Molecules associated with angiogenesis or with the tumor stroma represent particularly attractive targets for an antibody-based delivery due to their selective, abundant, and accessible expression in aggressive solid tumors (5). In this regard, neo-vascular and stromal antigens are especially suited for pharmacodelivery applications since (i) they are accessible from the blood-stream, (ii) are largely restricted to tumors as the growth of new blood vessels from pre-existing ones is a rare event in the healthy adult (mainly confined to the female reproductive cycle) and (iii) vascularization is a pathological characteristic of many serious conditions (23). In addition, components of the modified extracellular matrix, such as splice isoforms of fibronectin and tenascin C, were found to be ideal targets for antibody-based pharmacodelivery applications (5). Consequently IMMOMEC will avail tenascins for the targeted therapy of MCC.
Structure of Tenascin C. The antibody F16 binds to the domain A1 of tenascin C.
Tenascins are extracellular matrix glycoproteins (24). They are abundant in the extracellular matrix of developing vertebrate embryos, and they reappear around healing wounds and in the stroma of tumors. Tenascin C is currently the best understood isoform. It has anti-adhesive properties causing cells in tissue culture to become rounded after it is added to the medium. One mechanism to explain this effect may come from its ability to bind to the extracellular matrix glycoprotein fibronectin and thereby block fibronectin’s interactions with specific syndecans. Tenascin C comprises several fibronectin type 3 homology repeats that can be either included or omitted in the primary transcript by alternative splicing leading to small and large isoforms. Whereas the small isoform is expressed in several tissues, the large isoform of tenascin C exhibits a restricted pattern of expression: It is virtually undetectable in healthy adult tissues, but is extremely abundant in neoplastic tissue of various cancer entities, including MCC (25, 26). The human monoclonal antibody F16 binds specifically to the alternatively spliced A1 domain of tenascin C, and exhibits a virtually undetectable staining in most of normal organs (except for the placenta and the endometrium in the proliferative phase), whereas it strongly reacts with neovascular and stromal components of human cancers (25). Accordingly, strong tenascin C expression is usually observed around the vascular structures as well as in the invasion fronts of MCC tissue – typically with flame-like extensions. Interestingly, the expression of tenascin C in the stroma of tumors is associated with a poor prognosis.