Phase I/II Clinical Trial of the Anti-Podoplanin Monoclonal Antibody Therapy in Dogs with Malignant Melanoma

Abstract

Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed on tumor cells. PDPN is known to be linked with several aspects of tumor malignancies in certain types of human and canine tumors. Therefore, it is considered to be a novel therapeutic target. Monoclonal antibodies targeting PDPN expressed in human tumor cells showed obvious anti-tumor effects in preclinical studies using mouse models. Previously, we generated a cancer-specific mouse–dog chimeric anti-PDPN antibody, P38Bf, which specifically recognizes PDPN expressed in canine tumor cells. In this study, we investigated the safety and anti-tumor effects of P38Bf in preclinical and clinical trials. P38Bf showed dose-dependent antibody-dependent cellular cytotoxicity against canine malignant melanoma cells. In a preclinical trial with one healthy dog, P38Bf administration did not induce adverse effects over approximately 2 months. In phase I/II clinical trials of three dogs with malignant melanoma, one dog vomited, and all dogs had increased serum levels of C-reactive protein, although all adverse effects were grade 1 or 2. Severe adverse effects leading to withdrawal of the clinical trial were not observed. Furthermore, one dog had stable disease with P38Bf injections. This is the first reported clinical trial of anti-PDPN antibody therapy using spontaneously occurring canine tumor models.

Novel knock‐in mouse model for the evaluation of the therapeutic efficacy and toxicity of human podoplanin–targeting agents

“…28 Consistent with our report, a safety study that used a cancer-specific mouse-dog chimeric anti-PDPN mAb, which specifically recognizes canine PDPN-expressing tumor cells, found no severe adverse effects in normal dogs treated with mAb and in dogs with melanoma. 35 Furthermore, the synthesized small CLEC-2 inhibitor 2CP did not exhibit any impairment in the physiologic platelet function of hemostasis and cytotoxicity. 36 However, toxicity after repeated administrations of neutralizing anti-PDPN mAbs remains unclear.…”

Heterocellular N-cadherin junctions enable nontransformed cells to inhibit the growth of adjacent transformed cells

“…PDPN is also induced early in OSCC progression and can be used to identify premalignant lesions that are bound to develop into malignancies [39,40,61]. In addition to OSCC, PDPN promotes a variety of other cancers including mammary carcinoma [62,63], glioma [64][65][66][67], melanoma [59,68,69], ovarian cancer [70], and pulmonary adenocarcinoma [71][72][73]. Indeed, PDPN has been identified as an enticing target for chemotherapy [74,75].…”

Defucosylated Mouse–Dog Chimeric Anti-EGFR Antibody Exerts Antitumor Activities in Mouse Xenograft Models of Canine Tumors

“…Original antibody therapies for dogs have not been established for most diseases, including osteosarcoma; therefore, antibody drugs for humans have been used as alternatives. For example, several tumor antigens that have been used for targeted therapies in human cancers are also identified in canine malignancies, including EGFR, HER2, VEGFR2, CD20, podoplanin, PD-1, and PD-L1 [ 16 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Particularly, the hEGFR and dEGFR amino acid sequences are 91% identical, and some anti-hEGFR mAbs are effective against canine tumors that overexpress dEGFR in vitro and/or in vivo [ 16 , 50 ].…”