During the last two decades, two distinct monoclonal antibodies, RP215 and GHR106 were generated, respectively and extensively characterized, biologically and immunologically. Both antibodies target separately specifi...During the last two decades, two distinct monoclonal antibodies, RP215 and GHR106 were generated, respectively and extensively characterized, biologically and immunologically. Both antibodies target separately specific pan cancer markers and are being evaluated preclinically for potential therapeutic applications in cancer immunotherapy and/or fertility regulations. RP215 was shown to react specifically with carbohydrate-associated epitope located in the heavy chain variable regions of cancer cell expressed specific immunoglobulins, designated as CA215 which are distinct from those of normal B cell origins. The cancerous immunoglobulins may function to react with specific human serum proteins to facilitate growth/proliferation as well as protection of cancer cells in circulations. RP215-based enzyme immunoassays were designed to monitor serum CA215 levels among cancer patients. On the other hand, GHR106 was generated against N1-29 oligopeptide located in the extracellular domains of human GnRH receptor found either in the anterior pituitary or in most of the cancer cells. In vitro culture of cancer cells revealed that either of these two antibodies can induce apoptosis of cancer cells following 24 - 48 hours incubations. Anti-tumor activities of both antibodies were evaluated by typical nude mouse experiments. Either one was shown to effectively reduce the volumes of implanted tumors, dose-dependently. Humanized forms of either antibody were made available in CAR (chimeric antigen receptor)-T cell constructs. They were shown separately to induce cytotoxic killings of cancer cells in vitro by releasing cytokines upon incubations of tumor cells with either of CAR-T cell constructs. In addition, GHR106 also acts as GnRH antagonist by a specific targeting to pituitary GnRH receptor for reversible suppressions of reproductive hormones such as LH, testosterone or estradiol. Based on the above preclinical assessments, it can be generally concluded that both RP215 and GHR106 are restricted in normal tissue expressions and suitable for targeting cancerous immunoglobulins and GnRH receptor, respectively for cancer immunotherapy. Furthermore, specific targeting of pituitary GnRH receptor may suggest that the long acting GHR106 (5 - 21 days half-life) is an adequate GnRH antagonist for numerous gynecological treatments including ovulation inhibition in IVF/ART, endometriosis, premenstrual syndrome, precocious puberty, uterine fibroids and/or polycystic ovarian syndrome.展开更多
Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated ...Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that cancerous immunoglobulins play significant roles in the growth and proliferation of cancer cells in vitro and in vivo. RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. Through gene regulation studies, both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell proliferation (such as NFκB-1, IgG, P21, cyclin D1, ribosomal P1, and c-fos). Furthermore, selected toll-like receptor genes (TLR- 2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and anti-antigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and down- regulate TLR-4 and TLR-9 intwo types of cancer cells. Based on these studies, it is reasonable to postulate that cancerous immunoglobulins play important roles in the modulation of the innate immune system to allow the growth and survival of cancer cells within the human body. Consequently, RP215 inits humanized forms may be utilized to target cancer cells for potential therapeutic purposes.展开更多
RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically ...RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically on glycoproteins, known as CA215, from cancer cells. Further molecular analysis by matrix adsorption laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) revealed that CA215 consists mainly of immunoglobulin super-family (IgSF) proteins, including immunoglobulins, T-cell receptors, and cell adhesion molecules, as well as several other unrelated proteins. Peptide mappings and glycoanalysis were performed with CA215 and revealed high-mannose and complex bisecting structures with terminal sialic acid in N-glycans. As many as ten O-glycans, which are structurally similar to those of mucins, were also identified. In addition, two additional O-linked glycans were exclusively detected in cancerous immunoglobulins but not in normal B cell-derived immunoglobulins. Immunizations of mice with purified CA215 resulted in the predominant generation of RP215-related Mabs, indicating the immunodominance of this carbohydrate-associated epitope. Anti-idiotype (anti-id) Mabs of RP215, which were generated in the rat, were shown to contain the internal images of the carbohydrate-associated epitope. Following immunizations of these anti-id Mabs in mice, the resulting anti-anti-id (Ab3) responses in mice were found to be immunologically similar to that of RP215. Judging from these observations, anti-id Mabs, which carry the internal image of the RP215-specific epitope, may be suitable candidates for anticancer vaccine development in humans.展开更多
