Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates

Area of Science:

• Bioconjugation Chemistry
• Drug Delivery Systems
• Cancer Therapeutics

Background:

• Antibody-drug conjugates (ADCs) target cancer cells, but drug-antibody ratio (DAR) is limited, impacting efficacy.
• Current ADCs typically have a DAR of 3-4, affecting pharmacokinetics and tolerability.
• Developing methods for higher drug loading in homogeneous ADCs is crucial for improved cancer treatment.

Purpose of the Study:

• To synthesize monodisperse polysarcosine compounds.
• To utilize polysarcosine as a hydrophobicity masking agent for constructing highly-loaded homogeneous ADCs.
• To evaluate the impact of this novel platform on ADC properties and *in vivo* efficacy.

Main Methods:

• Synthesis of discrete polysarcosine compounds.
• Construction of homogeneous antibody-drug conjugates using a polysarcosine-based drug-linker platform.
• Assessment of drug-loading capacity, physicochemical properties, pharmacokinetics, and *in vivo* antitumor activity.

Main Results:

• Successful synthesis of monodisperse polysarcosine compounds.
• Creation of highly-loaded homogeneous ADCs with improved drug-loading and physicochemical characteristics.
• Demonstrated enhanced pharmacokinetics and significant *in vivo* antitumor efficacy of the novel ADCs.

Conclusions:

• Polysarcosine serves as an effective hydrophobicity masking agent for ADC construction.
• The developed platform enables highly-loaded, homogeneous ADCs with superior drug delivery capabilities.
• These advanced ADCs represent a promising strategy for improving cancer therapy.