Our Science

Our Science

Intercepting Cancer’s Survival Mechanism

Cancer can be subdivided into different histological subtypes at the phenotypic level, but in fact exhibits widespread heterogeneity at the molecular level. While primary tumors possess similar genetic alterations, little is known about the mutations and pathways that drive invasive and migratory processes.

THE PROBLEM:Effective cancer treatment remains a major clinical need, especially in treating metastatic disease and drug resistance.
AXL/GAS6 has been shown to be an important driver of metastatic disease and acquired drug resistance. The challenge in disrupting the GAS6/AXL pathway is the high affinity of the ligand and the receptor, which poses a challenge for antibody drugs in disrupting this interaction. In addition, the intracellular kinase domain shares a great deal of homology between all three TAM family members, making the development of specific and selective small molecules for AXL challenging. The left-hand panel depicts the binding of GASs6 ligand (blue) molecules to the AXL receptor at the cell surface. This occurs in a 2:2 ratio of ligand to receptor. The right-hand panel shows the consequences of dysregulated AXL/GAS6 on driving metastatic spread in the ovaries, liver and breast.

THE SOLUTION:Our solution to the affinity and specificity problem associated with GAS6/AXL signaling is to make a high-affinity decoy receptor that outcompetes the endogenous receptor at the cell surface for binding to GAS6.
In addition, this decoy receptor has the ability to strip off GAS6 molecules already bound to the endogenous receptors due to its ultra-high affinity. The left-hand panel demonstrates the high affinity of the AVB-S6-500 decoy receptor in binding to GAS6 before it binds to the receptor of the tumor cell, effectively neutralizing GAS6, intercepting the interaction, and silencing the AXL intracellular signaling. The right-hand panel shows free GAS6 molecules and AVB-S6-500 molecules in solution right after administration to inhibit intracellular signaling.

THE RESULT:AVB-S6 proteins as a single agent decreased metastasis in preclinical models.
This panel shows the reduction of breast and ovarian cancer metastasis when AVB-S6 proteins are given as a monotherapy in preclinical studies.

THE RESULT:AVB-S6 proteins have preclinical activity in combination with other chemotherapies to decrease metastasis.
This panel shows the reduction in metastasis when AVB-S6 proteins are given in combination with chemotherapy in preclinical studies. The combination therapy results in cures in some preclinical metastatic models.

The invasive and migratory ability of tumor cells is tightly associated with epithelial to mesenchymal transition (EMT). Tumor cells undergoing EMT exhibit a dramatic change in morphology as well as cell-to-cell and cell-to-matrix interactions. We have found that GAS6 through the AXL receptor tyrosine kinase is a critical driver of EMT, invasion, survival and metastasis. A growing number of publications also supports these roles for GAS6/AXL in many tumor types. In addition, inhibition of AXL signaling using small molecules has been reported to sensitize drug resistant mesenchymal cells to cytotoxic and targeted therapeutics.

Since cancer cells have survival mechanisms that let them flourish even under constant stress, the inhibition of GAS6/AXL has important therapeutic effects for the survival and expansion of tumor cells of different origins. Most importantly, loss of GAS6 & AXL function does not appear to harm normal tissues, and interestingly, increases with tumor grade and stage.

Affinity Matters

To date, other groups have pursued both small molecule kinase inhibitors and antibodies against AXL and GAS6. Prior anti-AXL and anti-GAS6 antibody programs have failed to produce an antibody of sufficient affinity to disrupt the interaction between AXL and GAS6. Selective target engagement for AXL kinase using small molecules has proven a difficult challenge as current anti-AXL compounds in development appear to inhibit other kinases more so than AXL and have significant off target activity limits their utility.

Affinity matters because the natural interaction between the ligand GAS6 and the AXL receptor is quite high (Kd~30 pM), and requires a decoy receptor with higher affinity to bind GAS6. Our approach is to target the GAS6/AXL signaling pathway using a Fc-fusion decoy receptor.

Preclinical data has demonstrated that AVB-S6 proteins have better than 100-fold tighter affinity for GAS6 compared to the natural affinity of the ligand and the receptor, providing high specificity and selectivity for the AXL/GAS6 pathway.

In models, intercepting the GAS6-AXL signaling pathway with a high affinity decoy has been shown to inhibit the survival of tumor cells, especially in vivo, resulting in decreased tumor growth and metastasis as well as development of resistance to cytotoxic chemotherapeutic agents.

Therefore, by targeting the adaptive response in tumors through the GAS6-AXL pathway with a high-affinity biologic molecule, we believe we can interrupt the signals and turn off the “survival switch” that otherwise allows cancer to grow and acquire resistance to cancer therapy.