Endoglin-targeted cancer therapy.

Vascular-targeting antiangiogenic therapy (VTAT) of cancer can be advantageous over conventional tumor cell targeted cancer therapy if an appropriate target is found. Our hypothesis is that endoglin (ENG; CD105) is an excellent target in VTAT. ENG is selectively expressed on vascular and lymphatic endothelium in tumors. This allows us to target both tumor-associated vasculature and lymphatic vessels to suppress tumor growth and metastasis. ENG is essential for angiogenesis/vascular development and a co-receptor of TGF-ß. Our studies of selected anti-ENG monoclonal antibodies (mAbs) in several animal models and in vitro studies support our hypothesis. These mAbs and/or their immunoconjugates (immunotoxins and radioimmunoconjugates) induced regression of preformed tumors as well as inhibited formation of new tumors. In addition, they suppressed metastasis. Several mechanisms were involved in the suppressive activity of the naked (unconjugated) anti-ENG mAbs. These include direct growth suppression of proliferating endothelial cells, induction of apoptosis, ADCC (antibody-dependent cell-mediated cytotoxicity) and induction of T cell immunity. To facilitate clinical application, we generated a human/mouse chimeric anti-ENG mAb termed c-SN6j and performed studies of pharmacokinetics, toxicology and immunogenicity of c-SN6j in nonhuman primates. No significant toxicity was detected by several criteria and minimal immune response to the murine part of c-SN6j was detected after multiple i.v. injections. The results support our hypothesis that c-SN6j can be safely administered in cancer patients. This hypothesis is supported by the ongoing phase 1 clinical trial of c-SN6j (also known as TRC105) in patients with advanced or metastatic solid cancer in collaboration with Tracon Pharma and several oncologists (NCT00582985).

[Effects of intratumoral injection therapy of dendritic cells combined with hyperthermia for cancer patients].

We proceeded with intratumoral injection therapy of dendritic cells (DC) in combination with hyperthermia for 41 cancer patients in the past two years. We confirmed a total of two CR cases (one of them already reported). We report two successful cases in this paper. Case 1: A uterine cervical cancer patient with metastases in cervical and abdominal lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a CR not only in cervical but also in abdominal lymph nodes. Case 2: A sialyl grand cancer patient with metastases in cervical and axillary lymphnodes was treated with intratumoral DC injection therapy combined with hyperthermia in cervical. She showed a PR.

Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin.

We generated a human/mouse chimeric antibody c-SN6j of human IgG1 isotype from a murine anti-human endoglin (EDG) monoclonal antibody (mAb) SN6j that suppressed angiogenesis, tumor growth and metastasis in mice. We determined pharmacokinetics (PKs) and immunogenicity of c-SN6j in monkeys after multiple i.v. injections. A dose-escalation study was performed by administration of c-SN6j into six monkeys at the dose of 1 mg, 3 mg and 10 mg per kg body weight. In addition, both c-SN6j (3 mg/kg) and doxorubicin (0.275 mg/kg) were injected into two monkeys. c-SN6j and doxorubicin were injected twice a week for 3 weeks. We developed a unique and sensitive ELISA by sequentially targeting the common and idiotypic epitopes of c-SN6j-Fv to quantify plasma c-SN6j. Application of the ELISA showed that increasing the c-SN6j dose resulted in a proportional increase in the circulating c-SN6j after the first injection. In addition, the estimated area under the curve (AUC) for the first injection of c-SN6j is proportional to dose. We carried out detailed analyses of PKs of c-SN6j during and after the repeated injections. Our model of PKs fitted the empirical data well. Addition of doxorubicin modulated the PK parameters. We developed two ELISAs to separately determine the immune responses to the murine part and the human part of c-SN6j in monkeys. Interestingly, the murine part induced a weaker immune response than the human part. Doxorubicin potentiated the immune responses. Increasing the dose of c-SN6j increased plasma levels of c-SN6j but did not increase the immune responses to c-SN6j.

[Successful immunotherapy combined with hyperthermia therapy for cancer patients].

We proceeded with activated lymphocytes immunotherapy for 149 cancer patients, and hyperthermia therapy for 126 patients, and DC therapy for 20 patients in the past year. We were successful in two cases. Case 1: A metastatic pelvic cancer (unknown origin) patient treated with lymphocytes and hyperthermia therapy. She showed a drastic response. Case 2: A metastatic lymph node cancer patient treated with DC, lymphocytes and hyperthermia therapy. She showed a CR.

[Intratumoral injection of immature dendritic cells (DC) for cancer patients].

We proceeded with DC immunotherapy for 21 cancer patients. Immature dendric cells were injected intratumorally to the 16 patients, and three good and effective cases were obtained: case 1: A 69-year-old male patient with papilla-vater carcinoma, case 2: A 49-year-old female patient with gastric cancer, case 3: A 66-year-old male patient with malignant melanoma.