A series of -diketone derivatives of RGD peptidomimetics that selectively bind to Rv 3 and Rv 5 integrins were synthesized and covalently docked to the reactive lysine residues of monoclonal aldolase antibody 38C2. The resulting targeting devices strongly and selectively bound to human cancer cells expressing integrins Rv 3 and Rv 5 as analyzed by flow cytometry. In vitro and in vivo studies revealed that these novel integrin-targeting devices efficiently inhibit tumor growth. Thus, the combination of -diketone derivatives of RGD peptidomimetics that target cell surface integrins Rv 3 and Rv 5 with monoclonal aldolase antibodies through formation of a covalent bond of defined stoichiometry holds promise as a new approach to cancer therapy.

Studies at the interface of chemistry and biology have allowed us to develop an immunotherapeutic approach called chemically programmed antibodies (cpAbs), which combines the merits of traditional small-molecule drug design with immunotherapy. In this approach, a catalytic antibody catalyzes the covalent conjugation of a small molecule or peptide to the active site of the antibody, effectively recruiting the binding specificity of the conjugated molecule to the antibody. In essence, this technology provides the tools for breaking the ''one antibody-one target axiom'' of immunochemistry. Our studies in this area have focused on using the chemistry of the well studied aldolase catalytic antibodies of which mAb 38C2 is a member. Previously, we explored reversible assembly of cpAbs available through diketone chemistry. In this article, we explore a unique proadapter assembly strategy wherein an antibody 38C2-catalyzed transformation unveils a reactive tag that then reacts to form a stable covalent bond with the antibody. An integrin ␣v␤3 antagonist was synthesized with the designed proadapter and studied using human breast cancer cell lines MDA-MB-231 and MDA-MB-435. We demonstrate that this approach allows for (i) the effective assembly of cpAbs in vitro and in vivo, (ii) selective retargeting of 38C2 to integrin ␣v␤3 expressing breast cancer cell lines, (iii) intracellular delivery of cpAbs into cells, (iv) dramatically increased circulatory half-life, and (v) substantial enhancement of the therapeutic effect over the peptidomimetic itself in animal models of breast cancer metastasis. We believe that this technology possesses potential for the treatment and diagnosis of disease.catalytic antibody ͉ chemical programming ͉ combinatorial antibody libraries M onoclonal antibodies are a rapidly growing class of therapeutics for a wide variety of diseases (1, 2). Some of the advantages of antibodies include their relative lack of nonspecific toxicity, long half-life, and ease of access from patient-derived or synthetic combinatorial antibody libraries. For certain diseases, such as cancer, that antibodies can carry their own effector functions is of prime importance because the antibody specificity directs the killing function endemic to the effector domain, the Fc. It has always been axiomatic in immunochemistry that even though one may desire one or more of the advantageous properties common to all antibodies, due to their clonal nature, each task requires a different antibody. A solution to this problem, namely chemically programmed antibodies (cpAbs), has emerged at the interface of chemistry and biology: One can use different low-molecular-weight targeting agents (programming agents or adapters) to selectively target the same antibody to different sites for different uses (3). This strategy has the advantage that only a single antibody is required for a multiplicity of tasks, and it taps into the unlimited chemical diversity and the specificity that can be engendered by organic synthesis (4). The antibody provides ...

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Amphidinolides A-V represent a family of cytotoxic marine natural products with diverse structural features and pronounced biological activities. Kobayashi and his research group have been reporting over the years the discoveries of these remarkable molecules, one after another, since 1986 when the first report of the series appeared. Thanks to their perseverance and painstaking research, the family is still expanding. The unique structural features and biological activity profiles of these macrolides have obviously attracted the attention of organic chemists worldwide. The total syntheses of three members of the family, amphidinolides J, K and P, have already been achieved. This review tries to chronicle the fascinating chemistries of amphidinolides, studies on the syntheses of some of these molecules and their biological activity profiles.

Integrins αvβ3 and αvβ6 are highly expressed on tumor cells and/or by the tumor vasculature of many human cancers, and represent promising targets for anti cancer therapy. Novel chemically programmed antibodies (cpAbs) targeting these integrins were prepared using the catalytic aldolase Antibody (Ab) programming strategy. The effects of the cpAbs on cellular functions related to tumor progression were examined in vitro using tumor cell lines and their cognate integrin ligands, fibronectin and osteopontin. The inhibitory functions of the conjugates and their specificity were examined based on interference with cell-cell and cell-ligand interactions related to tumor progression. Cell binding analyses of the anti-integrin cpAbs revealed high affinity for tumor cells that overexpressed αvβ3 and αvβ6 integrins, and weak interactions with αvβ1 and αvβ8 integrins, in vitro. Functional analyses demonstrated that the cpAbs strongly inhibited cell-cell interactions through osteopontin binding, and they had little or no immediate effects on cell viability and proliferation. Based on these characteristics, the cpAbs are likely to have a broad range of activities in vivo, as they can target and antagonize tumors and tumor vasculatures expressing one or multiple αv integrins. Presumably, these conjugates may inhibit the establishment of metastastatic tumors in distant organs through interfering with cell adhesion more effectively than antibodies or compounds targeting one integrin only. These anti-integrin cpAbs may also provide useful reagents to study combined effect of multiple αv integrins on cellular functions in vitro, on pathologies, including tumor angiogenesis, fibrosis, and epithelial cancers, in vivo