JS001 (toripalimab, anti-PD-1 mAb)
JS001, or toripalimab, is a recombinant humanized anti-PD-1 monoclonal antibody for injection addressing various malignant tumors. We optimized JS001 through various R&D steps, in particular the discovery and efficient identification of new molecular entities, the humanization of mouse antibodies, functional evaluation of antibody leads in vivo and the construction of productive and stable cell lines, all of which made JS001 an innovative drug with distinctive treatment advantages.
JS001 is our most advanced product candidate and obtained approval for the new drug application (NDA) from the National Medical Products Administration of China (NMPA). We currently are cooperating with KOLs and PIs in a number of clinical trial centers in the PRC to conduct Phase II and Phase III clinical trials of JS001 for oncological indications including malignant melanoma, urothelial cancer, gastric cancer, esophageal cancer and nasopharyngeal cancer. We also started Phase I clinical trial in the United States in March 2018.
Mechanism of Action
PD-1 is an immune checkpoint receptor on the surface of T cell. As shown in the following diagram, when PD-1 binds PD-L1/PD-L2 on the surface of a tumor cell, the T cell receives an inhibitory signal. The inhibition via PD-1 and its ligands leads to T-cell anergy and therefore blocks the productive antitumor immune response. Anti-PD-1 monoclonal antibody is designed to prevent PD-1 binding PD-L1/PD-L2 and thereby the function of T cell recovers.
Features of JS001
The binding affinity of JS001 for PD-1 was measured by Biacore T200. Such KD measure of the affinity of JS001 was approximately 0.3 nM. The result shows high binding affinity of JS001, which enables it to bind more firmly to its specific antigen PD-1 receptor and to better compete against the binding of PD-L1 and PD-L2 on tumor cells.
Strong internalization induction
Upon binding with its specific antigen PD-1 receptor, JS001 blocks the interaction of PD-1 and its ligand and simultaneously induces the internalization of PD-1 receptor and decreases the expression of PD-1 on the cell membrane surface. Immunofluorescence assay results below show that JS001 induced strong internalization induction.
JS001-induced PD-1 internalization was directly visualized by microscopy using 293T.hPD1 cells. 293T.hPD1 cells were incubated at 37°C with 0.3 μg/mL of CypHer5E-labeled JS001. Upon internalization, the endosomes containing the labeled antibody are acidified, rendering CypHer5E fluorescent and visualized. Shown are pictures of an individual cell taken at 30 min and 6 hours. By 6 hours, punctate fluorescence and the accumulation of fluorescent vesicles (dots or small circles of fluorescence) can clearly be visualized in the large cytoplasmic region of the 293T.hPD1 cell.
The following graphs show a decrease in PD-1 expression on the cell surface during internalization of JS001 by simultaneously staining the JS001 non-competitive anti-PD-1 monoclonal antibody (clone MIH4). A decrease in PD-1 expression can improve the reactivity of T cells to the antigen. This mechanism does not rely on PD-1 ligand (PD-L1) expression.
MFI= mean fluorescence intensity. PD-1 predominantly expressed on activated T lymphocytes. Dose dependent JS001-induced PD1 internalization was observed in activated T cells of human PBMC. PD-1 internalization were confirmed with CypHer5E-labeled JS001 and counter-stained with a PE-conjugated non-competing PD-1 mAb clone MIH4, which shows surface PD-1 level. In the left chart, a negative correlation was observed between CypHer5E fluorescence intensity (blue line) and surface PD-1 level after JS001 treatment (red line). In the right chart, JS001-induced PD-1 internalization (blue line) increased steadily over time, up to 6 hours (the longest time tested) following antibody incubation, while cell surface PD-1 level (red line), conversely, declined over time.
Clinical Trial Results
Combination Therapies of JS001
In addition to monotherapies, PD-1/L1 inhibitors have shown significant potential in combined therapies according to the F&S Report. In addition to the JS001+Axitinib combination therapy clinical trial for metastatic mucosal melanoma as described above, we are cooperating with third party pharmaceutical companies to develop other combination therapies.
