCs employing dissimilar payload classes – such as DNA-damaging agents or immune stimulants-have shown synergistic activity and even induced immunological memory, others failed to achieve enhanced efficacy, underscoring the importance of rational payload selection, potency balancing and optimized DARs. Overall, dual-drug ADCs offer a promising strategy for treating heterogeneous or refractory tumors, but further refinement in design and patient stratification will be key to maximizing their clinical potential.
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