Publications by authors named "Jeanne Magram"

6 Publications

  • Page 1 of 1

Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.

Proc Natl Acad Sci U S A 2019 04 20;116(14):6812-6817. Epub 2019 Mar 20.

Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada;

Aberrant activation of Wnt/β-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.
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http://dx.doi.org/10.1073/pnas.1817246116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452705PMC
April 2019

Therapeutic Effects of FGF23 c-tail Fc in a Murine Preclinical Model of X-Linked Hypophosphatemia Via the Selective Modulation of Phosphate Reabsorption.

J Bone Miner Res 2017 Oct 25;32(10):2062-2073. Epub 2017 Aug 25.

Center for Therapeutic Innovation, Pfizer, New York, NY, USA.

Fibroblast growth factor 23 (FGF23) is the causative factor of X-linked hypophosphatemia (XLH), a genetic disorder effecting 1:20,000 that is characterized by excessive phosphate excretion, elevated FGF23 levels and a rickets/osteomalacia phenotype. FGF23 inhibits phosphate reabsorption and suppresses 1α,25-dihydroxyvitamin D (1,25D) biosynthesis, analytes that differentially contribute to bone integrity and deleterious soft-tissue mineralization. As inhibition of ligand broadly modulates downstream targets, balancing efficacy and unwanted toxicity is difficult when targeting the FGF23 pathway. We demonstrate that a FGF23 c-tail-Fc fusion molecule selectively modulates the phosphate pathway in vivo by competitive antagonism of FGF23 binding to the FGFR/α klotho receptor complex. Repeated injection of FGF23 c-tail Fc in Hyp mice, a preclinical model of XLH, increases cell surface abundance of kidney NaPi transporters, normalizes phosphate excretion, and significantly improves bone architecture in the absence of soft-tissue mineralization. Repeated injection does not modulate either 1,25D or calcium in a physiologically relevant manner in either a wild-type or disease setting. These data suggest that bone integrity can be improved in models of XLH via the exclusive modulation of phosphate. We posit that the selective modulation of the phosphate pathway will increase the window between efficacy and safety risks, allowing increased efficacy to be achieved in the treatment of this chronic disease. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816679PMC
October 2017

Fully human antibodies against the Protease-Activated Receptor-2 (PAR-2) with anti-inflammatory activity.

Hum Antibodies 2011 ;20(3-4):83-94

Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.

PAR-2 belongs to a family of G-protein coupled Protease-Activated Receptors (PAR) which are activated by specific proteolytic cleavage in the extracellular N-terminal region. PAR-2 is activated by proteases such as trypsin, tryptase, proteinase 3, factor VIIa, factor Xa and is thought to be a mediator of inflammation and tissue injury, where elevated levels of proteases are found. Utilizing the HuCAL GOLD® phage display library we generated fully human antibodies specifically blocking the protease cleavage site in the N-terminal domain. In vitro affinity optimization resulted in antibodies with up to 1000-fold improved affinities relative to the original parental antibodies with dissociation constants as low as 100 pM. Corresponding increases in potency were observed in a mechanistic protease cleavage assay. The antibodies effectively inhibited PAR-2 mediated intracellular calcium release and cytokine secretion in various cell types stimulated with trypsin. In addition, the antibodies demonstrated potent inhibition of trypsin induced relaxation of isolated rat aortic rings ex vivo. In a short term mouse model of inflammation, the trans vivo DTH model, anti-PAR-2 antibodies showed inhibition of the inflammatory swelling response. In summary, potent inhibitors of PAR-2 were generated which allow further assessment of the role of this receptor in inflammation and evaluation of their potential as therapeutic agents.
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http://dx.doi.org/10.3233/HAB-2011-0243DOI Listing
April 2012

Overview of approaches to the identification of inhibitors of cytokine action.

Curr Protoc Pharmacol 2005 Jan;Chapter 1:Unit 1.31

Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.

Cytokines are key regulatory molecules that serve as critical mediators of cell-to-cell communication. They play a central role in immune function and are important molecular targets for drug discovery because of their dysregulation in immune disease. Initial attempts to develop agents that block the actions of cytokines focused on identifying small-molecule antagonists that would directly compete with these cytokines for their cognate receptors. These efforts were, for the most part, unsuccessful. Outlined in this unit are strategies for developing new approaches. The first section describes strategies for how one might build a conceptual framework to approach this problem. The second section focuses on the technical approaches that can be utilized to accomplish the strategies outlined in the first section. These concepts are illustrated using interleukin-2 (IL-2) as a prototype, since there is a substantial body of knowledge regarding this cytokine, including information on its functions, signaling pathways, and physiological effects in normal and diseased tissue.
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http://dx.doi.org/10.1002/0471141755.ph0131s27DOI Listing
January 2005

Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present.

J Immunol 2002 Feb;168(3):1322-7

Mycobacteria Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, CO 80523, USA.

Recent evidence suggests that absence of the IL-12p40 subunit is more detrimental to the generation of protective responses than is the absence of the p35 subunit. To determine whether this is the case in tuberculosis, both p35 and p40 knockout mice were infected with Mycobacterium tuberculosis. Mice lacking the p40 subunit were highly susceptible to increased bacterial growth, exhibited reduced production of IFN-gamma, and had increased mortality. In contrast, mice lacking the p35 subunit exhibited a moderate ability to control bacterial growth, were able to generate Ag-specific IFN-gamma responses, and survived infection longer. The superior Ag-specific responses of the p35 gene-disrupted mice, when compared with the p40 gene-disrupted mice, suggest that the p40 subunit may act other than as a component of IL-12. A candidate molecule capable of driving the protective responses in the p35 gene-disrupted mice is the novel cytokine IL-23. This cytokine is composed of the IL-12 p40 subunit and a p19 subunit. In support of a role for this cytokine in protective responses to M. tuberculosis, we determined that the p19 subunit is induced in the lungs of infected mice.
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http://dx.doi.org/10.4049/jimmunol.168.3.1322DOI Listing
February 2002
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