JS003 (anti-PD-L1 mAb)
JS003 is a humanized monoclonal antibody targeting PD-L1 protein. PD-L1 has emerged as an important cancer biomarker and a target for immunotherapy. The targeted blockade of PD-L1 may help to restore the antitumor response. PD-L1 is frequently expressed on tumor cells and tumor-infiltrating immune cells within the tumor microenvironment. The binding of PD-L1 to PD-1 induces T-cell exhaustion, a state of ineffective T-cell activity. Proven by a number of clinical researches, the blockade of PD-L1 binding to PD-1 reverses T-cell exhaustion and strengthens antitumor activity, which has become one of the promising strategies in immuno-oncology. A number of international pharmaceutical companies have developed antibody drugs targeting PD-L1, among which three PD-L1 inhibitor drugs have been marketed and shown significant efficacy.
Preclinical studies have demonstrated that JS003, which binds to PD-L1 with high affinity, is effective in blocking the interaction between PD-L1 and PD-1 and thereby activate the T cell’s antitumor activity. We have filed an IND application to the CDA. Based on the clinical results of the drugs targeting the same checkpoint inhibitor, we intend to further study on the mechanism of action of its cell and molecule, compare its efficacy, immunogenicity and safety with other marketed anti-PD-L1 products.
JS101 (CDK inhibitor)
JS101 is a chemical drug that inhibits the function of cyclin-dependent kinases (“CDKs”). CDK inhibitors are used to treat cancers by preventing over-proliferation of cancer cells. We developed JS101 and filed an IND to the CDA in July 2018. We have also applied for a patent regarding JS101. We plan to formulate our strategy for next steps of JS101 based on the progress of clinical trials.
JS002 (anti-PCSK9 mAb)
JS002 is a recombinant humanized anti-PCSK9 monoclonal antibody for injection, which is designed for the treatment of certain cardiovascular diseases. We are conducting Phase III clinical studies with larger patient population for further verification of efficacy and safety.
Mechanism of Action
PCSK9 has emerged as a promising treatment target to lower serum cholesterol, a major risk factor of cardiovascular diseases. PCSK9 binds the LDL receptor at the surface of hepatocytes, preventing LDL-R recycling and enhancing its degradation in endosomes/lysosomes. PCSK9 inhibitors block the interaction of PCSK9 and the LDL receptor, which enhances LDL-C clearance from plasma by increasing hepatic expression of LDL receptors. The FDA approved PCSK9 inhibitors for the treatment of hypercholesterolemia have demonstrated their ability to lower LDL-C levels and reduce the risk of cardiovascular disease.
Features of JS002
JS002 is an innovative anti-PCSK9 monoclonal antibody. JS002 can bind with high affinity to human PCSK9, block the binding of PCSK9 to LDL-R on the cell surface, reduce endocytosis of LDL-R, and enhance the uptake of LDL-C by the liver cells, to reduce LDL-C level in the blood. JS002 has the following main features demonstrated in the preclinical studies:
(1) With high affinity and a new CDR structure, it is able to identify more types of PCSK9;
(2) No obvious side effect was observed during the single-dose toxicity studies and repeated-dose toxicity studies of macaca fascicularis or rattus norvegicus;
(3) Based on the pharmacodynamics results from the preclinical studies, JS002 has demonstrated to be effective in lowering the LDL-C level in macaca mulatta models with hypercholesterolemia;
(4) The pharmacokinetic profile of JS002 is similar to the marketed PCSK9 inhibitors.
