Tumors undergoing rejection induced by monoclonal antibodies of the IgG2a isotype contain increased numbers of macrophages activated for a distinctive form of antibody-dependent cytolysis.

Abstract

Monoclonal antibodies of the IgG2a isotype specifically inhibit the growth of human tumors in nude mice; tumors in mice given no antibody, an antibody of the IgG2a isotype that does bind to the tumor cells, or an antibody of the IgG2b isotype grow progressively. In the present work it is demonstrated that tumors of mice given the IgG2a antibody are essentially masses of necrosis, while tumors from the control mice are sheets of healthy tumor cells. Tumors of the treated mice, in comparison to controls, contain an increased number of macrophages, and these macrophages are activated for a distinct form of cytolysis dependent on antibodies of the IgG2a isotype. The data suggest that changes in the number and function of intratumoral macrophages are a major component of tumor destruction mediated by IgG2a antibodies.The generation or administration in vivo of murine anti-tumor antibodies of the IgG2a isotype has been observed in several laboratories to cause the specific and effective destruction of growing neoplasms of murine (1, 2) or human (3) origin. In four distinct experimental systems, a need for host-derived cellular effectors, specifically macrophages (MO), to cooperate with antibodies (either host-derived or administered) has been identified (1, 3-5).Mononuclear phagocytes destroy tumor cells in two distinct circumstances: a slow lysis, independent of antibody and termed macrophage-mediated tumor cytolysis (MTC); and a rapid cytolysis, dependent upon polyclonal antibodies and termed antibody-dependent cell-mediated cytolysis (ADCC) (6,7). Monoclonal antibodies (MAbs) of the IgG2a isotype, however, can also induce M4-dependent destruction of tumor cells (8,9). This type of antibody-dependent cytolysis has recently been shown to be quite distinct from the usual form of the ADCC reaction, since the novel form of ADCC occurs slowly and requires interaction of antibodies of the IgG2a isotype with specific subsets of mouse MO (unpublished work). Specifically, the well-described or classic form of ADCC is generally effected by polyclonal antisera of all isotypes, occurs over 5-6 hr, and is mediated by MO fully activated for MTC (6,7,10). The novel form of ADCC, by distinct contrast, is effected by antibodies of the IgG2a isotype, requires 24-72 hr for completion, and is mediated only by selected subsets of MO that are in the early stages of activation for MTC (unpublished work). In fact, MO competence for mediating MTC is mutually exclusive with competence for mediating the novel ADCC reaction (unpublished work). The three forms of cytolysis can readily be distinguished from one another in vitro (7). In all three, a sufficient number of MO per tumor cell must be present, and the MO must be activated in an appropriate way (refs. 6, 7, and 10; unpublished work). It is not known, however, whether any of these lytic mechanisms are operative in the IgG2a-dependent destruction of tumors in vivo.To study this problem, we disaggregated neoplasms undergoing such immune attack and determined the number and funct...

Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors

“…Thus, a tumor-specific approach is even more important in the CNS. Furthermore, macrophages (40,41), microglia (42)(43)(44), and astroglial cells (45), all of which contain FcR, are abundant within brain tumors (46) and throughout the substance of the brain. Passive immunotherapy is also an attractive approach to immunotherapy in patients with brain tumors, because most of these patients suffer from a profound and intrinsic immunosuppression that predominantly affects the T cell arm of the immune system (47)(48)(49).…”

Enhancement of Immunoglobulin G2a and Cytotoxic T-Lymphocyte Responses by a Booster Immunization with Recombinant Hepatitis C Virus E2 Protein in E2 DNA-Primed Mice

“…ϩ CTLs could directly kill the CT26-hghE2t cells, as shown in the in vitro CTL assay, and antibodies, especially IgG2a, which strongly binds to Fc␥R on macrophages and natural killer cells, could mediate antibodydependent cell-mediated cytotoxicity (1,14,25).…”

The impact of antigen density and antibody affinity on antibody-dependent cellular cytotoxicity: relevance for immunotherapy of carcinomas

“…As ADCC is considered to be the major mechanism of MAb action in therapy (Adams et al, 1984), we performed this study on the importance of antigen density and MAb affinity for ADCC efficacy. In contrast to other studies in this field (Capone et al, 1984;Hagan et al, 1986; (Velders et al, 1995 (Velders et al, 1996).…”

“…The presence in tumours, surgically removed from MAb-treated patients, of infiltrating natural killer cells and of macrophages (Adams et al, 1984;Shetye et al, 1988) as well as of complement deposits (Adams et al, 1984), suggests that both ADCC and complement-mediated cytotoxicity may play a role in tumour cell destruction in vivo. However, as most tumour cells express increased amounts of complement-inhibiting regulators which protect the cells against lysis by autologous complement (Kumar et al, 1993;Gorter et al, 1996), the main anti-tumour mechanism of therapeutic antibodies in vivo is considered to be ADCC.…”