Cancer is a notoriously complex monster; hydra-like in its ability to seemingly grow new heads with each one severed. Although significant progress has been made in the development of oncologic therapies, there is still much room to grow in the field, and many more angles of attack to explore. Ironically, although some cancers arise from failures of the immune system to prevent the proliferation of malignant growths in the body due to tumor evasion of immune detection,1 immuno-oncology (IO) leverages the immune system as a method of cancer treatment now and in the years to come.2
As a surgery oncology fellow at the National Cancer Institute, I needed to make in-the-moment decisions regarding surgery that had a direct result for my patient. Though I enjoyed my time as a physician in clinical care, I was always pulled back to the research. During my tenure as Executive Vice President, Global Clinical Development at Regeneron, I’ve had the incredible opportunity to play a role in crafting potential therapies for patients in need. Most recently, the team and I have focused our efforts on advancing our research in immuno-oncology.
Transforming the treatment paradigm in cancer care over the past decade, immunotherapies are a prominent front-runner in the future of oncology.3 However, despite their promise, immunotherapies come with challenges such as the potential for immediate and long-term side effects, high cost, and the potential for a low number of patients responding.4,5,6
There are three major forms of therapy currently available in the realm of immuno-oncology: immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T cells, and bispecific antibodies (bsAbs).7 The eldest of these three is CAR T cell therapy, which entered the clinical landscape in 2006. Five years later, in 2011, immune checkpoint inhibitors entered the IO picture.3 The latest development in IO therapies, bsAbs, are being developed to navigate the complex landscape of immunotherapy.7
Traditional monoclonal antibodies were designed to target a single protein; however, bsAbs are designed to target two molecules/proteins.8 With recent research, Regeneron’s investigational bsAbs are now being explored for use in solid tumors in addition to hematologic malignancies.9
However, the engineering of bsAbs does not come without challenges. Various molecular and cellular factors in the body can impede the function of the lab-made protein, and development often falls into a balancing act of a multitude of factors influencing efficacy and safety.10
In an effort to overcome these obstacles, it is important to follow the science to keep moving forward.
We take this to heart at Regeneron. For more than 30 years, we have strived to be the front-runner of advancement, seeking to set the industry standard for progress.
Thinking outside the box, Regeneron’s guiding ethos is to follow the science with a focus on the end goal being the benefit of patients.
An advantage of spending over a decade researching the space of bsAbs is the opportunity to become experts in a rapidly expanding body of scientists in this field. Regeneron has exemplified this principle with our proprietary VelociSuite® technologies and more than a decade of experience in the novel field of antibody research. First introduced in 2003 and 2007, our VelociGene® and VelocImmune® platforms were used to create our first fully human antibody and are still in use to develop potentially innovative treatments today.11 The time we’ve invested in immunotherapy and oncology research allows us to deeply understand the tumor microenvironment and the complex mechanism of its interaction with the immune system.
Our work and research have led us into the arena of bsAbs. While bsAbs still face several challenges in clinical development, there is hope on the horizon for their use in improving the future of cancer care. Focusing on T cell manipulation via bsAbs, scientists at Regeneron are boldly pushing the boundaries of current knowledge. T cell manipulation via bsAbs creates room for flexibility in immunotherapy research, with the ability to be studied individually as monotherapy or in combination with other oncologic treatments. Regeneron’s T cell engaging bsAbs are artificially created antibodies that are engineered to imitate natural human antibodies as closely as possible.12 They carry two different antigen-binding sites – one arm binds a tumor-associated antigen (TAA) and the other a T cell – which allows for a “bridge” to be made, bringing T cells physically closer to cancerous cells to promote an immune response.13 BsAbs are designed to guide immune cells to tumor sites to help facilitate tumor destruction.6 Our bsAbs pipeline currently holds several types of T cell engagers, which include CD3 and costimulatory CD28 bsAbs, and also tumor-targeting bsAbs.8
An important pillar in our future oncology portfolio is the CD28 signaling pathway, critical for T cell survival and the maintenance of immune homeostasis.14 CD28 co-stimulation regulates a wide range of cellular processes, including proliferation and survival, and promoting the differentiation of specialized T cell subsets.15 More than a decade ago, we began investing in the research and development of costimulating CD28 bsAbs. Through our research into CD28 bsAbs, we hope to leverage the natural recognition of cancer by a T cell and provide costimulation which leads to a potential increase in T cell proliferation, survival, and differentiation into memory/effector-memory T cells.16 Our goal is to use them in combination with CD3 bsAbs or PD-1 inhibitors. We will continue growing our understanding of this key mechanism for enhancing T cell activation and engineer strategies for the use of bsAbs.
Staying the course for scientific advancement, our researchers at Regeneron continue to look ahead for opportunities to pursue new knowledge and share our discoveries with the world. To learn more about Regeneron’s antibody research, visit: https://www.regeneron.com/science/antibodies.
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9. Rader C. Bispecific antibodies in cancer immunotherapy. Curr Opin Biotechnol. 2020 Oct;65:9-16. doi: 10.1016/j.copbio.2019.11.020. Epub 2019 Dec 13. PMID: 31841859; PMCID: PMC7292752.
10. Middelburg J, Kemper K, Engelberts P, Labrijn AF, Schuurman J, van Hall T. Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors. Cancers (Basel). 2021 Jan 14;13(2):287. doi: 10.3390/cancers13020287. PMID: 33466732; PMCID: PMC7829968.
11. Data on file. Regeneron.com: History.
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13. Fahim Halim Khan,Chapter 25 – Antibodies and Their Applications,Animal Biotechnology, Academic Press, 2014,Pages 473-490, https://doi.org/10.1016/B978-0-12-416002-6.00025-0.(https://www.sciencedirect.com/science/article/pii/B9780124160026000250)
14. Esensten J, et al. CD28 costimulation: from mechanism to therapy. Immunity. 2016;44(5): 973–988.
15. Boomer JS, Green JM. An Enigmatic Tail of CD28 Signaling. Cold Spring Harb Perspect Biol 2010;2:a002436.
16. Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44(2):380-390. doi: https://doi.org/10.1016/j.immuni.2016.01.021.