CD22 is a B lymphocyte specific glycan binding protein that participates in regulation of B cell receptor signaling. The extra-cellular domain recognizes sialic acid containing glycans as ligands that regulate its activity during B cell activation and differentiation. Because it is specifically expressed on B cells, CD22 is also a clinical target for antibody based cell depletion therapies for treatment of B cell lymphoma and inflammatory autoimmune disease. We have developed an approach for targeting B cells using multivalent glycan ligands of CD22. In this project we will develop B cell targeted liposomes using glycan ligands of CD22, and test their utility for depletion of B cells in murine models of disease. The major objectives of the project are: 1) Develop chemotherapeutic loaded liposomes displaying ligands of human CD22 that efficiently and specifically target and kill B cells. 2) Assess the in vivo efficacy of CD22 targeted liposome formulations in a murine model of human B cell lymphoma. 3) Test the ability of CD22 targeted liposomes to bind to cancer cells in the blood of human B cell leukemia and non-Hodgkin's B cell lymphoma patients. 4) Determine if B cell depletion with CD22 targeted chemotherapeutic liposomes exhibit efficacy in a murine model of autoimmune disease. If successful, the results may lead to the development of cell-targeted therapies for treatment of B cell malignancies and inflammatory autoimmune diseases mediated by B cells.

Public Health Relevance

Many non-Hodgkin lymphomas and leukemias are derived from B lymphocytes. B lymphocytes are also increasingly recognized for their key roles in many autoimmune diseases such as rheumatoid arthritis. B cell depletion therapies have been demonstrated to provide significant clinical benefits in these diseases. Improvements in these approaches are likely to provide increased efficacy and stimulate their expanded uses to the benefit of patients with B cell malignancies and chronic inflammatory diseases. Our project is aimed at the development of novel methods of targeted B cell depletion therapy to meet these needs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138891-04
Application #
8389680
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Yovandich, Jason L
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$354,146
Indirect Cost
$163,966
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Kawasaki, Norihito; Rillahan, Cory D; Cheng, Tan-Yun et al. (2014) Targeted delivery of mycobacterial antigens to human dendritic cells via Siglec-7 induces robust T cell activation. J Immunol 193:1560-6
Macauley, Matthew S; Crocker, Paul R; Paulson, James C (2014) Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 14:653-66
Macauley, Matthew S; Paulson, James C (2014) Immunology: glyco-engineering 'super-self'. Nat Chem Biol 10:7-8
Rillahan, Cory D; Macauley, Matthew S; Schwartz, Erik et al. (2014) Disubstituted Sialic Acid Ligands Targeting Siglecs CD33 and CD22 Associated with Myeloid Leukaemias and B Cell Lymphomas. Chem Sci 5:2398-2406
Kawasaki, Norihito; Vela, Jose Luis; Nycholat, Corwin M et al. (2013) Targeted delivery of lipid antigen to macrophages via the CD169/sialoadhesin endocytic pathway induces robust invariant natural killer T cell activation. Proc Natl Acad Sci U S A 110:7826-31
Macauley, Matthew S; Pfrengle, Fabian; Rademacher, Christoph et al. (2013) Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis. J Clin Invest 123:3074-83
Chen, Weihsu C; Sigal, Darren S; Saven, Alan et al. (2012) Targeting B lymphoma with nanoparticles bearing glycan ligands of CD22. Leuk Lymphoma 53:208-10
Paulson, James C; Macauley, Matthew S; Kawasaki, Norihito (2012) Siglecs as sensors of self in innate and adaptive immune responses. Ann N Y Acad Sci 1253:37-48
Rillahan, Cory D; Paulson, James C (2011) Glycan microarrays for decoding the glycome. Annu Rev Biochem 80:797-823
O'Reilly, Mary K; Tian, Hua; Paulson, James C (2011) CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells. J Immunol 186:1554-63