Novel Anti-Angiogenics

Anti-VEGF/DLL4 Bispecific Antibody

Tumor angiogenesis, the formation of new blood vessels in solid tumors, contributes to cancer cell survival, growth and metastasis. An important driver of tumor angiogenesis is the vascular endothelial growth factor (VEGF) signaling pathway. The first FDA-approved inhibitor of the VEGF signaling pathway was bevacizumab (Avastin®, Genentech/Roche), a monoclonal antibody against the human VEGF ligand. The other protein-based inhibitors are ramucirumab (Cyramza®, Eli Lilly), a human monoclonal antibody against human VEGFR, and aflibercept (VEGF-Trap; Eylea®, Regeneron). However, VEGF inhibitors alone do not destroy all blood vessels in tumors. As a result of tumor resistance development to single agent anti-VEGF therapy, cancer patients become refractory to anti-angiogenic therapies. Thus, there is a strong clinical need for next-generation angiogenesis inhibitors to overcome resistance to anti-VEGF therapy.

The second target (DLL4) also plays an important role in vascular development and tumor angiogenesis. It is highly expressed in many human cancers, including gastric, colorectal, ovarian, cervical and lung cancers. Crosstalk between these angiogenesis signaling pathways suggests that the simultaneous blockade of both pathways would provide improved efficacy for the inhibition of tumor progression and angiogenesis. Thus, our bispecific antibody (BsAb) is being developed as a anti-cancer therapeutic antibody. In preclinical studies, the BsAb has demonstrated potent inhibition of each signaling pathway in endothelial cells

Currently, TR009 is being evaluated in clinical Phase 1 studies.

Immune Cell Engaging Bispecifics

4-1BB (CD137, TNFRSF9) is an inducible costimulatory receptor expressed on activated T and Natural Killer (NK) cells. 4-1BB ligation triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. Published preclinical results in a variety of induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies can lead to tumor clearance and durable anti-tumor immunity.

Immune cell costimulation via 4-1BB agonism has also shown anti-tumor activity in the clinic and is an important element of next-generation chimeric-antigen-receptor (CAR) adoptive T-cell therapy approaches. However, the clinical development of first-generation 4-1BB agonistic antibodies has been hampered by significant hepatic toxicity. Also, their activity typically depends on mAb/41BB receptor complex hyperclustering via Fc-gamma-receptor (FcgR)-binding.

TRIGR has licensed 41-BB activating BsAbs (TRIA001, TRIA002) that were designed by ABL Bio to recognize a tumor-associated antigen (TAA) while agonizing immune cells with their 4-1BB-engaging domain. TAA-engagement leads to tumor-targeted cross-linking of 4-1BB receptor, thus providing a safe and effective way for the co-stimulation of T cells and NK cells for cancer immunotherapy.

Future combinations with T-cell engaging bispecific antibodies may provide an alternative and convenient, off-the-shelf approach to CAR T-cell therapies. But a combination with CAR-T (or NK) cells could be envisioned to further enhance anti-tumor activity of cell therapies via 4-1BB-mediated immune activation in the tumor microenvironment.

Dual Immune Checkpoint Inhibitor Bispecifics

Combination therapy using immuno-modulatory therapeutic antibodies for the treatment of cancer patients has shown benefits over monotherapies. For example, the addition of anti-PD-1 antibodies to anti-CTLA-4 treatment in advanced melanoma patients has increased objective response rates from 19% to 57.6% (Larkin, J et al. 2015. NEJM 373:23-34). An alternative to combining two antibodies and achieve often even more potent or unique biological effects of is the generation of bispecific antibodies as it may result in mechanisms of action that were impossible to achieve by mere combination of the antibodies.

TRIO2-01 combines two inhibitory antibodies to well-characterized immune checkpoints into a bispecific antibody. TRIO2-01 has shown excellent potency in vitro re-activating human immune. Also it has demonstrated potent anti-tumor activity in vivo by inhibiting tumor growth more profoundly than the monotherapies using the parental antibodies.

Prospective Pipeline

(Global rights^ except where indicated)

PipelineTargetIndicationINDPhase 1Phase 2
TR009VEGF/DLL4Gastric Cancer, Other Solid TumorsApprovedOngoing2019
TRIO2-01*IO BsAbSolid TumorsQ4.2020

TRIA001**41BB/XXXMultiple MyelomaQ1.2021

TRIA00241BB/ZZZSolid TumorsQ2.20/21

*Excluding Greater China
**Excluding Asia Pacific (TRIGR retains China, Australia, and New Zealand)
^ABL Bio retains S Korean rights to all these assets