January 2024: Antibody-Drug Conjugates - Emerging into 2024

Entering into the new year, the popularity of antibody-drug conjugates (ADCs) in the biopharma industry shows no signs of slowing down. In 2023, there were a record number of licensing partnerships in the ADC space, particularly Merck’s $22 billion deal with Daiichi Sankyo, Inc.

New deals this month:

• Jan 23: Celltrion Inc and WuXi XDC sign partnership deal. WuXi XDC will provide process development through manufacturing services to support Celltrion’s ADC and other bioconjugates pipeline.

• Jan 8: Johnson & Johnson acquires Ambrx for $2 billion. J&J will now handle ARX517, an ADC aimed to treat prostate cancer which showed success in early-stage trials.

• Jan 2: MediLink Therapeutics enters into collaboration and license agreement worth potentially $1 billion with Roche to develop YL211, an ADC targeting c-Met against solid tumors.

• Dec 26: LegoChem Biosciences inks $1.7 billion ADC deal with Janssen Inc. The license agreement is for LCB84, a Trop2-targeted ADC with the aim of treating solid tumors and shows promising preclinical data.

Similarly, the research space into ADCs is also growing. ADCs comprise of an antibody, payload (toxic pharmaceutical molecules with high efficiency), and linker connecting them both. Because of this structure, ADCs can be highly valuable targeted chemotherapeutic drugs by the specific recognition of target antigens and release of payloads to eliminate target cells.

Last week, a paper by Guo et al. developed a strategy for ADC discovery with highly efficient bystander-killing effects, through the use of rational optimization strategy based on a graph attention network (GAT)-driven scoring model. They then constructed novel ADCs with improved approaches to combating tumor heterogeneity.

The target antigen of ADCs are what lead the direction of their pharmacological properties. Currently, the majority of targets are specific proteins which are overexpressed in typical tumor cells, including HER2, TROP2, CD19, and CD22. Over 150 clinical trials for ADCs are underway.

While there are many successes, there are many more failures during development. This month, the failed HER2-directed ADC DHES0815A Phase I trial results published. Meanwhile, the HER2-directed ADC SHR-A1201 revealed positive results from the development and validation of its pharmacokinetics assays. Also last week, Gilead’s Trodelvy (Trop2-directed ADC) failed to meet its Phase III study endpoints. On the other hand, OBI Pharma’s OBI-992 (TROP2 ADC) was approved for an FDA  investigational new drug (IND) clearance to conduct a Phase 1/2 study.

In news for the future, ADCs have several more years to advance its development, including the design of new antibody delivery tools, formats like bispecific ADCs, linker developments, conjugation methods, and payload optimization.

Furthermore, Wang et al. described peptide-drug conjugates (PDCs) as the new paradigm for targeted cancer therapy. PDCs are made up of the cell-targeting peptide, linker, and cytotoxic payload. While they appear similar in concept, the structure and nature of PDCs and ADCs are very different. PDCs are much smaller and flexible, thus achieving stronger tumor penetration and less immunogenicity, in addition to being metabolized by the kidney instead of the liver.