Preclinical characterization of a Fab-like CD3/CLDN18.2 XFab® bispecific antibody against solid tumors
Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved..
The claudin 18.2(CLDN18.2) antigen is highly expressed in gastric mucosa epithelial cells and frequently expressed in malignant tumors. Positive clinical outcomes have popularized claudin 18.2 as a novel cellular and antibody therapeutic. Here, we designed a bispecific antibody-ZWB67 using the XFab® platform, aimed at redirecting CD3+ effector T cells to CLDN18.2+ target cells or tissues. Physicochemical characterization, binding properties, T cell stimulatory activity, and T cell-dependent cellular cytotoxicity of ZWB67 were evaluated in dosage intervals using antigens of CD3 and target cells expressing CLDN18.2 or CD3. Then, the anti-tumor activity was assessed in humanized CD3EDG mice bearing MC-38-hCLDN18.2 tumors. Our data demonstrate that ZWB67 specifically binds to the human CD3e antigen (KD = 1.04E-08 M) and binds more strongly to CLDN18.2+ cells than to CD3+ cells (4.3- to 9.2-fold difference). ZWB67 showed good activity in the luciferase reporter system and exhibited dose-dependent activation, cytotoxicity of T cells, and cytokine release when co-cultured with CLDN18.2+ cells and CD3+ T cells. ZWB67 also exhibited high in vivo efficacy in the MC-38-hCLDN18.2 xenograft mouse model. In conclusion, the novel anti-CLDN18.2 × anti-CD3 bispecific antibody exhibited low affinity for anti-CD3, highly specific binding, potent cytotoxicity, and anti-tumor activity. These data provide a basis for future preclinical and clinical development of this therapeutic strategy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:227 |
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| Enthalten in: |
Immunobiology - 227(2022), 6 vom: 08. Nov., Seite 152283 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Guili [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Bispecific |
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| Anmerkungen: |
Date Completed 30.11.2022 Date Revised 16.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.imbio.2022.152283 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM34713615X |
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| 100 | 1 | |a Xu, Guili |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Preclinical characterization of a Fab-like CD3/CLDN18.2 XFab® bispecific antibody against solid tumors |
| 264 | 1 | |c 2022 | |
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| 520 | |a Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved. | ||
| 520 | |a The claudin 18.2(CLDN18.2) antigen is highly expressed in gastric mucosa epithelial cells and frequently expressed in malignant tumors. Positive clinical outcomes have popularized claudin 18.2 as a novel cellular and antibody therapeutic. Here, we designed a bispecific antibody-ZWB67 using the XFab® platform, aimed at redirecting CD3+ effector T cells to CLDN18.2+ target cells or tissues. Physicochemical characterization, binding properties, T cell stimulatory activity, and T cell-dependent cellular cytotoxicity of ZWB67 were evaluated in dosage intervals using antigens of CD3 and target cells expressing CLDN18.2 or CD3. Then, the anti-tumor activity was assessed in humanized CD3EDG mice bearing MC-38-hCLDN18.2 tumors. Our data demonstrate that ZWB67 specifically binds to the human CD3e antigen (KD = 1.04E-08 M) and binds more strongly to CLDN18.2+ cells than to CD3+ cells (4.3- to 9.2-fold difference). ZWB67 showed good activity in the luciferase reporter system and exhibited dose-dependent activation, cytotoxicity of T cells, and cytokine release when co-cultured with CLDN18.2+ cells and CD3+ T cells. ZWB67 also exhibited high in vivo efficacy in the MC-38-hCLDN18.2 xenograft mouse model. In conclusion, the novel anti-CLDN18.2 × anti-CD3 bispecific antibody exhibited low affinity for anti-CD3, highly specific binding, potent cytotoxicity, and anti-tumor activity. These data provide a basis for future preclinical and clinical development of this therapeutic strategy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bispecific antibody | |
| 650 | 4 | |a CD3 | |
| 650 | 4 | |a Claudin 18.2 | |
| 650 | 4 | |a Immunotherapy | |
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| 700 | 1 | |a Liu, Yujie |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hongjie |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Cuima |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jingjing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Fuyu |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Liting |e verfasserin |4 aut | |
| 700 | 1 | |a Bai, Guijun |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Qinzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Xiujie |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Xin |e verfasserin |4 aut | |
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