Over the past two decades, antibodies have seized many opportunities—which is to say, there has been a proliferation of therapeutic antibodies that can selectively bind to disease-associated antigens. Nonetheless, antibodies still allow many opportunities to slip through their fingers. Most of the fumbling is in immuno-oncology, where antibody candidates fail to recognize 90–95% of the abnormal antigens present in tumors.
“We’ve hit the wall in terms of how much more we can leverage an antibody,” says David Apelian, MD, PhD. As the CEO of BlueSphere Bio, Apelian is more than willing to consider alternatives to antibodies. Indeed, BlueSphere is interested in developing therapies that rely on T-cell receptors (TCRs). The company is already using TCR technology to seize opportunities presented by blood-based and solid tumors.
“I view TCRs as the guidance system for the next generation of cell therapeutics and bispecifics in immuno-oncology,” Apelian declares. “[TCRs] recognize the vast majority of abnormal proteins that are presented as small peptides on the tumor cell surfaces.”
However, exploiting TCRs for immuno-oncology applications poses two key challenges. One of them is that TCRs are extremely diverse. In most T cells, each TCR consists of two protein chains: an alpha chain and a beta chain. During TCR processing, the chains—which are encoded by different genes, and which contain variable regions—come together in unique pairings that easily number in the tens of millions. Little wonder, then, that compiling a TCR repertoire library is a daunting prospect, even if single-cell profiling is available.
An additional difficulty, Apelian notes, is that the TCR recognizes only the small peptides that are presented on the major histocompatibility complex of each individual’s cells, complicating the capture of a tumor’s neoantigen profile. He adds, “Those small antigens are specific to the patient’s human leukocyte antigen (HLA) type, the same marker used to match a bone marrow donor to a bone marrow recipient.”
Creating TCR/neoantigen libraries
The difficulties that are encountered when compiling TCR repertoire libraries and capturing neoantigen profiles can be overcome with two technology platforms developed by BlueSphere. The first platforms is TCXpress™. It is, according to Apelian, the company’s “foundational technology.” It isolates, amplifies, and clones tumor-infiltrating lymphocytes to create TCR repertoire libraries. The second platform is NEOXpress™. It generates tumor-specific neoantigen libraries.
“TCXpress can capture thousands of TCRs from a tumor or a blood sample in a functional format within days instead of weeks or months,” Apelian asserts. The platform identifies the mutations a tumor exhibits. According to Apelian, this approach to TCR search and capture is “probably 10- to 20-fold more cost effective and faster than traditional approaches.”
TCXpress can be used for patient-specific TCR selection on a tumor-by-tumor basis, as well as for shared antigens across the population. TCRs can be captured for any HLA type, enabling broader and more diverse population coverage. “That’s a unique feature of our platform,” Apelian remarks.
Its broader use, however, is to create clinical assets internally or with partners. “We’re developing a production version of TCXpress as a T-cell discovery platform,” Apelian explains. “It will support strategic partnerships with companies specializing in cell therapeutics, induced pluripotent stem cells, or bispecifics.”
Working together, TCXpress and NEOXpress can screen the TCR and neoantigen libraries against each other. That is, the platforms can pair TCRs to neoantigens and allow the best pairings to be selected for the creation of adoptive TCR T-cell therapies.
First target: High-risk leukemia
BlueSphere’s most advanced program is TCX-101, which uses an engineered TCR to target a minor histocompatibility antigen called HA-1 (miHA-1) in cancer patients who carry HLA-A201. (It has been estimated that HLA-A201 is present in 40–45% of the U.S. and European populations.) Because miHA-1 is expressed in blood cells but not in other tissues, it is an ideal target for treating leukemias. A panel of additional TCRs is being developed to target other miHA antigens with expression restricted to blood cells in less common HLA types to improve population coverage.
TCX-101 is under development for patients who have high-risk leukemias, such as acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome, and who have measurable residual disease after therapy.
“It is designed to increase the chance for success in the context of bone allogeneic stem cell transplantation,” Apelian points out. Specifically, it allows physicians to replace the patient’s stem cells with donor stem cells supplemented by engineered T cells that target only the miHA-1 expressed on the recipient’s leukemia and blood cells, thus providing a desirable effect while minimizing the risk of graft-versus-host disease.
Commercializing TCX-101 in-house is achievable, but the company is open to strategic partnering. Importantly, the same approach used to develop the TCR panel for the TCX-101 program can be applied to virtually any shared antigen and any tumor type, including solid tumors.
The second internal program, TCX-201, focuses on solid tumors. On a patient-specific level, it multiplexes the NEOXpress and TCXpress platforms in a way that rapidly enables researchers to identify foreign elements within a tumor and identify which TCRs elicit the strongest immune response. Then the patient’s own immune cells are engineered to express at least three of the most potent TCRs. The immune cells are amplified in the laboratory and then returned to the patient.
Multiple ways to build value
BlueSphere grew out of research initiated by Mark Shlomchik, MD, PhD, a UPMC Endowed and Distinguished Professor of Immunology at the University of Pittsburgh. To pursue this research, which concerns systemic autoimmune diseases, Shlomchik developed technology to clarify how TCRs trigger autoimmune reactions. When he realized that this work had implications in cancer research, Shlomchik helped launch BlueSphere, which he now serves as chief scientific officer.
Since BlueSphere was founded in 2017, the company has been funded by UPMC Enterprises. Apelian notes that $120 million has been invested in the company to date. “We are well capitalized, even in the current rocky market,” he continues, “and we can fund clinical trials well into 2024.” Currently, BlueSphere is on track to file an Investigational New Drug application this year for the lead product in the company’s TCX-101 program.
BlueSphere is also working to develop a new panel of TCRs to further expand its product portfolio. Although BlueSphere sees what Apelian calls “some very interesting opportunities,” the company is trying to cultivate a mature attitude about growth. “We want to grow and invest in the company aggressively, but without outpacing our ability to maintain focus,” Apelian explains. “It’s a delicate balance.”
(Just after GEN went to press, BlueSphere Bio announced that Keir Loiacono was replacing David Apelian as CEO.)