DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Antibody-Drug Conjugates (ADCs) are increasingly vital for treating solid and hematological malignancies.
• A need exists for novel payloads with unique mechanisms to overcome therapeutic resistance.
• DNA cross-linking agents represent a promising class of payloads for ADC development.

Purpose of the Study:

• To report a new class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads.
• To evaluate the efficacy and tolerability of an ADC utilizing a lead CBI-PDD payload.
• To assess the potential of these novel payloads in cancer therapy.

Main Methods:

• Synthesis and characterization of CBI-PDD payloads, including lead compound FGX8-46.
• Assessment of sequence-selective DNA alkylation at guanine (G) and adenine (A) bases.
• Determination of in vitro cytotoxicity across 11 human tumor cell lines.
• Conjugation of FGX8-46 to cetuximab to form an ADC (average DAR of 2).
• Evaluation of ADC antitumour activity and tolerability in a human tumor xenograft mouse model.

Main Results:

• FGX8-46 induces sequence-selective G-A DNA cross-links.
• The payload exhibits potent cytotoxicity in the picomolar range against multiple tumor cell lines.
• The cetuximab-ADC demonstrated significant antitumour activity at 1 mg/kg in vivo.
• The ADC showed high tolerability, with no weight loss observed even at 45 mg/kg.

Conclusions:

• CBI-PDD payloads, exemplified by FGX8-46, offer a novel mechanism for DNA cross-linking.
• The lead payload demonstrates potent preclinical efficacy and favorable safety profiles.
• ADCs incorporating CBI-PDD payloads represent a promising therapeutic strategy for cancer treatment, potentially overcoming resistance.