Inhibitions or blockages of ligand-receptor interactions on cancer cell surfaces by exogenous competetors or antibodies often result in apoptosis or “programmed cell death.” The underlying mechanisms of action for c...Inhibitions or blockages of ligand-receptor interactions on cancer cell surfaces by exogenous competetors or antibodies often result in apoptosis or “programmed cell death.” The underlying mechanisms of action for cellular apoptosis depend greatly on the molecular nature of specific ligand-receptor interactions and the signal transduction pathways involved. Two such unrelated systems which are potentially involved in apoptosis of cancer cells are described in this review. They are, respectively, gonadotropinreleasing hormone (GnRH) receptor and cancerous immunoglobulins, or CA215, both of which are widely expressed on the surface of cancer cells from diversified tissue origins. Bindings of GnRH or its decapeptide analogs as ligands to GnRH receptor were known to induce apoptosis of several extrapituitary cell types in gonadal tissues, as well as different cancer cells. Monoclonal antibodies against the GnRH receptor of cancer cells were shown to induce apoptosis, similar to the action of GnRH analogs. In contrast, RP215 monoclonal antibody reacts specifically with the carbohydrate-associated epitope of cancerous immunoglobulins and is known to induce apoptosis of cancer cells in vitro. It also causes growth inhibition of tumor cells in nude mouse experimental models. Elucidations of the specific mechanisms of apoptosis in cancer cells of these two molecular interaction systems will not only lead to a better understanding of cancer biology but also benefit patients in cancer monitoring and therapy.展开更多
文摘During the last two decades, two distinct monoclonal antibodies, RP215 and GHR106 were generated, respectively and extensively characterized, biologically and immunologically. Both antibodies target separately specific pan cancer markers and are being evaluated preclinically for potential therapeutic applications in cancer immunotherapy and/or fertility regulations. RP215 was shown to react specifically with carbohydrate-associated epitope located in the heavy chain variable regions of cancer cell expressed specific immunoglobulins, designated as CA215 which are distinct from those of normal B cell origins. The cancerous immunoglobulins may function to react with specific human serum proteins to facilitate growth/proliferation as well as protection of cancer cells in circulations. RP215-based enzyme immunoassays were designed to monitor serum CA215 levels among cancer patients. On the other hand, GHR106 was generated against N1-29 oligopeptide located in the extracellular domains of human GnRH receptor found either in the anterior pituitary or in most of the cancer cells. In vitro culture of cancer cells revealed that either of these two antibodies can induce apoptosis of cancer cells following 24 - 48 hours incubations. Anti-tumor activities of both antibodies were evaluated by typical nude mouse experiments. Either one was shown to effectively reduce the volumes of implanted tumors, dose-dependently. Humanized forms of either antibody were made available in CAR (chimeric antigen receptor)-T cell constructs. They were shown separately to induce cytotoxic killings of cancer cells in vitro by releasing cytokines upon incubations of tumor cells with either of CAR-T cell constructs. In addition, GHR106 also acts as GnRH antagonist by a specific targeting to pituitary GnRH receptor for reversible suppressions of reproductive hormones such as LH, testosterone or estradiol. Based on the above preclinical assessments, it can be generally concluded that both RP215 and GHR106 are restricted in normal tissue expressions and suitable for targeting cancerous immunoglobulins and GnRH receptor, respectively for cancer immunotherapy. Furthermore, specific targeting of pituitary GnRH receptor may suggest that the long acting GHR106 (5 - 21 days half-life) is an adequate GnRH antagonist for numerous gynecological treatments including ovulation inhibition in IVF/ART, endometriosis, premenstrual syndrome, precocious puberty, uterine fibroids and/or polycystic ovarian syndrome.
