Purpose: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein th... more Purpose: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody–drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker. Experimental Design: The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro. The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationshi...
Transferrin (Tf) conjugates of monomeric artemisinin (ART) and artemisinin dimer were synthesized... more Transferrin (Tf) conjugates of monomeric artemisinin (ART) and artemisinin dimer were synthesized. The two conjugates, ART-Tf and dimer-Tf, retained the original protein structure, and formed stable aggregates in aqueous buffer. ART-Tf induced declines in proteins involved in apoptosis (survivin), cell cycling (cyclin D1), oncogenesis (c-myelocytomatosis oncogene product (c-MYC)), and dysregulated WNT signaling (beta-catenin) in both the human prostate (DU145) and breast (MCF7) cancer cell lines. Both ART-Tf and dimer-Tf induced down-regulation of survivin, c-MYC and mutated human epidermal growth factor receptor-2 (ERBB2 or HER2) in the BT474 breast cancer cell line. To our knowledge, this is the first demonstration that an ART derivative can cause a decline of ERBB2 in a human cancer cell line. Potential mechanisms for the observed effects are presented. Both transferrin conjugates strongly inhibited the growth of BT474 cells in the same concentration range that the conjugates cau...
Artemisinin is a compound isolated from the wormwood Artemisia annua L. It reacts with iron and f... more Artemisinin is a compound isolated from the wormwood Artemisia annua L. It reacts with iron and forms cytotoxic free radicals. It is selectively more toxic to cancer than normal cells because cancer cells contain significantly more intracellular free iron. Previously, we found that covalently tagging artemisinin to transferrin enhanced the selectivity and toxicity of artemisinin toward cancer cells in vitro. In the present research, artemisinin-transferrin conjugate was tested in a rat breast cancer model. Breast tumors were induced in rats by subcutaneous implantation of rat MTLn3 breast cancer cells. Once tumors were formed, daily intravenous injections of artemisinin-transferrin conjugate were administered. The conjugate significantly retarded the growth rate of breast tumors in the rat. No significant side effect was observed in the rats during treatment. Artemisinin-transferrin conjugate could be developed into a potent therapeutic agent for cancer in humans.
Artemisinin, a natural product isolated from Artemisia annua, contains an endoperoxide group that... more Artemisinin, a natural product isolated from Artemisia annua, contains an endoperoxide group that can be activated by intracellular iron to generate toxic radical species. Cancer cells over-express transferrin receptors (TfR) for iron uptake while most normal cells express nearly undetectable levels of TfR. We prepared a series of artemisinin-tagged transferrins (ART-Tf) where different numbers of artemisinin units are attached to the N-glycoside chains of transferrin (Tf). The Tf bearing approximately 16 artemisinins retains the functionality of both Tf and artemisinin. Reduction of TfRs by TfR siRNA transfection significantly impaired the ability of ART-Tf, but not dihydroartemisinin, to kill cells. We also demonstrate that the ART-Tf conjugate kills the prostate carcinoma cell line DU 145 by the mitochondrial pathway of apoptosis.
Purpose: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein th... more Purpose: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a glycoprotein that has limited expression in normal adult tissues, but is overexpressed in carcinomas of the gastrointestinal tract, the genitourinary and respiratory systems, and breast cancer. As such, CEACAM5 is an attractive target for antibody-based therapies designed to selectively deliver cytotoxic drugs to certain epithelial tumors. Here, we describe preclinical data for a novel antibody–drug conjugate (ADC), SAR408701, which consists of an anti-CEACAM5 antibody (SAR408377) coupled to a maytansinoid agent DM4 via a cleavable linker. Experimental Design: The specificity and binding affinity of SAR408701 to human and cynomolgus monkey CEACAM5 were tested in vitro. The cytotoxic activity of SAR408701 was assessed in CEACAM5-expressing tumor cell lines and using patient-derived xenograft mouse models of CEACAM5-positive tumors. Pharmacokinetic-pharmacodynamic and pharmacokinetic-efficacy relationshi...
Transferrin (Tf) conjugates of monomeric artemisinin (ART) and artemisinin dimer were synthesized... more Transferrin (Tf) conjugates of monomeric artemisinin (ART) and artemisinin dimer were synthesized. The two conjugates, ART-Tf and dimer-Tf, retained the original protein structure, and formed stable aggregates in aqueous buffer. ART-Tf induced declines in proteins involved in apoptosis (survivin), cell cycling (cyclin D1), oncogenesis (c-myelocytomatosis oncogene product (c-MYC)), and dysregulated WNT signaling (beta-catenin) in both the human prostate (DU145) and breast (MCF7) cancer cell lines. Both ART-Tf and dimer-Tf induced down-regulation of survivin, c-MYC and mutated human epidermal growth factor receptor-2 (ERBB2 or HER2) in the BT474 breast cancer cell line. To our knowledge, this is the first demonstration that an ART derivative can cause a decline of ERBB2 in a human cancer cell line. Potential mechanisms for the observed effects are presented. Both transferrin conjugates strongly inhibited the growth of BT474 cells in the same concentration range that the conjugates cau...
Artemisinin is a compound isolated from the wormwood Artemisia annua L. It reacts with iron and f... more Artemisinin is a compound isolated from the wormwood Artemisia annua L. It reacts with iron and forms cytotoxic free radicals. It is selectively more toxic to cancer than normal cells because cancer cells contain significantly more intracellular free iron. Previously, we found that covalently tagging artemisinin to transferrin enhanced the selectivity and toxicity of artemisinin toward cancer cells in vitro. In the present research, artemisinin-transferrin conjugate was tested in a rat breast cancer model. Breast tumors were induced in rats by subcutaneous implantation of rat MTLn3 breast cancer cells. Once tumors were formed, daily intravenous injections of artemisinin-transferrin conjugate were administered. The conjugate significantly retarded the growth rate of breast tumors in the rat. No significant side effect was observed in the rats during treatment. Artemisinin-transferrin conjugate could be developed into a potent therapeutic agent for cancer in humans.
Artemisinin, a natural product isolated from Artemisia annua, contains an endoperoxide group that... more Artemisinin, a natural product isolated from Artemisia annua, contains an endoperoxide group that can be activated by intracellular iron to generate toxic radical species. Cancer cells over-express transferrin receptors (TfR) for iron uptake while most normal cells express nearly undetectable levels of TfR. We prepared a series of artemisinin-tagged transferrins (ART-Tf) where different numbers of artemisinin units are attached to the N-glycoside chains of transferrin (Tf). The Tf bearing approximately 16 artemisinins retains the functionality of both Tf and artemisinin. Reduction of TfRs by TfR siRNA transfection significantly impaired the ability of ART-Tf, but not dihydroartemisinin, to kill cells. We also demonstrate that the ART-Tf conjugate kills the prostate carcinoma cell line DU 145 by the mitochondrial pathway of apoptosis.
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