Antibody-drug conjugates (ADCs) have become an important treatment method in the field of oncology, offering superior clinical characteristics compared to chemotherapy. However, the application of ADCs still faces two significant challenges. First, there are very few validated payloads with proven mechanisms of action (MoA), which limits the expansion of indications. Approved ADC payloads cover three types of cytotoxic MoA, including anti-mitotic, DNA alkylation, and topoisomerase I inhibition. These payloads are traditional chemotherapeutic drugs and lack tumor targeting; thus, they typically require the aid of specific target antigens that are overexpressed in tumors, such as HER2, CD20, and BCMA, to ensure that the payload is delivered adequately and safely. Secondly, the delivery of payloads is non-specific and insufficient, narrowing the therapeutic window of ADCs. The delivery components of approved ADCs are generally cleavable peptide linkers that are randomly conjugated to monoclonal antibodies through a cysteine reduction reaction, which may lead to the problem of early payload release. Additionally, the large molecular weight of antibodies also contributes to poor tumor permeability of ADCs, and an unstable drug-to-antibody ratio can affect the efficacy of ADCs. The Nature subsidiary, Nature Reviews Drug Discovery, published an article discussing the impact of next-generation ADC technologies on these challenges. The authors evaluated the potential for expanding indications or widening therapeutic windows based on innovations across five dimensions of the ADC clinical pipeline, including targets, payload MoA, antibodies, linkers, and conjugation methods.
Clinical Pipeline Assessment
Based on the potential to overcome the above two challenges, developing ADCs can be divided into two main categories. The first category uses new targets and/or new payload MoAs, possessing first-in-class potential. The second category utilizes combinations of known targets and payload MoAs but innovates delivery components to achieve best-in-class status. The patritumab deruxtecan developed by Daiichi Sankyo targets the new target HER3, belonging to the first category. Recent data from the Phase II HERTHENA-LungO1 study show that the overall response rate (ORR) for patients with EGFR mutations who previously received EGFR inhibitors and platinum-based chemotherapy is 30%, compared to an estimated real-world ORR of only 14% in similar patient populations. Merck and Kura Oncology’s SKB264 belongs to the second category, with the same target and payload MoA as the approved ADC, trastuzumab (Herceptin; Genentech). The differentiated 2-methylsulfonyl pyrimidine linker of SKB264 improves circulating stability compared to trastuzumab. A Phase II study conducted in treated metastatic triple-negative breast cancer reported an ORR of 40% for SKB264, with a ≥ grade 3 adverse event (AE) occurrence rate of 56%. This is superior to the reported 21% ORR and 74% AE rate for trastuzumab in similar patient populations. Among the 168 ADCs in clinical development, approximately 85% target solid tumor indications, with breast cancer and lung cancer being the most common. Of the ADCs in Phase III clinical stages, about 60% are second-category pipelines that use known targets and payload MoAs but have improved delivery components, which may indicate that second-category ADCs are more likely to achieve success in the near term and have a lower risk tolerance in later development stages. The biological risks are greater in early development stages, with about 75% of ADCs in Phase I/II clinical trials being first-category pipelines with new targets and new payload mechanism combinations. Figure 1 shows the components used in ADCs under development, with the most concentrated being components validated in approved drugs, while innovative components show a more scattered characteristic.
Figure 1. Assessment of ADCs in clinical development: Innovations across various dimensions in clinical R&D. The top 10 targets and technologies for each dimension are displayed. Ab, antibody; ADC, antibody-drug conjugate; IgG, immunoglobulin.
Next Generation Target Assessment
Biological targets are a major area of innovation for ADCs, with 61 unique targets currently in clinical research. Overall, approximately 90% of the targets are antigens that are highly expressed on the surface of tumor cells, while about 10% of the targets are associated with unique characteristics of the tumor microenvironment. For example, Pyxis Oncology’s PYX-201 targets fibronectin, an extracellular protein highly secreted by cancer-associated fibroblasts. ADCs targeting stromal components may be effective against tumors with a high stromal-tumor ratio (such as breast cancer and prostate cancer) and may eliminate the evolution of resistance due to the genetic stability of stromal cells.
Next Generation Technology Assessment
The authors categorized next-generation technologies and assessed their characteristics compared to marketed ADCs. Figure 2 shows some technologies that may be innovative and/or have promising preclinical and clinical data. 
Figure 2. Evaluation of next-generation ADC technologies: Assessing the potential of next-generation ADC components to expand the applicability of ADCs or optimize delivery components. New biological targets are not considered a technology and are therefore excluded from the assessment. ADC, antibody-drug conjugate.
Next Generation Payloads
Small molecule degraders represent a promising class of payloads due to their high specificity, picomolar potency, and ability to target various tumor-associated intracellular proteins. ORM-5029 from Orum Therapeutics is an ADC targeting HER2/HER3, using a GSPT1 degrader as the payload. GSPT1 is a GTPase overexpressed in various tumors (including gastric cancer, colorectal cancer, and breast cancer). In preclinical breast cancer models, ORM-5029 reported anticancer activity similar to that of trastuzumab.
Next Generation Linkers
By engineering antibodies to alter their affinity for antigen binding, ADC toxicity to non-target tissues can be reduced, and tumor-specific exposure can be increased. Strategies include using peptide masks that are easily cleaved by proteases overexpressed in tumors to shield the Fab domain of antibodies (Fab is the antigen recognition region of the antibody), and engineering modifications to antibodies so that their affinity for antigens changes with variations in pH levels in the microenvironment. Antibody engineering has the potential to expand the therapeutic window of ADCs and treat patients with lower levels of therapeutic target expression. For example, MYTX-011 developed by Mythic Therapeutics is a c-Met-ADC that has a higher antigen affinity at neutral or mildly acidic pH levels representative of the tumor microenvironment, but lower antigen affinity in acidic endosomal pH environments, leading to rapid separation of the payload from c-Met. In preclinical studies, this therapy showed increased internalization, cytotoxic activity, and efficacy against tumor animal models expressing c-Met compared to unengineered antibodies and clinical c-Met-ADCs.
Next Generation Conjugation
Incorporating non-natural amino acids into antibody carriers facilitates site-specific conjugation through oxime bonds. ARX788 from Ambrx is a HER2-ADC that features an irreducible PEG linker conjugated to a non-natural amino acid in a site-specific manner. Phase I data indicate that ARX788 exhibits anticancer activity and improves serum stability compared to approved HER2-ADCs. Reducing early payload release may increase the amount delivered to tumor cells, driving higher response rates.
Conclusion
As ADCs evolve and new technologies emerge, companies must effectively evaluate emerging platforms, determine investment strategies to maximize expertise and capabilities, and decide whether the path of “first-in-class” or “best-in-class” is more attractive. A “one-size-fits-all” technology is unlikely to emerge in the short term, and it is expected that companies will build various component collections to achieve targeted, specific indications through “plug-and-play” development.
Flynn P, Suryaprakash S, Grossman D, Panier V, Wu J. The antibody-drug conjugate landscape. Nat Rev Drug Discov. 2024 Apr 16. doi: 10.1038/d41573-024-00064-w. Epub ahead of print. PMID: 38627573.
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