Polymeric drugs based on conjugates of synthetic and natural macromolecules. II. Anti-cancer activity of antibody or (Fab ')(2)-targeted conjugates and combined therapy with immunomodulators

We provide data on in vivo targeting of the Thy 1.2 (CDw90) cell surface re ceptor expressed on neoplastic T cells, mouse EL4 T cell lymphoma. The targ eting antibody and the anticancer drug, doxorubicin (DOX) were conjugated t o a water-soluble copolymer based on N-(2-hydroxypropyl)methacrylamide (HPM A) acting as a carrier responsible for controlled intracellular release of the conjugated drug. The in vivo therapeutic efficacy of HPMA copolymer-bou nd DOX targeted with anti-EL4 antibody, polyclonal anti-thymocyte globulin (ATG), monoclonal anti-Thy 1.2 antibody or its F(ab')(2) fragment was compa red with the efficacy of DOX conjugated to HPMA copolymer containing nonspe cific IgG or bovine serum albumin (BSA). Anti-EL4 antibody-targeted conjuga te caused a significant retardation of tumor growth and an extension of the life span of treated mice. The effect was comparable with that of HPMA cop olymer-bound DOX targeted with ATG, anti-Thy 1.2 antibody or its F(ab')(2) fragment. However, considerable antitumor effect was seen also in conjugate s targeted instead of specific antibodies with syngeneic nonspecific IgG or BSA. Patients with advanced cancer are often immunocompromised due to dysf unction of their immune system induced by cancer and cytotoxic drugs. A sig nificant decrease of unwanted side-effects of targeted drugs against a numb er of vital organs was already documented. In this study we have compared i mmunotoxic effects of free DOX with those of its antibody-targeted form on NK cells and cytolytic T lymphocytes (CTLs) isolated from C57BL/10 mice bea ring EL4 T cell lymphoma. In the same model we have tested the combination therapy with immunomodulators (beta-glucan dr AM-2) injected together with targeted daunomycin. We have observed a significant protective effect of ta rgeted DOX against NK cells and CTLs. Moreover, the data revealed that comb ination therapy considerably enhances antitumor efficacy of the targeted an ticancer drug. (C) 2000 Elsevier Science B.V. All rights reserved.