Background and Opportunity

This invention relates to the selective delivery of cancer therapeutics via a peptide drug conjugate (PDC) that is specifically recognised and activated within the tumour microenvironment by aminopeptidase (known as CD13) which is a metalloproteinase highly expressed in multiple solid tumours. By conjugating a peptide to the anticancer agent, the active drug is rendered inactive and non-toxic, sparing normal tissues. CD13 is over-expressed in tumour tissue and associated vasculature. Highly expressed in multiple solid tumours, including breast cancer, lung cancer, colon cancer and neuroblastoma. Implicated in growth, angiogenesis, invasion and metastasis in vivo. Highly upregulated in response to tumour hypoxia. The global PDC market garnered $718 Million in 2022, expanding at a historical CAGR of 16%. It is estimated that the PDCs market value will reach $ 5.3 billion by 2033.

The Problem

According to the National Cancer Institute (US), there are more than 250 FDA approved chemotherapeutic drugs used in treatment of malignant tumours. However, the major drawback associated with such small molecules is uncontrolled toxicity resulting in severe side effects.    

Application

Peptide Drug Conjugates are biologically inactive compounds that are activated post-administration into their pharmacologically active forms. Once in the tumour microenvironment, the peptide is recognised and hydrolysed at a specific point in the sequence. Tumour expressed endopeptidases then hydrolyse the remaining amino acid and releases the cytotoxic drug. A self-immolative linker may be required between the active drug and the final amino acid (this spontaneously releases the drug following APN and exopeptidase cleavage).

The team at the ICT have exemplified this technology with the drug AZD6738 (ceralasertib), in a model of human breast cancer, which expresses APN. AZD6738 is an Ataxia Telangiectasia and Rad3 related (ATR) serine/threonine protein kinase inhibitor developed by Astra Zeneca for oncology indications which has been entered into multiple clinical trials for a range of cancers. The ataxia telangiectasia and rad3-related-checkpoint kinase 1 (ATR-CHK1) pathway is involved in DNA damage responses in many cancer cells, so this drug was studied in combination with standard DNA damaging chemotherapies such as cisplatin, carboplatin, gemcitabine and bendamustine or ionising radiation (IR). Furthermore, the research team have demonstrated the technology is amenable to multiple other drugs, with drug conjugates of the following anticancer agents and probes having been synthesised and evaluated: AZD6738, AZD7762, azademethylcolchicine, paclitaxel, duocarmycins (CBI-MI, CPI-MI, DSA-TMI), palbociclib, AMC (7-amino-4-methylcoumarin) and anthraquinone.

Benefits

Drug conjugates are formulated to overcome pharmacokinetic barriers such as poor solubility and absorption, extensive first-pass metabolism, or rapid excretion, and pharmacodynamic barriers such as toxicity, side effects, and poor efficacy. CD13 is expressed in normal tissues, BUT the isoform of CD13 expressed in tumours and associated vasculature has unique endopeptidase activity that has been exploited in the drug conjugate design (Ref 1). A high level of tumour selective release was demonstrated by the ICT team.

Moreover, increasing drug resistance of tumour cells to such chemotherapy agents has led to demand for a better treatment approach like targeted Peptide Drug Conjugates (PDC). Before considering PDCs, it is important to acknowledge another well-studied example of bioconjugates: antibody–drug conjugates (ADCs). The large size and molecular weight of antibodies limit their application. As a result, antibodies are unable to freely diffuse through the plasma membrane, with few (if any) membrane proteins capable of transporting these macromolecules into the intracellular space; therefore, ADCs are restricted to antibodies that recognize proteins that present an antigen to the extracellular space.

This therapeutic strategy requires ADCs to be endocytosed for effective delivery of the small-molecule payload to elicit the desired therapeutic effect. In contrast, peptides are much smaller than antibodies, and several membrane transport proteins exist that traffic peptides into the intracellular space. Thus, peptides that recognize intracellular proteins can be used in PDC design, which greatly increases the number of target proteins accessible to PDCs.

IP Status and Investment Opportunity

Patent Status: Application pending expected priority filing Q1 2026

Patent fully owned by UoB In-vivo data is expected in Q1 2026

We are seeking an Investor/collaborator to further develop the lead candidate and move it through the preclinical phase.

References

1. Barnieh, Galuska, Loadman, Ward, Falconer, El-Khamisy, 2023