Genetically Engineered Monoclonal Antibodies for Direct Anti-Neoplastic Treatment and Cancer Cell Specific Delivery of Chemotherapeutic Agents

Abstract

Classical therapeutic modalities such as surgery, radiation, and chemotherapy not only fail to cure the great majority of malignant tumors, but their employment often leads to severe and debilitating side effects. The severe cancer related morbidity is also in direct correlation with the use of x-radiation and chemotherapy, making them less than ideal forms of therapy. The development of hybridoma technology and the advances in monoclonal antibody (MoAB) production have revitalized the initial concept of Ehrlich concerning the existence of cancer cell-targeted, specific "magic bullets". Entirely new approaches to cancer therapy that are neoplastic cell-directed, and specifically lethal to malignant cells and less toxic to normal tissues are being observed and developed, adhering to the old prayer: "Destroy the diseased tissues, preserve the normal." Immunotherapy as a fourth modality of cancer therapy has already been developed and proven to be quite effective. Strategies for the employment of antibodies for anti-cancer immunotherapy include: 1) Immune reaction directed destruction of cancer cells; 2) Interference with the growth and differentiation of malignant cells; 3) Antigen epitope directed transport of anti-cancer agents to malignant cells; 4) Anti-idiotype vaccines; and 5) Development of engineered (humanized) mouse monoclonals for anti-cancer therapy. In addition, a variety of different agents (e.g. toxins, radionuclides, chemotherapeutic drugs) have been conjugated to mouse and human MoABs for selective delivery to cancer cells. Preclinical observations in athymic, nude mice using xenografted human cancers and mouse, anti-human MoABs were more than impressive and have lead to the development of clinical trials. Phase I studies established the safety of employing immunoconjugates in humans, but the in vivo therapeutic results were less impressive. The clinical use of mouse MoABs in humans is limited due to the development of a foreign anti-globulin immune response by the human host. Genetically engineered chimeric human-mouse MoABs have been developed by replacing the mouse Fc region with the human constant region. Moreover, the framework regions of variable domains of rodent immunoglobulins were also experimentally replaced by their human equivalents. These antibodies can also be designed to have specificities and effector functions determined by researchers, which may not appear in nature. The development of antibodies with two binding ends (bispecific antibodies) provided a great improvement in targeting cancer cells. The existing inadequacies of MoABs in immunotherapy may also be improved by increasing their efficiency with chemical coupling to various agents such as bacterial or plant toxins, radionuclides or cytotoxic drugs. The astonishing immunophenotypic (IP) heterogeneity of neoplastically transformed cells, the different cytotoxic activity associated with the moiety linked to given MoABs, and mostly the impressive genetic modulation capabilities of cancer cells still remain as yet unsolved dif...

Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer

“…MMPs induce extracellular matrix breakdown associated with normal tissue remodeling and are associated with tissue destruction in arthritis, cancer invasion, and metastasis (Nelson et al, 2000;Visse and Nagase, 2003). Overexpression of MMP-10 has been reported in cancers of the lung, head, and neck (Muller et al, 1991), esophagus (Mathew et al, 2002;Sharma et al, 2004), brain (Thorns et al, 2003), and liver (Bodey et al, 2000). The present immunohistochemical study showed MMP-10 to be correlated with a poor prognosis in patients with GC.…”

Expression of the TGF-β coreceptor endoglin in epidermal keratinocytes and its dual role in multistage mouse skin carcinogenesis

“…However, transformation to a more malignant phenotype is observed in these mice, suggesting that normal levels of endoglin would inhibit the effect of TGF-b 1 on malignant progression. It can be argued, however, that defects in neovascularization could play an additional role in the phenotype observed in our Eng þ /À mice, since endoglin is highly expressed on the tumor-associated angiogenic vascular endothelium (Burrows et al, 1995;Bodey et al, 1998;Kumar et al, 1999;Li et al, 2001;Takahashi et al, 2001). The importance of angiogenesis for the growth of solid tumors is well recognized (Hanahan and Folkman, 1996).…”

Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C

“…By immunohistochemistry of cancer specimens, MMPs and in particular gelatinases have been found to be up-regulated in almost every tumor entity, including breast cancer (22)(23)(24)(25)(26)(27)(28). Cell culture and mouse experiments with mammary epithelial cells and cancer cells have revealed a crucial role for MMP-9 in tumor growth, invasion, metastasis, and angiogenesis (29)(30)(31)(32).…”

“…It has been determined that MMP-9 is overexpressed in primary breast carcinomas by immunohistochemistry (22)(23)(24)(25)(26). The cellular distribution of MMP-9 protein in paraffin sections is typically cytoplasmic (23)(24)(25)(26)(27). We stained sequential, serial sections of the breast microtissue arrays with anti-sera to MMP-9 and observed a strong cytoplasmic and perinuclear staining in 27% of these tumor specimens (ϩϩϩ), moderate staining in 32% (ϩϩ), and no to little staining in 38%(0͞ϩ) (Fig.…”