WP13 – Antibody-drug conjugate based GBM targeting approach

Rationale

Antibody-drug-conjugates (ADCs) are a class of emerging, targeted cancer drugs with remarkable specificity. In short, ADCs rely on a toxin-coupled antibody against a cell surface receptor expressed on the cancer cell type in focus (Figure 12). Importantly, ADCs are at the core of personalised therapy since the patient´s expression of the target receptor dictates the likelihood of treatment success. We have already developed an ADC directed against the receptor uPARAP which is highly upregulated in the majority of GBM specimens (see below), whereas other potential targets will be identified during the course of this project.

Objectives

1) Investigation of the utility of ADCs against uPARAP for eradication of tumour cells in GBM.

2) Identification of novel molecular targets in GBM that are suitable for an ADC-based therapy.

Approach

Preclinical validation of ADCs against uPARAP in GBM. ADCs against uPARAP were conceptually developed by our groups [37] and are currently being matured in preclinical work performed by the company Adcendo ApS with soft-tissue sarcoma as the primary indication. It is likely that the resulting, humanized ADC will reach Phase I trial during the course of the current project.

These ADCs are also efficient against GBM cells, as shown so far in subcutaneous mouse models (Figure 12). We will use these ADCs for therapy experiments with several patient-derived GBM cells, orthotopically xenografted in immunocompromised mice (WP4 and commercially available PDX models).

ADCs for these studies will be made available by Adcendo as a collaborator. Using IHC (Figure 12), we will also determine the degree of uPARAP expression in a large collection of GBMs and establish the correlation between uPARAP expression and tumour sensitivity.

Identification of novel ADC-targets in GBM. We will exploit the results of gene expression analysis in WP1 to identify at least two novel GBM molecular target candidates, associated with particularly high surface receptor expression (which will be investigated by IHC) to be put forth as novel candidates for development of novel ADC-targets.

From our previous work with anti-uPARAP ADCs, we are fully capable of creating active ADCs against such targets, both in terms of constructing the ADCs and testing their efficiency in vitro and in vivo. When efficient reagents have been produced, their further development and validation towards clinical implementation will follow the same line as outlined above.

Endpoints

Identify potent ADC-based therapies that could constitute novel, targeted therapies with high specificity.

Endpoints

1) Proof-of-concept with anti-uPARAP ADC in orthotopic GBM mouse models, based on human patient-derived xenografts.

2) Validation of at least 3 novel molecular targets for ADC-based GBM-treatment at the level of tumour cell eradication.

Expected impact

1) Demonstrating relevance at the highest pre-clinical level of a uPARAP-directed treatment of GBM.

2) Finding new candidates for GBM targeting.

Disclaimer / Conflict of interest
Investigators NB and LHE are co-founders of the company Adcendo ApS that works to develop ADC-based cancer drugs.