Chemotherapy Development is ‘In’ Again

Cancer therapy development has advanced to researching targeted immunotherapies and are moving into gene-specific therapies.  Some companies, however, are focusing on reviving cytotoxic therapies that were too toxic for patients when administered generally. These companies are developing targeted transportation mechanisms to deliver cytotoxic release at tumor cells while minimizing overall toxicity to patients. Bill Newell, Chief Executive Officer of Sutro Biopharma, will discuss the use of a cell-free protein synthesis approach to developantibody-drug conjugates, bispecific antibodies, andcytokine derivatives to deliver cytotoxic therapies.

Moe Alsumidaie: What is XpressCF cell-free protein? And why is this approach unique in research? 

Bill Newell:The cell-free protein synthesis approach involves taking the machinery that is inside a cell, in our case, a highly engineered E. coli strain, growing that strain and harvesting the machinery to become an extract. From that extract, we then use the mechanism with DNA to make a large molecule in 10 to 12 hours.  Rather than having to grow a cell line for weeks, break it open and then try and purify out the wanted antibody, we have an extract that's ready to go, and when coupled with DNA (as well as a few other things), the machinery singles out the protein of interest.We also can take advantage of a roboticizedresearch environment which means that, overnight, we can have hundreds, if not thousands, of different molecules ready to test.

MA: How does this approach enable the development of highly customized and highly personalized oncology therapies?

BN: We're trying to customize therapy development by efficiently making complex molecules. For example, an antibody-drug conjugate (ADC) is comprisedof an antibody, a linker, sites of linkage or attachment, and a warhead. A bispecific antibody has two binding sites, but the orientation of the molecule and how you try to engage with those binding sites can vary. A cytokine derivative, NKTR-214 for example, has an IL-2 cytokine, and it's pegylated in six different positions. These are not simple molecules to make, and so what we're trying to do is deconvolute the molecule and understand its mechanism through the applicationof structure/activity relationship principles.  This allows us to optimize the structure for maximum patient benefit. 

When we change the structure just a little bit, how does that affect the performance of the molecule as a tumor killer? We want the optimal tumor killing with the widesttherapeutic window. Why? Because when you're dosing a highly potent cytotoxin, or you're trying to use the body's immune defenses to kill a tumor cell, you risk excessive toxicity. Therefore, you want it to be exquisitely targeted; you want it to have as wide a therapeutic window as possible, so you can deliver the maximum kill effect to the tumor microenvironmentwhile sparing the healthy cells and tissues in the patient. 

MA: How does this new method address some of the issues that you would typicallysee with current immunotherapy development?

BN: One of the difficulties in cell-based expression platforms when you're making immunotherapies, is that each cell line is one shot on goal. When you produce a therapy that looks good enough, you run with it. However,you're not able to easily modulate the structure of the molecule (if there are undesired toxicities) because that takes multiple cell lines and iterations which can take years to explore fully. 

At Sutro, we can make many different modalities and empirically determine which ones have the right characteristics to give us a wider therapeutic window. We can then rapidly scale the molecule, because unlike cells where you start with transient expression that can take nine to fifteen months to establish a stable cell line that gives you enough material to test the principle that you saw atsmall scale right away, we can do more massivescale production within a matter of days. 

Scaling a molecule and getting ready for animal studies can take months. If there are characteristics of the molecule’s performance that we don’t like, we have to redesign it and tweak many different variables until we are ready to take it back to animal models. This can take many months, if not years for a large company to do; even the best of the large companies will take a long time because each cell line takes so much time and energy to produce.For us, it's a matter of weeks and at most a few months to develop these molecules.

MA: How does the cell-free protein work?

BN: Let’s first think about the way we've been attacking cancer. The first round of cancer therapeutics were poisons such as mustard gas derivatives. We were trying to poison the tumor cells in the person with chemotherapy. Then along came antibodies, which are by definition a targeted therapy, and they're relying on the immune reaction that the antibody can generate to kill a cell. However,if you don't kill all the tumor cells, you get mechanisms of resistance developing, andthe antibody becomes less effective. You can't go stronger in chemotherapy, because we already have the strongest chemotherapiesthat patients can tolerate. 

In our case, we can take a potent cell killer like a cytotoxin, in this case,(we call it a warhead) and we conjugate it optimally for targeted delivery and release in the tumor; essentially, creating a smart bomb for cancer.Thisenables you to guide the antibody with the toxin to the tumor cell, get it internalized, have the toxinor the warhead take the tumor cell out, and then we can pay attention to howthe part of the toxinis excreted to eliminate what is a so-called bystander effect. We want to minimize the amount of toxicity to surrounding healthy cells and tissues to improve tolerability for patients and allow for combination therapies. 

MA: What companies have you partnered with on your technology and why are they so important?

BN: We're thrilled with our collection of partners. We've got Merck for cytokine derivatives. We have Celgene for a significantmyeloma drug, B Cell Maturation Antigen (BCMA) antibody-drug conjugate. Moreover,we have three other immuno-oncology programs with Celgene. We also have EMD Serono as our partner for someADCs, the lead one being a bispecific-drug conjugate. Why these companies? Each company that engaged with Sutro Biopharma had an idea of a molecule that they wanted, but they couldn't get at using their conventional technology. 

Using our process to deliver best-in-class molecules to our partners is a truesynergy. Manybiotech companies make something and hand it off to their partner, but never hear about it again. We can't understand the mechanisms of action behind some therapies as well as big pharma developers do.However,we are collaborating with them to create delivery mechanisms to enable them to develop a drug more successfully. 

MA: What can we expect from Sutro this year?

BN:This is an interesting and exciting year for us. We've talked a lot about how our molecules should perform, and this year, we're going to have somedata read-outs that start to give the first indications of whether or not our molecules are performingin people as we have designed them to do. Our first program, STRO-001 for multiple myeloma and lymphoma, is expected to have initial safety data by the middle of this year and then we'll have initial efficacy data by the end of the year. Our second program, STRO-002 for ovarian and endometrial cancers, is expected to have initial safety data by the end of the year. Moreover,I'm hopeful that our third program, the BCMA-ADC (partnered with Celgene), will have initialclinical news by the end of the year.