Synthesis of a reactive linker for the construction of antibody-drug hybrid molecules

MEDI 110

Joshua D. Thomas, josthom@ncifcrf.gov1, Thomas Hofer2, Christoph Rader, raderc@mail.nih.gov2, and Terrence R. Burke Jr., tburke@helix.nih.gov1. (1) Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Bldg. 376 Boyles St., CCR, NCI-Frederick, NIH, Frederick, MD 21702, (2) Experimental Transplantation and Immunology Branch, National Cancer Institute, 10 Center Dr, Building 10 CRC, Bethesda, MD 20892
Although small synthetic molecules and monoclonal antibodies are valuable therapeutic agents in their own right, superior selectivity and pharmacokinetics may result from a merging of these two technologies. Previous applications of such an approach have involved the covalent attachment of a chemotherapeutic drug to a specific monoclonal antibody. In order to broaden the utility of this technique, we have developed methodology by which an antibody or antibody fragment can be selectively conjugated through a C-terminal selenocysteine to various small synthetic molecules. In the present work, we describe the synthesis of a reactive linker through which a high-affinity alpha4beta1 integrin binding ligand is selectively conjugated to an antibody fragment (Fc protein). The resulting bioconjugate is able to bind to primary human peripheral blood mononuclear cells by virtue of the Fc protein and selectively target cells expressing human integrin alpha4beta1.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007