Development and evaluation of β-galactosidase-sensitive antibody-drug conjugates

Area of Science:

• Oncology
• Bioconjugation Chemistry
• Pharmacology

Background:

• Targeted cancer therapy faces challenges in selectively destroying tumor cells while sparing healthy tissues.
• Antibody-drug conjugates (ADCs) represent a rapidly growing class of targeted cancer therapies.
• Efficient drug conjugation and release technologies are critical for ADC development.

Purpose of the Study:

• To develop a novel class of β-galactosidase-cleavable linkers for antibody-drug conjugates (ADCs).
• To synthesize and evaluate novel payloads comprising a galactoside linker, monomethyl auristatin E (MMAE), and cysteine-reactive groups conjugated with trastuzumab.
• To assess the in vitro and in vivo therapeutic efficacy of these novel ADCs.

Main Methods:

• Synthesis of novel payloads with galactoside linkers, MMAE, and cysteine-reactive groups.
• Conjugation of synthesized payloads to trastuzumab to create new ADCs.
• In vitro and in vivo evaluation of the developed ADCs' efficacy in a preclinical cancer model.

Main Results:

• Novel ADCs incorporating β-galactosidase-cleavable galactoside linkers were successfully synthesized and conjugated.
• The developed ADCs demonstrated potent cytotoxic activity in vitro.
• In vivo studies in mice showed superior therapeutic efficacy for the galactoside linker ADCs compared to trastuzumab emtansine.

Conclusions:

• The novel β-galactosidase-cleavable galactoside linkers offer an efficient system for drug release in ADCs.
• These ADCs exhibit enhanced therapeutic potential for cancer treatment, particularly in comparison to existing therapies like trastuzumab emtansine.
• This linker technology represents a promising advancement in the field of targeted cancer therapy.