Lilin Zhang

Abstract 5586: PPMX-T003, a fully human anti-TfR1 antibody with potent efficacy against hematologic malignancies

Transferrin receptor1 (TfR1) is a type II transmembrane glycoprotein that involves intracellular uptake of iron. TfR1 is ubiquitously expressed at low levels in normal cells except erythroblasts and placental trophoblasts, which express high levels of TfR1 due to the need of up taking a large amount of iron. Accumulating studies have shown elevated levels of TfR1 in both solid tumor cells, as well as hematologic malignant cells when compared to their normal counterparts. Since TfR1 is implicated in growth and survival in various cancer cells, targeting TfR1 could be attractive strategy for cancer therapeutics. To this end, we have developed a fully human antibody against TfR1, PPMX-T003, which displayed potent anti-tumor activity in vitro and in vivo. PPMX-T003 induced apoptosis or cell cycle arrest with EC50s of 3~200ng/ml in various tumor cell lines. Mechanistically, PPMX-T003 triggers apoptosis or cell growth arrest by inhibiting binding of TfR1 to its ligand transferrin and blocking iron uptake. In addition, PPMX-T003 elicits antibody dependent cellular cytotoxicity (ADCC) activity in cancer cells. Importantly, PPMX-T003 showed potent efficacy against several blood cancer xenograft models. PPMX-T003 completely eradicated established subcutaneous tumors in two acute myeloid leukemia (AML) models generated by Kasumi-1 and HL-60, at a dose of 10 mg/kg when administrated (I.V.) once a week for 4 weeks. Moreover, PPMX-T003 completely eradicated established tumors in a lymphoma xenograft model (SU-DHL-2) at a dose of 3 mg/kg. Furthermore, PPMX-T003 greatly prolonged mice survival in a disseminated leukemia model (CCRF-CEM: acute lymphoblastic leukemia cell line). The control mice engrafted with CCRF-CEM cells (n=10) developed leukemia and died within 42 days, whereas 8 of the 10 mice treated with PPMX-T003 survived 179 days until the experiment was terminated. A preliminary toxicology study in Cynomolgus monkeys with multiple doses was also carried out. Although moderate anemia was observed at the dose of 30 mg/kg, no other abnormalities were observed, indicating a tolerable safety profile. Taken together, these results indicate that PPMX-T003 could be a potent therapeutic antibody for the treatment of hematologic malignancies. Citation Format: Lilin Zhang, Fumiko Nomura, Yoichi Aikawa, Yoshikazu Kurosawa, Kazuhiro Morishita, Yukio Sudo. PPMX-T003, a fully human anti-TfR1 antibody with potent efficacy against hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5586. doi:10.1158/1538-7445.AM2017-5586

Abstract 4323: Antibodies against TfR inhibit growth of tumor cells both in vitro and in vivo.

Transferrin receptor (TfR) is a type II transmembrane glycoprotein regulating intracellular uptake of iron, and is therefore involved in cell survival and proliferation. TfR has been reported to be more abundantly expressed in dividing cells, e.g. malignant cells, than in quiescent cells, as in most normal cells. Therefore, it is regarded as a potential target for usage in cancer therapy. In the present study, we generated a panel of human anti-TfR antibodies and evaluated its anti-tumor effect both in vitro and in vivo. We found that several antibodies inhibited cell proliferation in various tumor cells, and elicited antibody dependent cellular cytotoxicity (ADCC) activity. Among these antibodies, PPMXT001 and PPMXT002 exerted a significant anti-tumor activity in several xenograft models. PPMXT001 completely suppressed tumor growth in a pancreatic cancer model (MIAPaCa2). PPMXT002 also inhibited tumor growth by 60∼80% in several solid cancer xenograft models including bladder cancer, colon cancer, prostate cancer, and pancreatic cancer. These findings showed that PPMXT001 and PPMXT002 could be potent candidates for developing antibody therapeutics to treat cancer. Citation Format: Lilin Zhang, Yoshinori Ukai, Fumiko Nomura, Youichi Aikawa, Yoko Kayukawa, Katsuyuki Mitomo, Katsushi Kouda, Romi Kodaka, Gene Kurosawa, Yoshikazu Kurosawa, Kazuhiro Morishita, Yukio Sudo. Antibodies against TfR inhibit growth of tumor cells both in vitro and in vivo . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4323. doi:10.1158/1538-7445.AM2013-4323

Abstract 2428: PPMX-2017: Antibody against CDH3 with potent efficacy against lung cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Cadherin 3/P-cadherin (CDH3) is a member of cadherin family proteins involved in the cell-cell adhesion. Based on a genome-wide cDNA microarray analysis of pancreatic cancer, we found that CDH3 is overexpressed in pancreatic cancer. We also confirmed by our immunohistochemistry study that CDH3 protein was expressed highly in pancreatic, lung, colon and other types of cancer tissues but not in normal tissues. Since CDH3 is a transmembrane glycoprotein and overexpressed in cancer tissues, it is an attractive therapeutic target for various kinds of cancer. In this present study, we generated a series of monoclonal antibodies against CDH3 and evaluated their anti-tumor effect both in vitro and in vivo. PPMX2017, an antibody from the series, is an anti-human CDH3 specific mouse IgG2a antibody. The in vitro studies demonstrated that PPMX2017 elicited strong antibody dependent cellular cytotoxicity (ADCC) activity on CDH3-positive cancer cell lines (lung cancer: NCI-H358 and A431, pancreatic cancer: KLM1 and Bxpc3.). Furthermore, PPMX2017 showed a significant antitumor effect in a therapeutic xenograft model of lung cancer where NCI-H358 cell-generated tumors grew to 70∼90 mm3 before administration of this antibody. PPMX2017 suppressed tumor growth by 60∼80% compared with control IgG in a dose range of 0.3mg∼5mg/kg. These findings show that CDH3 is a potential target for cancer therapy and PPMX2017 is a candidate for the development of antibody therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2428.