Antibody-drug conjugate (ADC) as a targeted drug delivery platform has been studied and clinically translated due to its enhanced efficacy and reduced off-target toxicity. However, the potential of ADC still suffers from tedious linker-payload optimization and limited drug-to-antibody ratio. Thus, we developed antibody-nanogel conjugate (ANC) platform utilizing polymeric nanoparticles with chemical tunability to address these concerns, enabling a broader range of therapeutic choices.
First, we focus on optimizing the antibody-nanogel conjugation chemistry to reduce formulation time and improve therapeutic effects. Using an inverse electron-demand Diels-Alder reaction (iEDDA), we reduced the formulation time from four to two days compared to the traditional strain-promoted azide-alkyne click chemistry (SPAAC). We also demonstrate that site-specific disulfide modification minimally affects the efficacy compared to the traditional lysine modification. Meanwhile, the antibody surface density greatly impacts the cell specificity. With our design guidelines, we obtained ANCs with potent and selective anti-cancer outcomes.
The ANC platform is further expanded to be investigated in triple-negative breast cancer (TNBC) mice models. We have identified a potent drug with specificity towards PD-L1-expressed TNBC. However, the drug is “non-ADCable”, lacking a reactive handle for ADC conjugation. Thus, we nominated the ANC system as a suitable delivery platform. For a larger-scale ANC production required for rodent studies, we also optimized the formulation process and achieved improved cargo encapsulation. We are delighted to find our PD-L1 ANC showcases boosted tumor specificity and prolonged circulation time, leading to superior tumor inhibition in TNBC-xenografted mice.
Overall, our ANC platform demonstrates several advantages including: i) simple and reproducible formulation processes, ii) stable and high drug encapsulation, iii) minimal optimization required for different drug-antibody combinations, iv) neglectable toxicity and off-target effects, and v) maximized therapeutic efficacy compared to the traditional chemotherapy. These merits render ANC a promising next-generation nanomedicine platform for a greater disease scope.

S. Thayumanavan

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