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Updated: Aug 14, 2026
Preparation of CD4+ T Cells for Analysis of GD3 and GD2 Ganglioside Membrane Expression by Microscopy
Published on: November 8, 2016
Therapeutic potential of chimeric anti-(ganglioside GD3) antibody KM871: antitumor activity in xenograft model of
J Kanazawa1, S Ohta, K Shitara
1Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co Ltd, Sunto-gun, Shizuoka-ken, Japan.
Abstract:
KM871 is a chimeric antibody recognizing ganglioside GD3, which is one of the major gangliosides expressed on the cell surface of human tumors of neuroectodermal origin. This study demonstrates the antitumor activity of KM871 against human melanoma xenografts in nude mice, and analyzes the effector function operating in mice. In a well-established tumor model, KM871 showed antitumor activity against H-15 and SK-MEL-28 human melanoma but not against H-187 and G361 human melanoma when administered intravenously 5 days/week for 2 weeks. The G361 tumor became sensitive when KM871 was first administered on the day of tumor inoculation. In this assay, it was observed that almost all the mice were tumor-free, but a few mice developed tumors. Therefore, we examined the amount and expression pattern of GD3 antigen on G361 tumors escaping from KM871 treatment, but no change was observed. Next we examined the optimal administration schedule for KM871 in mice, using H-15 melanoma. KM871 showed antitumor activity when administered intravenously either 5 days/week for 2 weeks or three biweekly doses. However, the effect of the former schedule was stronger than three biweekly doses. To compare the effector function in humans and mice, we studied the complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity and antibody-dependent macrophage-mediated cytotoxicity of KM871 using complement or effector cells prepared from humans and mice. It was found that the antibody-dependent cell-mediated cytotoxicity exerted by polymorphonuclear cells and antibody-dependent macrophage-mediated cytotoxicity were the only antitumor mechanism of KM871 in mice. However their action was very weak compared with that in humans, and complement-mediated cytotoxicity, which was strong in humans, was not observed in mice. Therefore, the antitumor activity of KM871 against human melanomas evaluated by the nude mouse model might be underestimated. These results indicate that KM871 shows good antitumor activity against GD3-positive human melanoma and the antitumor activity expected in humans might be superior to that of the nude mouse model.
Insights
KM871, a chimeric antibody targeting ganglioside GD3, demonstrated antitumor activity against human melanoma xenografts in mice. Effector functions in mice were weaker than in humans, suggesting potential underestimation of KM871
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Ganglioside GD3 is a key antigen on neuroectodermal tumors.
- Chimeric antibodies offer targeted cancer therapy.
- Understanding antibody effector functions is crucial for efficacy.
Purpose of the Study:
- To evaluate the antitumor activity of KM871 against human melanoma xenografts in nude mice.
- To analyze the underlying effector mechanisms of KM871 in a murine model.
- To compare mouse and human effector functions for KM871.
Main Methods:
- Intravenous administration of KM871 to mice bearing human melanoma xenografts.
- Assessment of antitumor activity based on tumor growth inhibition.
- In vitro analysis of complement-mediated cytotoxicity (CMC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent macrophage-mediated cytotoxicity (MDMC) using human and murine effector cells.
Main Results:
- KM871 exhibited antitumor activity against specific human melanoma xenografts (H-15, SK-MEL-28) but not others (H-187, G361) under certain conditions.
- Early administration of KM871 improved efficacy against G361 melanoma.
- The optimal administration schedule involved 5 days/week for 2 weeks, showing stronger effects than tri-weekly doses.
- In mice, ADCC and MDMC were the primary antitumor mechanisms, but were significantly weaker than in humans.
- CMC, a potent mechanism in humans, was absent in mice.
Conclusions:
- KM871 demonstrates antitumor potential against GD3-positive human melanomas.
- The nude mouse model may underestimate KM871's true therapeutic efficacy due to differences in effector functions.
- The expected antitumor activity of KM871 in humans could be superior to that observed in the murine model.
