- Studies provide rationale to investigate KTN0158, an anti-KIT monoclonal antibody, targeting mast cells to potentiate T-cell checkpoint inhibitor drugs in oncology
- KTN0158 clinical studies in oncology planned for 2016
NEW HAVEN, CT, USA I November 6, 2015 I Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs), today announced results from preclinical studies using an anti-KIT monoclonal antibody to enhance T-cell checkpoint blockade in the treatment of cancer. The data are being presented in an oral session at the 30th Annual Society for Immunotherapy of Cancer (SITC) Conference, being held November 4-8 in National Harbor, Maryland. Kolltan plans to initiate clinical studies early next year for KTN0158, a selective and potent anti-KIT antibody drug candidate that targets KIT as an oncogenic tumor driver and in mast cell diseases.
The preclinical results will be presented in a poster titled, “Targeting KIT on Innate Immune Cells enhances the Antitumor Activity of Checkpoint Inhibitors in vivo” (Abstract ID 112276, Session Title: Innate Immunity, Oral Presentation Time 5:00pm to 5:15pm EST, Session Time: 4:05pm to 5:30pm EST on Saturday, November 7, 2015).
Mast cells highly express KIT and are present in the tumor microenvironment where they play an important role in immune regulation either directly or in relationship to myeloid derived suppressor cells (MDSCs). Kolltan will present data at the SITC Conference from preclinical studies showing that inhibition of KIT with anti-KIT antibodies resulted in a marked decrease in these MDSCs in tumor-bearing mice. The studies also showed that selective blockage of KIT with a monoclonal antibody enhanced the antitumor activity of T-cell checkpoint inhibitors in syngeneic mouse tumor models. KTN0158 is a proprietary, humanized anti-KIT IgG1 monoclonal antibody drug candidate that selectively and potently inhibits KIT and is being developed as a potential therapy for cancer and mast cell-related diseases. The Company plans to file an investigational new drug application (IND) for KTN0158 with the FDA in the fourth quarter of 2015.
“Kolltan’s initial clinical trial for this program will focus on the evaluation of KTN0158 as a single agent to treat human cancers based on recently disclosed positive preclinical data showing substantial tumor shrinkage in canine mastocytomas. Our new data being presented at SITC this week support the use of KTN0158 to enhance T-cell checkpoint inhibition, and the Company is planning clinical studies for KTN0158 in combination with checkpoint inhibitor drugs,” said Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.
Dr. McMahon added, “Kolltan has four RTK programs targeting different receptor tyrosine kinases expressed on mast cells and macrophages. Our development program, targeting KIT, and our research efforts, focusing on Tyro3, Axl and MerTK (TAMs), address different RTK roles in innate immunity and have potential applications in oncology, autoimmunity, and inflammation.”
“We are excited to move the KTN0158 program forward to understand the potential of how our KIT-targeting antibody may benefit cancer patients with different tumor types. There is compelling third party literature with preclinical and clinical data showing that the presence of high levels of MDSCs limits the effectiveness of checkpoint inhibitor drugs, including those that target CTLA4 and the PD1 axis,” said Theresa LaVallee, Ph.D., Senior Vice President Translational Medicine and Product Development of Kolltan. “Kolltan’s impressive preclinical findings showing inhibition of MDSCs and improved antitumor activity with the combination of an anti-KIT antibody and checkpoint inhibitors support our efforts to advance KTN0158 into clinical development early next year.”
The presentation at the SITC Conference includes the following results and data:
- Third party published preclinical data indicate that inhibiting KIT signaling in tumors decreases the number of mast cells and myeloid derived suppressor cells (MDSCs) immunosuppressive cells, in the tumor microenvironment. Further third party preclinical studies show this increased the survival of tumor bearing mice.
- In third party published clinical studies, patients with high levels of circulating MDSCs have reduced clinical benefit from ipilimumab treatment.
- The combination of anti-KIT and anti-CTLA4 antibodies in preclinical studies had substantial antitumor effects, comparable to that observed for anti-CLTA4 plus anti-PD1 antibodies.
- Anti-KIT antibody treatment substantially reduces monocytic MDSC numbers in spleens and tumors in preclinical studies.
About KTN0158
KTN0158 is a proprietary, humanized monoclonal antibody designed using structure-based approaches to block the activation of KIT, an RTK that is expressed on many cancers and mast cells. Kolltan applied novel insights about the x-ray crystallographic structure of the KIT receptor to identify a unique way to inhibit the function of KIT through binding to the domain that is near the cell membrane and blocking dimerization. This targeting of KIT proximal to the membrane is a novel approach compared to targeting the ligand and led to Kolltan’s discovery of KTN0158.
There are currently no KIT-targeting antibodies on the market for any disease indication. In oncology, KIT is expressed in tumors such as GIST, melanoma, AML, SCLC, and others. Additionally, KIT is expressed in immune suppressive cells in the tumor microenvironment and thus, may provide a novel combination treatment for immuno-oncology. There are several KIT-targeting small molecule drugs approved for use in GIST where mutant KIT is present. However, no KIT-targeting drugs are approved for non-GIST tumor types, and treatment of GIST tumors does not always lead to long-term clinical benefit due to resistance, including secondary mutations that overcome small-molecule drug approaches.
The Company believes KTN0158 as a monoclonal antibody is particularly suited to block KIT dimerization and inhibit activation and signaling of the receptor and therefore result in potent and selective inhibition of both wild-type and mutant KIT forms. Kolltan is planning to file an IND with the FDA for KTN0158 in 2015 followed by the initiation of clinical trials in oncology (GIST and other KIT-expressing tumors) in 2016. A second IND filing for KTN0158 is anticipated in 2016 for neurofibromatosis 1 (NF1). KIT and mast cells have been associated with the etiology of NF1, an orphan disease afflicting approximately 100,000 individuals in the U.S.
About Kolltan Pharmaceuticals
Kolltan, a privately held clinical-stage company, is focused on the discovery and development of novel, antibody-based drugs targeting RTKs for the treatment of cancer and other diseases with significant unmet need. Kolltan’s founders and members of its management team have deep expertise and a proven track record in drug discovery, development, and commercialization of innovative therapeutics, including drugs targeting RTKs. Kolltan is working in close collaboration with the laboratory of Kolltan Co-Founder, Dr. Joseph Schlessinger, as well as the Yale University medical and scientific community. The Company has a broad and novel portfolio of therapeutic biologics targeting multiple RTKs that are advancing in clinical and preclinical development and are expected to generate multiple near-term milestones. Kolltan’s most advanced product candidates include KTN3379, a human monoclonal antibody designed to block the activity of ErbB3 which is in Phase 1b clinical trials in solid tumors, and KTN0158, a humanized monoclonal antibody designed to block the activation of KIT, which is being developed as a potential therapy for cancer and mast cell-related diseases and is anticipated to enter clinical trials in early 2016.
SOURCE: Kolltan Pharmaceuticals
