On January 8, 2020 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported a publication featured on the cover of Science Translational Medicine describing the potential of a new class of cancer immunotherapy known as "costimulatory bispecific antibodies (Press release, Regeneron, JAN 8, 2020, View Source [SID1234552874])." Regeneron and others have previously shown that CD3 bispecifics can result in meaningful clinical responses in previously untreatable cancer settings. The results published today show that adding a novel class of CD28 costimulatory bispecifics to Regeneron’s CD3 bispecifics can lead to synergistic anti-tumor activity in multiple cell culture and animal model experiments, without inducing systemic cytokine release (cytokine storm).
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"This novel class of CD28 costimulatory bispecifics are key to our strategy of developing a broad oncology portfolio – based on rational combinations to efficiently engage the immune system – to address a broad range of cancers, including those that are not responsive to currently available immunotherapy," said George D. Yancopoulos, M.D., Ph.D., Co-Founder, President and Chief Scientific Officer at Regeneron. "We have dosed prostate cancer patients with our first CD28 costimulatory bispecific, REGN5678, in combination with Libtayo (cemiplimab), and we plan to advance additional CD28 costimulatory bispecifics into the clinic for other cancers this year, including in combinations with CD3 bispecifics."
The rationale for combining CD3 and CD28 bispecific antibodies is based on the fact that T-cells require two signals to fully activate. The first "recognition" signal occurs when the T-cell identifies a foreign or mutated protein (antigen), via its T-cell receptor/CD3 complex. However, the T-cell is only fully activated for cancer cell killing after it receives a second "costimulatory" signal, most powerfully via the CD28 costimulatory receptor. Regeneron’s CD3 and CD28 investigational bispecifics are designed to bridge T-cells to cancer cells and simultaneously provide activation through these two signals. The publication demonstrates that this combination approach can drive markedly enhanced T-cell killing of prostate and ovarian tumors in sophisticated genetically-humanized animal models.
"Cancer researchers have long known that CD28-targeted therapies have the ability to supercharge T-cells against cancer, but little progress was made in harnessing this powerful opportunity given historic safety findings with CD28 superagonists. Our goal was to engage the CD28 pathway in a completely novel and targeted way to avoid the issues with generalized CD28 activation," said Dimitris Skokos, Ph.D., Senior Director, Cancer Immunology Research at Regeneron. "Costimulatory bispecifics offered an innovative solution that allowed us to design antibodies with molecular controls to use CD28 to boost T-cell activation only in the presence of cancer cells and after the ‘recognition’ signal had been received. To see this design work preclinically is gratifying, and we are excited to see if these results will translate in human clinical trials."
CD28 superagonists were investigational CD28-targeted monoclonal antibodies. In a Phase 1 trial conducted in 2006 by another company, a CD28 superagonist overactivated T-cells throughout the bodies of healthy volunteers. This caused life-threatening levels of cytokine release syndrome (known as cytokine storm), leading to multiple organ failure. As a result, clinical research into CD28-based treatments was largely stopped.
This led Regeneron to carefully select CD28 costimulatory bispecific antibody candidates that would only activate T-cells when they were bridged to cancer cells and after having received the first "recognition" signal. Regeneron also tested the safety of its CD28 costimulatory bispecifics in several animal models and showed they did not induce cytokine storm when administered as monotherapy or in combination. These findings support the further investigation of CD28 costimulatory bispecifics in combination with other treatments.
"Checkpoint inhibitors and CAR-T cell therapy have transformed cancer treatment over the past decade, but many patients still don’t respond to these immunotherapies. That’s why it’s exciting to see Regeneron’s CD28 costimulatory bispecifics emerge as promising future off-the-shelf solutions," said Jill O’Donnell-Tormey, Ph.D., Chief Executive Officer and Director of Scientific Affairs at the Cancer Research Institute. "The data published in Science Translational Medicine show that Regeneron is helping to expand the boundaries of what may be possible with immunotherapy."
Among the investigational medicines studied in the paper were two CD28 costimulatory bispecifics (PSMAxCD28 and MUC16xCD28) and two CD3 bispecifics (CD20xCD3 and MUC16xCD3).
About the Regeneron Bispecific Antibody Platform
All of Regeneron’s bispecifics are designed to closely resemble natural human antibodies and bind to two different targets. They are derived from a next-generation version of Regeneron’s proprietary VelocImmune technology and created using the company’s Veloci-Bi platform. These allow for the creation of bispecifics with no linkers or artificial sequences. Additionally, Regeneron bispecifics are manufactured using similar approaches used for human antibody medicines, with similar pharmacokinetics.
There are six Regeneron investigational bispecific antibodies currently in ongoing clinical trials for multiple blood cancers and solid tumors. These bispecifics fall into three categories:
CD3 bispecifics are designed to bridge T-cells and tumor cells. At the tumor site, they activate T-cells via their CD3 receptors and promote T-cell killing of the cancer cells. Investigational candidates include:
CD20xCD3 (REGN1979) for non-Hodgkin B-cell lymphomas;
Two distinct BCMAxCD3s (REGN5458 and REGN5459) for multiple myeloma;
MUC16xCD3 (REGN4018) for ovarian cancer.
CD28 costimulatory bispecifics are also designed to bridge T-cells and tumor cells. At the tumor site, they costimulate T-cells via their CD28 receptors and may synergize with PD-1 inhibitors and/or CD3 bispecifics. Investigational candidates include:
PSMAxCD28 (REGN5678) in combination with Libtayo for prostate cancer.
Tumor-targeted bispecifics are designed to target proteins only on the cancer cell. In this way, they may affect various signaling pathways to hamper the cancer cells’ ability to survive and proliferate. Investigational candidates include:
METxMET (REGN5093) for non-small cell lung cancer that is driven by MET mutations and/or amplifications. REGN5093 targets two different parts of the MET receptor on cancer cells to degrade the receptor and block its ability to trigger cell proliferation.
Regulatory Status of Oncology Programs
The bispecifics mentioned in this release are currently under clinical development, and their safety and efficacy have not been evaluated by any regulatory authority.
Libtayo in combination with REGN5678 is currently under clinical development for prostate cancer, and its safety and efficacy have not been evaluated by any regulatory authority for this use. Libtayo is currently approved in the U.S. for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation, and in other countries for similar indications. In the U.S., the generic name for Libtayo is cemiplimab-rwlc, with rwlc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration.
As part of a global collaboration agreement, Regeneron and Sanofi are jointly developing Libtayo, as well as Regeneron’s BCMAxCD3 and MUC16xCD3 bispecific programs.