David Chantry

A Crucial Role for the p110δ Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation

Mice lacking the p110δ catalytic subunit of phosphatidylinositol 3-kinase have reduced numbers of B1 and marginal zone B cells, reduced levels of serum immunoglobulins, respond poorly to immunization with type II thymus-independent antigen, and are defective in their primary and secondary responses to thymus-dependent antigen. p110δ−/− B cells proliferate poorly in response to B cell receptor (BCR) or CD40 signals in vitro, fail to activate protein kinase B, and are prone to apoptosis. p110δ function is required for BCR-mediated calcium flux, activation of phosphlipaseCγ2, and Brutons tyrosine kinase. Thus, p110δ plays a critical role in B cell homeostasis and function.

CCR4-bearing T cells participate in autoimmune diabetes

Chemokine receptor expression is exquisitely regulated on T cell subsets during the course of their migration to inflammatory sites. In the present study we demonstrate that CCR4 expression marks a pathogenic population of autoimmune T cells. CCR4 was found exclusively on memory CD4(+) T cells during the progression of disease in NOD mice. Cells expressing the CCR4 ligand TARC (thymus- and activation-regulated chemokine) were detected within infiltrated islets from prediabetic mice. Interestingly, neutralization of macrophage-derived chemokine (MDC) with Ab caused a significant reduction of CCR4-positive T cells within the pancreatic infiltrates and inhibited the development of insulitis and diabetes. Furthermore, enhanced recruitment of CCR4-bearing cells in NOD mice resulting from transgenic expression of MDC resulted in acceleration of clinical disease. Cumulatively, the results demonstrate that CCR4-bearing T cells participate in the development of such tissue-driven autoimmune reactions.

Abstract C196: Identification of first-in-class, highly potent FGFR kinase inhibitors that spare FGFR1

Background: The fibroblast growth factor receptor (FGFR1-4) family of tyrosine kinases plays an important role in normal physiologic processes, including angiogenesis, wound healing and regulation of calcium and phosphate metabolism. In addition, dysregulation of FGFR signaling through genetic alterations or altered expression of individual receptors and their ligands has been frequently observed in human tumors. While tyrosine kinase inhibitors (TKIs) with anti-FGFR activity have produced clinical responses in patients whose tumors harbor FGFR alterations, currently available FGFR TKIs inhibit multiple other kinases, including multiple FGFRs. As a result, dose-limiting toxicities have been frequently observed in patients, including hyperphosphatemia which may arise from the inhibition of FGFR1 in the kidney. These toxicities may ultimately limit the efficacy of pan-FGFR inhibitors. However, the ability to develop inhibitors that spare individual FGFRs has been hampered by the high degree of structural similarity between FGFR1, FGFR2, and FGFR3. The development of these tools to distinguish the functional contributions of the individual FGF receptors not only advances the biological understanding of the individual receptors in the context of their expression but may also provide therapeutic agents that have an improved therapeutic index. Methods: In vitro and in vivo evaluations including both enzyme and cell-based assays, pharmacokinetic (PK) studies, measurement of drug metabolism and non-clinical safety evaluation were conducted using standard methods. Tumor growth inhibition and pharmacodynamics (PD) measurements were carried out using subcutaneous xenografts of RT112/84 (which harbor an FGFR3-TACC fusion) bladder cancer cells in nude mice. Results: We have developed compounds with nanomolar FGFR3 enzyme and cell potency, but relatively spare FGFR1 and have minimal activity against an enzyme panel of >200 diverse kinases. This series was further optimized to provide high oral exposure in rodent species. One representative compound was evaluated in a single dose mouse PK at doses of 10, 30 and 100 mg/kg and provided predicted pharmacokinetic coverage of the FGFR3 cell IC50 for >8, >12 and >24 hrs respectively, which correlated with phospho-FGFR3 reduction. The compound demonstrated greater than 40% and greater than 65% tumor regressions of RT112/84 subcutaneous xenografts at doses of 30 and 45 mg/kg/day x 14 day, respectively. These doses were well tolerated and minimal hyperphosphatemia was observed. Conclusions: We have identified potent and selective FGFR inhibitors that spare FGFR1 and other related kinases, and possess high oral bioavailability and favorable PK properties in animals. This next-generation class of compounds will be able to examine selectively the biology of selective FGFR inhibition. The identification of potent and selective FGFR inhibitors with minimal activity against FGFR1 may improve the efficacy and tolerability compared to the currently available pan-FGFR inhibitors. Citation Format: Shannon Winski, Nisha Nanda, Eric Brown, Tony Tang, Barbara Brandhuber, Robyn Hamor, Brian Tuch, Kevin Ebata, Jennifer Low, Francis Sullivan, Darin Smith, Guy Vigers, Megan Strough, Rob Rieger, James Blake, David Moreno, David Chantry, S. Michael Rothenberg, Steven Andrews. Identification of first-in-class, highly potent FGFR kinase inhibitors that spare FGFR1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C196.

The Chemokine Gene Family

Our understanding of the function of chemokines has been reshaped over the past few years because of the large number of new chemokines recently discovered. Earlier reviews on chemokine structure and function presented a relatively simple picture of the chemokine family: a handful of CXC and CC chemokines, whose genes clustered on chromosomes 4 and 17, respectively, involved in the recruitment of leukocyte subsets to sites of inflammation (1,2). Over the past few years, however, the use of computer technology to search vast libraries of randomly sequenced cDNAs has brought to light many novel chemokines that complicate the picture described above, but also enrich our understanding of the functional diversity of chemokines. Not only have new chemokine families and chromoobtained, and how they have broadened our understanding of the structure and function of chemokines.