Remakes, book-to-movie adaptations, and sequels are tricky. No matter what, someone will always say, “It’s just not as good as the original.” Atreca, a biopharmaceutical company that develops antibody-based therapeutics, shares that sentiment. Scientists at the company are searching for originality in cancer therapies by going to the source. On the assumption that the body knows best, they study antibodies against foreign invaders and rogue cells produced by an individual’s B cells with the hope that they’ll be better than their lab-made doppelgangers.
Antibody-based cancer therapies target proteins that are abundant in cancer cells but absent in normal cells, called tumor specific antigens (TSAs). Cancer researchers inject these antigens into animals such as mice and sharks to induce an antibody response. Then they take a blood sample and find antibodies that target the TSA and adapt them for therapeutic use in the human body.
The animal to human discovery platform is effective. The FDA and European Medicines Agency (EMA) have approved more than 100 monoclonal antibody therapies to date for treating cancer, autoimmune disorders, and infectious diseases. More than 80 more are in clinical trials (1).
Scientists at Atreca think that researchers are leaving some antibodies on the table since most of the monoclonal antibodies used to treat cancer seek out the same handful of targets. Tito Serafini, cofounder and chief strategy officer of Atreca, finds novel TSAs and effective antibody therapeutics that work for many patients with different types of cancers.
How do researchers at Atreca find new antibodies?
We let the human immune system guide us to new antibody targets in cancer cells. Immune systems are constantly scanning the environment looking for what is different, whether it’s from an infectious disease or cancer.
There are lots of tumor antigens generated by cancer cells that the immune system hasn’t seen before. Immunotherapies target these antigens to enhance the cancer immune response. To find antibodies relevant to human biology, why not look at the immune response in a patient with a tumor? That’s what we do. And we're only interested in an active immune response.
For example, when someone gets an mRNA vaccine, the immune system immediately generates antibodies against the new foreign mRNA. Long lived plasma cells go to the bone marrow and make antibodies over a long period of time and become memory B cells that float around in the blood just waiting for the antigen to show up again. Looking through all the memory B cells floating around would be like looking for a needle in a haystack, so we look at a specific type of B cell that is released after affinity maturation — when antibodies gain increased affinity and anti-pathogen activity — that we can easily find the blood. This way, we don’t need a tumor biopsy. We only need a blood sample to find a subset of antibody-producing B cells that are potentially useful to us in building therapeutics to target tumor cells.
We have this huge collection of patient blood samples taken at different times over the course of an individual’s cancer progression. We process several of these longitudinal samples for one patient and look for antibodies present throughout the course of disease. Then we test if the antibodies respond to tumors from other patients by checking if they can bind to tissue samples from patient tumors. If they do, then we synthesize the antibody and test it in the wet lab. We determine if the antibody can effectively target cancer cells in a dish and in animals. Then we start doing experiments needed to apply for an investigational new drug application and start clinical trials.
What is the most exciting project or finding you’ve worked on since you cofounded Atreca?
Our most advanced therapeutic, ATRC-101, is an antibody identified in a patient with lung adenocarcinoma. It targets a novel ribonucleoprotein (RNP) complex that was never described in the literature before we discovered it. The immune system is often directed to RNP complexes that include RNA viruses. In 2020, we started a phase Ib clinical trial and so far, ATRC-101 is very well tolerated. We see clear correlation between clinical activity and target level in the patients; not all patients have the same amount of novel RNP complex in their tumors. We’ve had a complete response in combination therapy with the FDA-approved immunotherapeutic pembrolizumab, which is used to treat a variety of cancers such as breast and skin cancer.
A 78-year-old woman with metastatic melanoma was previously treated with pembrolizumab alone and combination therapy with inhibitors against cancer-causing proteins B-raf proto-oncogene, serine/threonine kinase (BRAF) and mitogen-activated protein kinase kinase (MEK). Each of the prior treatments stabilized her disease, but she had a complete response to our therapy. It’s really exciting that a woman who probably wouldn’t have qualified for a lot of clinical trials due to her metastatic melanoma is now cancer free as far as we can tell so far.
What does the antibody target?
The proteins and mRNA that make up the RNP are in every cell, but the target of ATRC-101 is specific to cancer cells. We don’t know the exact epitope. It could be a tumor-specific post-translational modification to one of the proteins. The modification could change the shape of the complex or how the proteins interact and reveal the antigen.
The complex is interesting. It has hallmarks of being a biomolecular condensate, which is a membrane-free organelle. If it’s a complex that forms in response to a certain type of stress, introducing a stress such as chemotherapeutics could reveal the antigen and make it more effective. It’s pretty exciting.
Reference
- Jin, S. et al. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduction and Targeted Therapy 7, 39 (2022).
