Novel Dual-Payload ADC: A More Effective XDC Therapy
Antibody-drug conjugates (ADCs) are a class of drugs designed as a targeted therapy for treating disease [1], While ADCs have proven successful in both solid and hematological cancers, resistance and tumor heterogeneity are major causes of failure clinically[2]. This challenge has led to the exploration of Dual-Payload ADCs capable of delivering two mechanistically distinct payloads simultaneously. Co-delivery of small molecules can overcome resistance, generate additive or synergistic effects, and enhance therapeutic efficacy.
Two different construction strategies of Dual-Payload ADC
The most common strategy for dual-payload ADC synthesis has involved the installation of both payloads onto the same linker. Research has shown that MMAE and MMAF possess complementary physicochemical properties, The generated dual-payload ADC exhibits potent anti-tumor activity and can overcome tumor cell resistance by incorporating complementary payloads.
Figure 1.Multi -payload ADC conjugation process
In addition to coupling different payloads to the same linker, there is another conjugation approach, which involves attaching different payloads to distinct sites on the antibody[4], In preclinical studies, researchs have found that dual payload drug sexhibit enhanced tumor-killing capabilities and prolonged immune memory.
Figure 2. Dual PNU-159682/MMAF conjugation
Advantages of dual-payload ADCs
The research on dual payload ADCs shows high potential in the field of oncology treatment and may constitute growing fields in ADC research. Some of the advantages of dual payload ADCs include:
◆ Dual payload ADCs can flexibly adjust the drug-to-antibody ratio (DAR) based onthe treatment objective, enabling them to exhibit varying therapeutic effects.
◆ Dual payload ADCs are a promising class of drugs to address tumor heterogeneityand drug resistancet[2].
◆ Codelivery of multiple therapeutic agents with diferent anticancer mechanismscan overcome drug resistance as well as generate additive or synergisticanticancer effects that may enhance the antitumor efficacy[5].
References:
[1] Antibodies (Basel). 2021.10(4):42
[2] Nat Commun.2021.12(1):3528
[3] Angew Chem Int Ed Engl. 2017.56(3):733-737
[4] Antib Ther. 2019.2(4):71-78
[5] Bioorg Med Chem Lett. 2018. 28(23-24):3617-3621