UMBRALISIB (TGR-1202) IS A DUAL-ACTING INHIBITOR OF PI3K-DELTA AND CK1-EPSILON
TG-1801 IS A FIRST-IN-CLASS ANTI-CD47/CD19 BI-SPECIFIC MONOCLONAL ANTIBODY
TG-1701 IS A NOVEL COVALENT BTK INHIBITOR
TG-1501 IS A NOVEL ANTI-PDL1 MONOCLONAL ANTIBODY
UBLITUXIMAB (TG-1101) IS A NOVEL GLYCOENGINEERED ANTI-CD20 MONOCLONAL ANTIBODY
PI3k-Delta/ CK-1 Epsilon
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PI3k-Delta/ CK-1 Epsilon
Umbralisib (TGR-1202) is an investigational dual inhibitor of PI3K delta and CK1 epsilon, which is administered orally once daily. The phosphoinositide-3-kinases (PI3Ks) are a family of enzymes involved in many important cellular functions, including cell proliferation and survival, cell differentiation, intracellular trafficking, and immunity. There are 4 isoforms of PI3K (alpha, beta, delta, and gamma), of which the delta isoform is highly expressed in hematopoietic cells. Dysregulation of the PI3K pathway is among one of the most commonly mutated pathways across all of cancer biology.
Umbralisib is highly selective for the delta isoform of PI3K and has limited to no impact on the other isoforms. Umbralisib also inhibits casein kinase 1 epsilon (CK1 epsilon). CK1 epsilon is a major regulator of oncoprotein translation, which drives growth and survival of lymphoma cells, including c-Myc, and may contribute to a protective effect against autoimmune-related toxicities. In addition, umbralisib has a pharmacokinetic (PK) profile that allows for oral, once daily dosing.
Presently, umbralisib is being evaluated in phase 2b and phase 3 trials in patients with NHL and CLL, both as a single agent and in combination with other agents including ublituximab.
TG-1801 is an investigational first-in-class, bispecific anti-CD47/CD19 monoclonal antibody. It is the first therapy to target both CD19, a B-cell specific marker widely expressed across all B-cell malignancies, and CD47, the “don’t eat me” signal used by tumor cells to evade macrophage mediated phagocytosis. CD47 is also expressed ubiquitously on normal cells, including red blood cells and platelets, where it helps to regulate the population of aging normal cells in the body. The CD19 component is designed to improve the targeting of TG-1801 to malignant cells that express CD19, while avoiding blockade of CD47 on normal cells. By co-targeting both CD47 and CD19, TG-1801 is designed to avoid indiscriminate blockade of CD47 on healthy cells. In addition, the co-targeting of CD19 may provide a secondary mechanism of direct anti-tumor activity through the engagement of effector cells and induction of antibody dependent cellular cytotoxicity (ADCC).
In preclinical assays, TG-1801 has demonstrated a potent ability to induce antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) of malignant B-cell lines and primary tumor B cells from patients with acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL). and numerous other subtypes of NHL.
A first-in-human phase 1 study of TG-1801 is ongoing in patients with B-cell lymphoma.
TG-1701 is an investigational oral, once-daily BTK inhibitor that irreversibly binds to and inhibits Bruton’s tyrosine kinase (BTK), a crucial driver of B-cell proliferation.
B-cell receptor (BCR) signaling drives normal B-cell development and supports the growth and survival of malignant B cells. Targeting BTK has been validated as a therapeutic strategy for B-cell malignancies such as CLL and NHL.
A phase 1 study evaluating TG-1701 as a single agent alone and in combination with ublituximab and umbralisib in patients with CLL and NHL is ongoing.
TG-1501 (cosibelimab) is an investigational fully humanized monoclonal antibody that binds to the programmed death-ligand 1 (PD-L1) and blocks its interactions with PD-1. It has been well established that cancer cells can evade anti-tumor immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Signals from PD-L1 on tumor cells and in the tumor microenvironment help those tumors avoid immune mediated elimination by preventing activation of tumor-specific effector T-cells. Anti-PD-L1 antibodies are designed to block that signal, permitting effector T-cells to attack and kill the cancer.
Despite the demonstrated activity of anti-PD-L1and PD-1 therapy across a variety of cancers, there is limited clinical trial experience with this class of drugs across different types of B-cell cancers such as Non-Hodgkin’s Lymphoma (NHL) and chronic lymphocytic leukemia (CLL), which is the focus of our team.
Preclinically, it has been shown that the effects of anti-PD-L1 can be enhanced by complementing other mechanisms in the tumor microenvironment, like targeting CD20 and CD47 for example, which may render the malignant cells more vulnerable to the host immune system. Based on this preclinical data, we are exploring combination regimens in an effort to optimize the effects of the anti-PD-L1 antibodies against lymphoma and CLL.
A phase 1 trial in the United States is evaluating TG-1501 alone and in combination with umbralisib and ublituximab in patients with CLL and NHL.
Ublituximab (TG-1101) is an investigational glycoengineered monoclonal antibody that targets a unique epitope on CD20-expressing B cells. When ublituximab binds to the B cell it triggers a series of immunological reactions (including antibody-dependent cellular cytotoxicity [ADCC] and complement dependent cytotoxicity [CDC]), leading to destruction of the cell. Additionally, ublituximab is uniquely designed, to lack certain sugar molecules normally expressed on the antibody. Removal of these sugar molecules, a process called glycoengineering, has been shown to enhance the potency of ublituximab, especially the ADCC activity.
Targeting CD20 using monoclonal antibodies has proven to be an important therapeutic approach for the management of B-cell malignancies and autoimmune disorders, both diseases driven by the abnormal growth or function of B cells.
Ublituximab is being evaluated in pivotal and early phase clinical trials for patients with NHL, CLL, and relapsing forms of multiple sclerosis (RMS).