SMDC Technology

SMDC_illustration2An innovative modular technology platform

Our technology platform has enabled us to develop multiple new small molecule drug conjugates (SMDCs) for a range of disease indications. Each SMDC is comprised of three modules: a targeting ligand, a spacer/linker, and a drug payload. Our companion imaging agents employ the same targeting ligand and modular structure as our SMDCs, replacing the drug payload with an imaging agent.

Targeting ligand—Our high-affinity, small molecule ligands bind to receptors expressed on target cells. We are developing a number of targeting ligands to address a broad range of cancers and other diseases.

Spacer/linker system—Our proprietary spacer/linker systems attach the targeting ligand to the drug payload or imaging agent. These systems are designed to be stable in the bloodstream and to release the active drug from the targeting ligand when the SMDC is taken up by the diseased cell through endocytosis. The spacer/linker system can be customized for each SMDC and each companion imaging agent to improve its pharmacologic properties.

Drug payload—This module is the biologically active component of our SMDCs. The majority of our drug payloads are highly active molecules that are too toxic to be administered in their untargeted forms at therapeutic dose levels. We are using drug payloads in our SMDCs that were shown in our in vitro preclinical studies to be thousands of times more active than traditional cancer cell-killing drugs, such as cisplatin.

The potential and versatility of SMDCs

With our modular approach, we use a variety of different targeting ligands, linker systems, and drug payloads to create a pipeline of novel SMDC candidates for clinical development. For example, in addition to folate-targeting, our prostate-specific membrane antigen (PSMA)-targeting technology uses a targeting ligand that specifically binds to a receptor expressed on the surface of prostate cancer cells. 

A variety of spacer/linker systems perform specific functions

We have developed alternative spacer/linker systems that modulate the pharmacologic and biodistribution properties of our SMDCs. In addition, we have developed a spacer/linker system that allows us to conjugate multiple drug payloads to a single targeting ligand, thus offering the potential to simultaneously disrupt multiple pathways within cancer cells, forming a novel strategy for addressing drug resistance.

Being studied with a range of drug classes

We can attach a wide variety of different drug payloads to our targeting ligands to address different disease indications. For example, we have SMDCs in preclinical development that incorporate proven anti-cancer and anti-inflammatory drug classes, such as microtubule destabilizers, DNA alkylators, proteasome inhibitors, mTOR inhibitors, and various inhibitors of key intracellular enzymes.

Maximizing the effect of each component

We design our targeted drugs in modular fashion from three distinct modules. The targeting ligand is attached to a spacer/linker that contains a cleavable bond connecting the linker to the drug.

The ligand is selected to be as high in affinity for its receptor as possible. We spend considerable effort designing the ligand so that its affinity is at least 10 nanomolar or greater.

The cleavable bond is designed so that when it is broken, it releases the drug in its totally unmodified, most active form. It is also designed so that it is only cleaved following endocytosis in the diseased cell, thereby reducing the amount of free drug in circulation. Most of the drugs that we incorporate into our SMDCs are highly hydrophobic and would penetrate all cells indiscriminately and bind the serum proteins avidly if they were not targeted. We design our conjugates with spacer/linker systems that are highly hydrophilic, with the goal of preventing these undesirable processes from occurring.

Finally, because many receptors are present in low numbers, we design the therapeutic component to be as potent as possible. We’ve modified existing drugs to improve their potencies and increase the likelihood of killing the targeted malignant cell.