文摘Antigen receptors, including immunoglobulins and T-cell receptors, are known to be widely expressed by cancer cells through unconfirmed mechanisms and for unknown purposes. Recently, a monoclonal antibody, designated as RP215, was generated against the ovarian cancer cell line, OC-3-VGH, and was shown to react with CA215, which consisted mainly of these cancer cell-expressed antigen receptors. Experimental evidence has clearly indicated that cancerous immunoglobulins play significant roles in the growth and proliferation of cancer cells in vitro and in vivo. RP215 and anti-antigen receptor antibodies were equally effective in inducing apoptosis and complement-dependent cytotoxicity reactions to cultured cancer cells. Through gene regulation studies, both RP215 and antibodies against antigen-receptors were shown to affect more than a dozen of genes involved in cell proliferation (such as NFκB-1, IgG, P21, cyclin D1, ribosomal P1, and c-fos). Furthermore, selected toll-like receptor genes (TLR- 2, -3, -4, and -9) were also found to be highly regulated by both RP215 and anti-antigen receptor antibodies. For example, RP215 and anti-antigen receptor antibodies were found to both up-regulate TLR-2 and/or TLR-3 and down- regulate TLR-4 and TLR-9 intwo types of cancer cells. Based on these studies, it is reasonable to postulate that cancerous immunoglobulins play important roles in the modulation of the innate immune system to allow the growth and survival of cancer cells within the human body. Consequently, RP215 inits humanized forms may be utilized to target cancer cells for potential therapeutic purposes.
文摘RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically on glycoproteins, known as CA215, from cancer cells. Further molecular analysis by matrix adsorption laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) revealed that CA215 consists mainly of immunoglobulin super-family (IgSF) proteins, including immunoglobulins, T-cell receptors, and cell adhesion molecules, as well as several other unrelated proteins. Peptide mappings and glycoanalysis were performed with CA215 and revealed high-mannose and complex bisecting structures with terminal sialic acid in N-glycans. As many as ten O-glycans, which are structurally similar to those of mucins, were also identified. In addition, two additional O-linked glycans were exclusively detected in cancerous immunoglobulins but not in normal B cell-derived immunoglobulins. Immunizations of mice with purified CA215 resulted in the predominant generation of RP215-related Mabs, indicating the immunodominance of this carbohydrate-associated epitope. Anti-idiotype (anti-id) Mabs of RP215, which were generated in the rat, were shown to contain the internal images of the carbohydrate-associated epitope. Following immunizations of these anti-id Mabs in mice, the resulting anti-anti-id (Ab3) responses in mice were found to be immunologically similar to that of RP215. Judging from these observations, anti-id Mabs, which carry the internal image of the RP215-specific epitope, may be suitable candidates for anticancer vaccine development in humans.
文摘Inhibitions or blockages of ligand-receptor interactions on cancer cell surfaces by exogenous competetors or antibodies often result in apoptosis or “programmed cell death.” The underlying mechanisms of action for cellular apoptosis depend greatly on the molecular nature of specific ligand-receptor interactions and the signal transduction pathways involved. Two such unrelated systems which are potentially involved in apoptosis of cancer cells are described in this review. They are, respectively, gonadotropinreleasing hormone (GnRH) receptor and cancerous immunoglobulins, or CA215, both of which are widely expressed on the surface of cancer cells from diversified tissue origins. Bindings of GnRH or its decapeptide analogs as ligands to GnRH receptor were known to induce apoptosis of several extrapituitary cell types in gonadal tissues, as well as different cancer cells. Monoclonal antibodies against the GnRH receptor of cancer cells were shown to induce apoptosis, similar to the action of GnRH analogs. In contrast, RP215 monoclonal antibody reacts specifically with the carbohydrate-associated epitope of cancerous immunoglobulins and is known to induce apoptosis of cancer cells in vitro. It also causes growth inhibition of tumor cells in nude mouse experimental models. Elucidations of the specific mechanisms of apoptosis in cancer cells of these two molecular interaction systems will not only lead to a better understanding of cancer biology but also benefit patients in cancer monitoring and therapy.
