The therapeutic use of anticancer monoclonal antibodies has risen to prominence through the development of various immunotherapeutic strategies. As described in our recent dossier, “Targeted immunotherapy of cancer: Strategic analysis and target exploitation” (Click here for access), these strategies have included the targeted delivery of toxins, isotopes and chemotherapies to tumor cells. The potential advantages of such approaches are immense and in particular they allow the selective destruction of cancer cells, even if they have escaped the tumor mass and entered the tumor margin or disseminated as metastatic cells. This selective anti-tumor activity is associated with much reduced systemic toxicity. Consequently, immunotherapies are entering the market. However, success has so far been largely limited to hematological tumors. Solid tumors are relatively resistant to targeted immunotherapy since the size of antibodies has precluded effective tumor penetration and retention. Other problems have been related to the antigenicity of first generation murine antibodies. The latter has been overcome through the development of humanized or fully human antibodies. More recently the use of camel antibodies has been shown to overcome the problems of antibody size and antigenicity. The variable domain of functional heavy chain antibodies (VHH) devoid of light chains, found in camels, constitute the smallest intact antigen-binding domain fragment. Belgium researchers have recently, for the first time shown the potential use of these antibody fragments in cancer therapy. Two camel single-domain fragments, cAb-Lys2 and cAb-Lys3, recognizing an overlapping epitope of lysozyme with a dissociation constant of 2 nM and 65 nM, respectively, and a bivalent cAb-Lys3 were investigated for their ability to target transgenic tumors expressing lysozyme on their membrane. Biodistribution studies revealed that these non-immunogenic monomeric and bivalent camel single-domain antigen binders specifically target lysozyme-expressing tumors and metastatic lesions. The excess of antibody is rapidly eliminated from the blood circulation and no cAb retention was observed in normal organs. The tumor to organ cAb-ratios at 2 and 8 hr were impressive. This study demonstrates the successful and specific in vivo targeting of tumors by camel single-domain fragments. It may open perspectives for their future use as tumor-targeting vehicle, due to their small size, soluble behaviour and because they are non-immunogenic and interact with epitopes that are less antigenic for conventional antibodies

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