CEO Q&A: Ovarian Cancer Target

We asked our CEO and co-founder, Dr. Al Luderer to answer some questions about our translational biology progress. Indi Molecular is designing and testing molecules that could one day be used to identify ovarian cancer, then treat the identified cancer and finally, provide for the drug to be inactivated by the kidney to avoid/reduce treatment-related toxicity.

Why is Indi Molecular Looking at Ovarian Cancer?

We’re looking for an indication with substantial need. Ovarian cancer fits the bill.

Patients are often diagnosed at a late disease stage and many will be treated with platinum-based chemotherapy. It’s likely their cancer will become resistant to the chemotherapy -- and far too many will end up dying from the disease. 

This is an area that really needs some help -- and some new approaches. 

Why Target Folate Receptors?

We’re looking for a target that has already been validated -- something that allows us to reliably distinguish between cancer and normal tissue. In ovarian cancer, folate receptors are overexpressed versus nonmalignant tissue. This is a good starting point to create a targeted drug.

Those folate receptors exist to bind with folate and transport it inside the cell for metabolic processes. Our early research in mice suggests we’ve been able to design two complementary molecules that can bind with those receptors. The role of the first molecule is to identify the cancer via a PET image. The role of the second molecule is to kill the cancer: it shares the imaging agent’s folate-binding structure but now carries a therapeutic warhead. 

Broadly speaking, this strategy of combining a therapeutic and an in vivo diagnostic is called theranostics and it has real potential to improve treatment outcomes. 

Targeting Folate Receptors Sounds Like a Simple Strategy, Why Hasn’t It Been Done Before?

The strategy is simple enough, the execution is difficult. That difficulty is part of the reason it’s well suited to our technology. We are able to create custom tailored molecules with our PCC (protein catalyzed capture agent) technology. More about this below. 

Think of it as bespoke chemistry. With PCCs we can build molecules that are small, able to carry a payload and that are highly specific in their binding ability. These attributes are essential when you’re looking at folate receptors, because this receptor comes with a huge Achilles heel: the kidneys. 

Why Are The Kidneys Important?

Kidneys also absorb folate. A molecule that is powerful enough to kill cancer, likely also poses a serious risk to the kidneys - unless you can find a way to keep it away from the kidneys or change its properties when it reaches them. 

How Are Your Molecules Different?

In this case, we’ve built a custom molecule that does three things really well: 

First, it has an extremely high affinity for the folate receptor. Ours is 30 fold higher than native folate. In our research on mice transplanted with a human ovarian tumor (xenograph mouse model), it’s done a really good job finding the receptors on the tumor. This work uses whole body PET imaging to visualize the binding event. There are several radionuclides that can be used for PET imaging, we have used both 18F (fluorine) and 68Ga (gallium) with our targeting molecule. 

Second, we attach a therapeutic radioactive payload (the warhead I mentioned) to our molecule. We used 177Lu (lutetium). Once it’s transported into the cell by the folate receptor, our work shows it’s capable of providing durable control of the mouse’s transplanted human ovarian tumor. 

Third -- and this is where our technology really shines -- when our molecule reaches mouse kidneys, they react with a kidney-associated enzyme that cleaves off the radioactive payload. That means the toxic, cancer killing part of the molecule can now flow into the bladder for elimination. 

Indi Molecular is still preclinical – we have not begun human testing. However, our translational mouse data suggests a path forward for a theranostic ovarian cancer program with the potential to address the problem of kidney toxicity.

Tell Us More About PCCs

PCC molecules are very small in contrast to other targeting molecules such as monoclonal antibodies. We get the benefit of small molecule performance, very high affinity and the capability to engineer many therapeutic performance attributes without affecting the binding properties of the molecule. 

Where Does This Technology Come From?

PCC Technology was originally developed by Jim Heath and Heather Agnew at Caltech. Since our inception, we have also collaborated with UCLA to help us test our chemistries in biological systems. This translational biology capability has become even more important as we have focused on theranostics - a field that UCLA has been pioneering and one that is well suited to our PCC platform.