Site-Specific Quadruple-Functionalised Antibodies

Area of Science:

• Bioconjugation Chemistry
• Oncology Therapeutics
• Protein Engineering

Background:

• Antibody-drug conjugates (ADCs) show clinical success but face limitations due to tumor heterogeneity and resistance.
• Existing ADCs often struggle with efficacy due to these challenges.
• Multi-payload ADCs, featuring multiple distinct payloads on a single antibody, are emerging as a solution.

Purpose of the Study:

• To develop highly homogeneous multi-functionalized antibody conjugates with multiple distinct payloads.
• To overcome the limitations of current ADCs in treating heterogeneous and resistant tumors.
• To establish a new platform for next-generation ADC development.

Main Methods:

• Utilized multiple orthogonal site-specific protein modification strategies.
• Engineered antibody conjugates with up to four different functionalities at unique antibody sites.
• Employed a site-specific cyclopropenone (CPO)-based reagent for payload attachment.

Main Results:

• Successfully generated highly homogeneous multi-functionalized antibody conjugates.
• Demonstrated the ability to install up to four distinct functionalities on a single antibody.
• Achieved the first homogeneous multi-payload ADC with a payload count exceeding two.

Conclusions:

• This work presents a novel approach to creating advanced multi-payload ADCs.
• The developed methodology facilitates the creation of next-generation ADCs with enhanced therapeutic potential.
• The homogeneous nature and high payload capacity of these conjugates offer a promising strategy against tumor resistance.