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Updated: Sep 3, 2025
Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
DNA sequence-selective G-A cross-linking ADC payloads for use in solid tumour therapies
George Procopiou1, Paul J M Jackson1, Daniella di Mascio2
1Femtogenix, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire, AL5 2JQ, UK.
Abstract:
Antibody-Drug Conjugates (ADCs) are growing in importance for the treatment of both solid and haematological malignancies. There is a demand for new payloads with novel mechanisms of action that may offer enhanced therapeutic efficacy, especially in patients who develop resistance. We report here a class of Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads that simultaneously alkylate guanine (G) and adenine (A) bases in the DNA minor groove with a defined sequence selectivity. The lead payload, FGX8-46 (6), produces sequence-selective G-A cross-links and affords cytotoxicity in the low picomolar region across a panel of 11 human tumour cell lines. When conjugated to the antibody cetuximab at an average Drug-Antibody Ratio (DAR) of 2, an ADC is produced with significant antitumour activity at 1 mg/kg in a target-relevant human tumour xenograft mouse model with an unexpectedly high tolerability (i.e., no weight loss observed at doses as high as 45 mg/kg i.v., single dose).
Insights
Researchers developed novel Cyclopropabenzindole-Pyridinobenzodiazepine (CBI-PDD) DNA cross-linking payloads for Antibody-Drug Conjugates (ADCs). These payloads show potent anti-tumor activity and high tolerability in preclinical models.
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.
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