ADCs at a glance
Antibody-drug conjugates (ADCs) combine the targeting capabilities of an antibody, with the potent effects of an attached (conjugated) drug moiety, into one single drug molecule. Thus, by combining several biological components and processes, one can achieve targeted delivery of these conjugated drugs to cancer cells.
Key components of an ADC strategy are as follows:
An antibody forms the ADC scaffold, actively binding the target receptor, highly expressed by cancer cells, thereby mediating the targeted effect of the drug.
A drug, in the form of a cytotoxic substance is attached to the targeting antibody, thereby arming the antibody with the ability to kill the cancer cells to which it binds. The drug is inactive in circulation, but is activated upon cellular internalization.
A linker, between the antibody and drug compound, may be utilized to enable particular biological effects, such as improved solubility and stability in circulation, or specific mechanisms for release of the cytotoxic compound in particular intracellular compartments.
Last, but not least, a target receptor with suitable molecular properties, and a high cancer specificity to normal tissue, is essential to obtain targeted, ADC-mediated drug delivery to cancer cells.
ADCs are named from the process of attaching, or conjugating, a drug covalently to the targeting antibody.
By combining antibodies with cytotoxic compounds and linkers possessing certain key properties, ADCs which are highly efficient at targeting and killing cancer cells, based on the characteristics of a given type of cancer, can be designed.
Our novel target
ADCendo are first to exploit our novel ADC target uPARAP for targeted drug delivery.
In order for an ADC to effectively kill a cancer cell, it is not enough for the ADC to bind a target receptor expressed at the cell surface.
The ADC must be internalized, as well as processed correctly in intracellular compartments, in order to release and thereby activate the cytotoxic payload, which will otherwise remain inactivated, or result in degradation products benign to the cancer cell.
To this end, the properties of the ADC target receptor are key to successful, selective and efficient drug delivery.
ADCendo has a unique focus on professional endocytic receptors with a strong and selective expression in particular types of cancer. This in contrast to other, more commonly exploited ADC receptors that are expressed at high copy-numbers, but rely on more passive internalization methods.
The collagen receptor uPARAP has been found to be expressed especially by cancer cells of soft-tissue sarcoma, as well as other cancer types, with a limited expression in healthy tissue. uPARAP is a constitutively active, recycling endocytic receptor, that efficiently delivers bound cargo into the endosomal/lysosomal pathways, to efficiently mediate ADC processing and intracellular drug release in cancer cells.
We believe that by exploiting these particular mechanisms in our ADC design, we obtain more efficient ADC internalization, processing, and drug release, in comparison to more conventional targeting strategies.
A general overview of the mechanism of action of an ADC, is depicted in the figure below.
Each step is explained in more detail in the image slide show below.