Non-Hodgkin lymphoma (NHL) is an umbrella term for a group of cancers that develop in the body’s lymphatic system. Examples of sub-indications are patients with Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL) and Marginal Zone Lymphoma (MZL). Examples of subindications are patients with Mantle Cell Lymphoma, Follicular Lymphoma, and Marginal Zone Lymphoma. Aggressive lymphomas are usually treated with combinations of various chemotherapeutic agents and monoclonal anti-bodies such as rituximab (Rituxan®, Mabthera®, Roche). Low-grade lymphomas have a better prognosis and treatment is often only initiated once a patient has disease symptoms.
Strategic collaboration with Pfizer - developing antibodies that act on tumour-associated myeloid cells
In partnership with Pfizer Inc. since December 2016, BioInvent works to identify novel oncology targets and therapeutic antibodies that may either reverse the immunosuppressive activity of tumor-associated myeloid cells or reduce the number of tumor-associated myeloid cells in the tumor.
BioInvent announced in July 2019 selection of the first target and in December 2019 the second target discovered by BioInvent’s proprietary F.I.R.S.T™ technology platform under the collaboration with Pfizer Inc. The selection of targets triggered two payments from Pfizer to BioInvent of $0.3 million. Under the terms of the 2016 agreement, potential selection and development of antibodies directed against this target, as well as potential selection of further targets and development of antibodies directed at them, would allow BioInvent to be eligible for further milestone payments.
In July 2020 BioInvent announced that the research term under its collaboration and license agreement with Pfizer had been further extended until the end of 2020. The purpose of the research extension is to permit the companies to further identify and characterize new targets and antibodies binding to these targets.
BioInvent is eligible for potential future development milestones in excess of $500 million (assuming five antibodies are developed through to commercialization). The Company could also receive up to double digit royalties related to product sales. In exchange, Pfizer will have the right to develop and commercialize any antibodies generated from this agreement.
BioInvent received an upfront payment of $3 million when the agreement was signed in December 2016, and research funding has been received during 2017, 2018 and 2019. Pfizer also made a $6 million equity investment in new shares of BioInvent when the agreement was signed.
Developing antibodies that act on regulatory T cells (Tregs) via novel or validated targets
Tregs can substantially inhibit various immune responses, enabling tumor cells to escape detection. BioInvent is utilizing its F.I.R.S.T™ platform to identify and characterize monoclonal antibodies to cancer-associated Treg targets in a function-first, target-agnostic, manner. The company is also pursuing differentiated antibodies to known targets through novel mechanisms and pathways.
BI-1808 and BI-1910 (anti-TNFR2)
Two different types of TNFR2 targeting antibodies are being developed by BioInvent – BI-1808 (a ligand blocker), and BI-1910 (an agonist).
A clinical trial application was submitted in June 2020 to begin a Phase I/IIa, first-in-human study of BI-1808, as a single agent and in combination with KEYTRUDA® (pembrolizumab) for the treatment of solid tumors or cutaneous T-cell lymphoma (CTCL). Phase I clinical trial with BI-1808 expected to start before the end of 2020
The study will explore the safety, tolerability, and potential signs of efficacy of BI-1808 as a single agent and in combination with KEYTRUDA® in patients with ovarian cancer, non-small cell lung cancer and cutaneous T cell lymphoma. It will also investigate the expression of potential immunological markers that might be associated with clinical responses. It will be conducted at several sites across Europe and the U.S. and is expected to enroll approximately 120 patients.
The Phase I stage is divided into two sections. Part A is a dose escalation of BI-1808 to assess safety, tolerability, and pharmacokinetics & pharmacodynamics, and to determine the recommended dose as a single agent for Phase II trials. It will be followed by part B, which will explore the safety, tolerability and recommended dose of BI-1808 in combination with KEYTRUDA®. Phase IIa will consist of expansion cohorts to assess signs of efficacy of BI-1808 as single agent and in combination with KEYTRUDA® in lung cancer and ovarian cancer patients. A separate cohort will explore the activity as single agent in CTCL (Sézary syndrome and mycosis fungoides).
Exciting translational data was presented at AACR Virtual Annual Meeting II in June 2020. In vivo studies show that both ligand-blocking and agonistic antibodies regress large established tumors and synergize with anti-PD-1 therapy. Further mode-of-action dissection demonstrate that while the ligand-blocking antibody depleted intratumoral Tregs, the agonist increased intratumoral CD8+ T effector cells. Both antibodies expanded tumor-specific CD8+ T cells and induced long-lasting T cell memory.
BioInvent has identified tumor necrosis factor receptor 2 (TNFR2), a member of the so called TNFR superfamily (TNFRS) as a target within the Treg program.
TNFR2 is particularly upregulated on tumor-associated regulatory T cells (Tregs) and has been shown to be important for their expansion and survival. As a part of its Treg program, BioInvent identified and characterized a wide panel of TNFR2-specific antibodies, generated from its proprietary n-CoDeR® library and unique F.I.R.S.TTM discovery tool, of which BI-1808 and BI-1910 are the lead development candidates.
BT-001 - Partnership with Transgene – developing next generation oncolytic viruses expressing an anti-CTLA-4 antibody to treat solid tumors
BioInvent and Transgene announced in March 2020 that the first clinical trial application for BT-001 was submitted and that the first-in-human trial is expected to start before the end of 2020 in Europe and the US.
Promising findings was presented at AACR Virtual Annual Meeting II in June 2020. Cure rates exceeding 70% were seen in multiple mouse models, demonstrating the powerful therapeutic effect of BT-001 when used as a single agent, providing a solid basis for BT-001’s upcoming clinical development. BT-001 has multiple mechanisms of action. It has been designed to combine the killing of cancer cells (oncolysis), and the production of the anti-CTLA4 antibody and GM-CSF directly in the tumor site, while also generating an immune response against tumor cells. It was shown that the anti-CTLA-4 antibody and GM-CSF accumulate in tumors with low systemic exposure. When new tumor cells were implanted in mice that had been cured after a first BT-001 treatment, a strong tumor-specific response and long-lasting immune memory were developed by these mice. These data indicate that BT-001 has the potential to make a significant difference in the treatment of solid tumors.
BioInvent and Transgene collaborate to co-develop oncolytic virus (OV) candidates encoding a validated anti-CTLA-4 antibody sequence – potentially with additional transgenes – aimed at treating solid tumors, with the potential to be significantly more effective than the combination of a virus and an antibody as single agents.
Transgene is contributing both engineering expertise, as well as its proprietary Vaccinia viruses, designed to directly and selectively destroy cancer cells by intracellular replication of the virus in the cancer cell (oncolysis). Oncolysis induces an immune response against tumors, while the “weaponized” virus allows the expression of genes carried by the viral genome, here an immune modulatory anti-CTLA-4 antibody, which will further boost immune response against the tumor.
BioInvent is providing its cancer biology and antibody expertise to the collaboration, as well as anti-CTLA-4 antibody sequences generated through its proprietary n-CoDeR®/F.I.R.S.TTM platforms.
In March 2019 BioInvent and Transgene announced an extension of their collaboration to co-develop multifunctional oncolytic viruses encoding antibodies targeting an undisclosed target, which can be used in the treatment of a broad range of solid tumors.
The research and development costs, as well as revenue and royalties from candidates generated from the collaboration, are shared 50:50.