Anti-KIT monoclonal antibody CDX-0159 induces profound and durable mast cell suppression in a healthy volunteer study.

BACKGROUND: Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC-targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX-0159, an anti-KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. METHODS: CDX-0159-mediated KIT inhibition was tested in vitro using KIT-expressing immortalized cells and primary human mast cells. CDX-0159 safety and pharmacokinetics were evaluated in a 13-week good laboratory practice (GLP)-compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double-blinded placebo-controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX-0159. RESULTS: CDX-0159 inhibits SCF-dependent KIT activation in vitro. Fc modifications in CDX-0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX-0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX-0159 led to dose-dependent, profound suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. CONCLUSION: CDX-0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell-driven disorders.

Novel 6-aminofuro[3,2-c]pyridines as potent, orally efficacious inhibitors of cMET and RON kinases.

A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.

KTN0158, a Humanized Anti-KIT Monoclonal Antibody, Demonstrates Biologic Activity against both Normal and Malignant Canine Mast Cells.

Purpose: KTN0158 is a novel anti-KIT antibody that potently inhibits wild-type and mutant KIT. This study evaluated the safety, biologic activity, and pharmacokinetic/pharmacodynamics profile of KTN0158 in dogs with spontaneous mast cell tumors (MCT) as a prelude to human clinical applications.Experimental Design: Cell proliferation, KIT phosphorylation, and mast cell degranulation were evaluated in vitro KTN0158 was administered to 4 research dogs to assess clinical effects and cutaneous mast cell numbers. Thirteen dogs with spontaneous MCT were enrolled into a prospective phase I dose-escalating open-label clinical study of KTN0158 evaluating 3 dose levels and 2 schedules and with weekly assessments for response and clinical toxicities.Results: KTN0158 was a potent inhibitor of human and dog KIT activation and blocked mast cell degranulation in vitro In dogs, KTN0158 was well tolerated and reduced cutaneous mast cell numbers in a dose-dependent manner. Clinical benefit of KTN0158 administration in dogs with MCT (n = 5 partial response; n = 7 stable disease) was observed regardless of KIT mutation status, and decreased KIT phosphorylation was demonstrated in tumor samples. Histopathology after study completion demonstrated an absence of neoplastic cells in the primary tumors and/or metastatic lymph nodes from 4 dogs. Reversible hematologic and biochemical adverse events were observed at doses of 10 and 30 mg/kg. The MTD was established as 10 mg/kg.Conclusions: KTN0158 inhibits KIT phosphorylation, demonstrates an acceptable safety profile in dogs, and provides objective responses in canine MCT patients with and without activating KIT mutations, supporting future clinical evaluation of KTN0158 in people. Clin Cancer Res; 23(10); 2565-74. ©2016 AACR.

Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression.

The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8+ and CD4+ T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types. Mol Cancer Ther; 16(4); 671-80. ©2017 AACR.

Educational and health services innovation to improve care for rural Hispanic communities in the US.

BACKGROUND: Access to comprehensive and quality health care services is difficult for socioeconomically disadvantaged groups in rural regions. Barriers to health care for rural Latinos include lack of insurance, language barriers and cultural differences. For the Latino immigrant population in rural areas, barriers to access are compounded. HEALTH NEEDS OF RURAL AREAS: THE CASE OF WALHALLA, SC: The town of Walhalla, South Carolina is a rural community located in Oconee County, the northwest corner of the state. Disparities exist between rural and urban residents in several health categories, and these disparities illustrate the need to provide competent, appropriate and affordable healthcare to rural populations. The Hispanic population of Oconee has dramatically increased in the past decade, and the majority of these immigrants have no health insurance and have limited access to health services. DESIGNING A PROGRAM TO FIT THE COMMUNITY--THE "WALHALLA EXPERIENCE": The purpose of the Accessible and Culturally Competent Health Care Project (ACCHCP) is to provide care for underserved populations in Oconee County, South Carolina while providing rural educational opportunities for health services students. Funded by the Health Resources and Services Administration of DHHS, the program is designed to offer culturally appropriate, sensitive, accessible, affordable and compassionate care in a mobile clinic setting. In this interdisciplinary program, nurse practitioners, health educators, bilingual interpreters, medical residents and Clemson University students and professors all played key roles. Women in the community also serve as Promotoras or lay health advisors. The program is unique in using educational initiatives and innovative strategies for bringing health care to this underserved community and offers important information for rural health care initiatives targeting minority groups. This paper reports on the challenges and successes in the development and implementation of the ACCHCP program in Walhalla, South Carolina.

Connecting rural African American and Hispanic women to cancer education and screening: the Avon Health Connector project.

BACKGROUND: Many barriers prevent minority women in rural areas from being screened for breast and cervical cancer. METHODS: A partnership was formed to screen low-income women in a Southern Appalachian area, with particular focus on African American and Hispanic populations. A lay health advisor model was utilized, and 45 LHAs were trained to participate in the program. RESULTS: In this program, 456 women were screened for breast and cervical cancer, 1943 received health education, and 59 health professions students participated. CONCLUSION: A successful partnership model builds on the strengths and assets of partners, provides culturally competent services, and benefits from continual project evaluation.