Background and Opportunity

Scientists at the Institute of Cancer Therapeutics (ICT) at the University of Braford have designed, synthesised and tested a novel set of payloads based on Duocarmycins, natural products that are ultrapotent. The team at ICT are also developing novel Anti-body Drug Conjugates (ADCs) containing these novel warheads, which offer a number of benefits. 12 ADCs are currently approved for clinical use, and 100 new ADCs in clinical trials, this reflects a strong investor confidence with market size estimated at $10.8billion (2023) and projected to grow at 27.8% CAGR to $50billion in 2030 (Ref 1).

The Problem

Duocarmycins are a class of highly potent small molecules derived from naturally occurring compound; first isolated in the 1970s from the culture broth of Streptomyces bacteria. They exhibit ultra-potent (picomolar) anti-tumour activity in a wider range of solid tumours through binding with DNA via irreversible alkylation of the nucleobase adenine at the N3 position; known as minor groove-binding this disrupts the nucleic acid architecture, which eventually leads to tumour cell death. However, despite their considerable potential as therapeutics, market approval for their clinical use has not yet been granted. Clinical administration (between 1998-2003) of duocarmycins; adozelesin, bizelesin and the two carbamate prodrugs carzelesin and KW-2189 was associated with severe adverse effects and no therapeutic index, leading to all trials being discontinued.

Recent interest is focused on developing new approaches for duocarmycins such as antibody-drug conjugates (ADCs) and enzyme activated prodrugs which protect the cytotoxic payload until it is delivered to the site of action where it is released reducing the high systemic toxicity of these highly potent warheads, hence expanding the therapeutic index. Despite market approval, current clinically-used ADCs suffer from limitations including:

• Safety: due to undesired (off-target) release of payloads in normal tissues
• Treatment failure: Tumour cells do not all express antigen / receptor target required for ADC binding. Insufficient payload release to kill all cancer cells & resistance mechanisms towards payloads.

Application

The novel duocarmycins warheads developed at the ICT have molecular structural modifications to the DNA alkylating subunit. In general, the structural modifications, as compared to traditional duocarmycins (CPIs) are changing the indole sub-unit generating well-known synthetic analogues (CBIs) of CPIs being more biologically potent, stable and synthetically accessible. CBIs are used in most duocarmycin loaded ADCs including sec-DUBA. The main modification for the new molecules is around the alkylating activating phenol group either by forming an ether derivative or replacing the oxygen with a different functional group such as a phenyl or secondary amine.

Benefits

Despite clinical failure of duocarmycins, interest in these molecules has remained high due to the inherent capacity of duocarmycins to evade traditional resistance mechanisms and retain exquisite potency in multidrug-resistant cells. Re-engineered payloads for ADCs with ‘smarter and safer’ activity profile can still kill ‘non-tagged’ cancer cells via effective bystander impact. The structural modifications have led to changes in the observed cytotoxicity of the compounds in tumour cells (MDA MB 231, MCF7) causing a significant reduction in the cytotoxicity (IC50 in the 1-200nM range) compared to traditional duocarmycins (IC50 in the 1-100pM range) a decrease in potency of 1000 fold.

The pharmacophore modulation also extends electronic conjugation properties, which potentially offers opportunities to track and monitor these agents via fluorescence measurements; the latter is not possible with the traditional duocarmycins and is an attractive property to measure off-target activity in normal tissues.

IP Status and Investment Opportunity

Patent Status: Priority date (UK) 17th Jan 2023

PCT/EP2024/051080

Patent fully owned by UoB

Investor/collaborator required for investment to establish spin-out company UNIK Tx Ltd and to progress development of novel ADCs and drug conjugates based on novel duocarmycin payloads.

References

1. Antibody-Drug Conjugates: Technologies and Global Markets Report Code: PHM161C : Sep 2024

BCC Publishing.