The development trends of the next generation of ADC (antibody-drug conjugate) drugs can be observed to show improved specificity and cytotoxicity compared to earlier generations, driven by technological advancements. However, it’s important to note that there are still challenges in the development of ADC drugs. Below, we will summarize the trends in the development of the next generation of ADC drugs:
Trend 1: Targeting Mutated Proteins with ADCs
Current research indicates that the internalization and intracellular transport pathways have a crucial impact on the cytotoxic activity of ADCs. Mutated proteins, as compared to wild-type proteins, often exhibit higher levels of ubiquitination, making them more prone to internalization and degradation. This suggests that using ADCs targeting mutated proteins could lead to significant clinical responses. For instance, ADCs targeting oncogenic mutant proteins (such as certain EGFR mutants) could maximize tumor specificity, approaching the selectivity of targeted kinase inhibitors.
Trend 2: Dual-Site or Dual-Target ADCs
Advancements in bispecific antibody technologies have opened up new possibilities for ADC innovation. These ADC designs can improve antibody internalization and enhance tumor specificity. Therapies currently in development are exploring these possibilities. Dual-specificity ADCs targeting different epitopes of the same antigen can improve receptor clustering and facilitate rapid target internalization. Additionally, dual-specificity ADCs targeting both HER2 and LAMP-3 have demonstrated better lysosomal aggregation and payload delivery in preclinical experiments.
Trend 3: Dual-Payload ADCs Using Two Different Cytotoxins to Reduce Resistance
By precisely controlling the ratio of two drugs, delivering two synergistic payloads to cancer cells can achieve greater therapeutic efficacy. Furthermore, the occurrence of resistance can be significantly reduced with the application of two payloads with different mechanisms of action. For example, a homogeneous anti-HER2 ADC containing both MMAE and MMAF was designed and showed significantly greater anti-tumor activity in xenograft mouse models compared to the co-administration of respective single-payload ADCs.
Trend 4: Peptide-Drug Conjugates (PDCs)
Another ADC development strategy involves departing from the traditional mAb structure and coupling the payload with smaller molecular weight peptide fragments. The primary goal of these strategies is to reduce the molecular weight of ADCs, thereby enhancing penetration efficiency and payload delivery to tumor tissues. For instance, PEN-221 is an ADC composed of DM-1 conjugated to a peptide chain targeting somatostatin receptor 2. Its molecular weight is only 2 kDa, far lower than the 150 kDa of traditional IgG molecules in ADCs. Currently, these types of ADCs face technical challenges related to potential rapid clearance in the bloodstream. However, if this hurdle can be overcome, they hold great potential for treating hard-to-reach tumors, including tumors with poor vascularization and central nervous system tumors.
Trend 5: Developing Non-internalizing ADCs
Traditionally, ADCs required antibodies with high internalization capabilities to deliver the payload into cancer cells. However, due to the antigen barrier, mAbs often struggle to diffuse into solid tumor masses. Therefore, non-internalizing antibodies can be developed for ADCs. The principle is that, under reducing conditions, the payload is directly released into the tumor microenvironment and then diffuses into cancer cells, leading to cell death.