UBP1211 (anti-TNF-α mAb)
UBP1211 is a recombinant human anti-TNF-α monoclonal antibody injection targeting autoimmune diseases. UBP1211 is a biosimilar of Humira (adalimumab), a TNF-α-inhibiting, anti-inflammatory biologic medication indicated for several immune-mediated inflammatory diseases. Pursuant to the Technical Guideline for Development and Evaluation of Biosimilars (Proposed Guideline) issued by the CDA in February 2015, we are concurrently conducting Phase I and Phase III studies to compare the similarities between UBP1211 and Humira in patients with moderate to severe rheumatoid arthritis. The extensive comparison of the physicochemical structure and biologic function of UBP1211 and Humira we have conducted showed structural similarity and comparable functionality, demonstrating that UBP1211 has similar efficacy, safety and immunogenicity to Humira.
Mechanism of Action
TNF-α is a potent inducer of the inflammatory response and key regulator of innate immunity. It is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis and psoriasis. Anti-TNF-α monoclonal antibody, which suppresses the immune response of TNF-α, is a new generation therapy treating immune-mediated inflammatory diseases with high efficacy and safety profile and convenient administration methods.
Humira and Its Biosimilar UBP1211
Humira is a fully human monoclonal antibody targeting TNF-α. It is an established biologic treatment for a number of autoimmune diseases including rheumatoid arthritis. Based on several studies to evaluate the effectiveness and safety of Humira in patients with rheumatoid arthritis, Humira has not only demonstrated significant, rapid, and sustained improvements in disease activity, but has also improved functional status, quality of life and work productivity in rheumatoid arthritis patients with acceptable safety profile.
The structural, functional and pharmacokinetic evaluations of UBP 1211 have shown that it is highly similar to Humira, proving UBP1211’s potential to reduce the signs and symptoms of moderate to severe rheumatoid arthritis in adults with an acceptable safety profile.
The Phase I clinical trial is a randomized double-blind trial to compare the similarities between UBP1211 and Humira. The safety data were collected from all subjects in the study without distinguishing between the two drugs. As at June 25, 2018, a total of 154 subjects were enrolled in the study.
Development Collaboration with Jiangsu T-mab BioPharma Co., Ltd (“T-mab”)
In August 2017, we entered into a collaborative research, development and commercialization agreement with T-mab, a biotech company focused on the development of biologics.
UBP1213 (anti-BLyS mAb)
UBP1213 is a recombinant humanized anti-BLyS monoclonal antibody injection, which is being developed for the treatment of systemic lupus erythematosus (“SLE”) and other autoimmune diseases. We received IND approval from the CDA in October 2016.
Mechanism of Action
BLyS is produced by macrophages, neutrophils and monocytes SLE. It is required for the survival of B cells. Excessive level of BLyS induces abnormally high survival of autoreactive B cells and differentiation of B cells into antibody-producing plasma cells, which causes SLE and other autoimmune diseases. The FDA approved BLyS inhibitor for the treatment of SLE has shown statistically significant, albeit modest, efficacy, representing a step forward in treating SLE.
Features of UBP1213
UBP1213 has the following main features demonstrated in the preclinical studies:
(1) The dissociation rate of UBP1213 and BLyS is slow and the affinity is strong;
(2) UBP1213 has a strong ability to inhibit the binding of soluble BLyS and BR3-Fc;
(3) In single dose toxicity study with 40 times the Minimal Anticipated Biological Effect Level (MABEL) dosage and repeated dose toxicity study with 10 times the MABEL dosage on cynomolgus monkeys, the findings in the studies were reversible and could be related to the pharmacological effect of the test article, reflecting high safety profile of UBP1213;
(4) Typical pharmacokinetic behavior of monoclonal antibodies was demonstrated in the pharmacokinetic studies on cynomolgus monkeys adopting single doses of low, medium and high doses and multiple doses of medium dose.
Based on the above features of UBP1213, we are advancing UBP1213 to the clinical trials stage for the treatment of adult patients with SLE.
Cooperation with WHKB
Shanghai Union Biopharm entered into an agreement (the “WHKB Agreement”) in May 2012 with Wuhan Huaxin Kangyuan Biopharma Co., Ltd. (“WHKB”).