Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models
Background Concurrent KRAS LKB1 (STK11, KL) mutant non-small cell lung cancers (NSCLC) do not respond well to current immune checkpoint blockade therapies, however targeting major histocompatibility complex class I-related chain A or B (MICA/B), could pose an alternative therapeutic strategy through...
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BMJ Publishing Group
2025-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e009867.full |
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| author | Shohei Koyama Yujiro Naito John D Minna David E Gerber Ryan R Kowash Manoj Sabnani Laura T Gray Qing Deng Nusrat U A Saleh Luc Girard Kentaro Masahiro Zhiqian Lucy Liu Hemanta Baruah Esra A Akbay |
| author_facet | Shohei Koyama Yujiro Naito John D Minna David E Gerber Ryan R Kowash Manoj Sabnani Laura T Gray Qing Deng Nusrat U A Saleh Luc Girard Kentaro Masahiro Zhiqian Lucy Liu Hemanta Baruah Esra A Akbay |
| author_sort | Shohei Koyama |
| collection | DOAJ |
| description | Background Concurrent KRAS LKB1 (STK11, KL) mutant non-small cell lung cancers (NSCLC) do not respond well to current immune checkpoint blockade therapies, however targeting major histocompatibility complex class I-related chain A or B (MICA/B), could pose an alternative therapeutic strategy through activation of natural killer (NK) cells.Methods Expression of NK cell activating ligands in NSCLC cell line and patient data were analyzed. Cell surface expression of MICA/B in NSCLC cell lines was determined through flow cytometry while ligand shedding in both patient blood and cell lines was determined through ELISA. We engineered an antibody-dependent cellular cytotoxicity (ADCC) enhanced MICA/B monoclonal antibody, AHA-1031, which prevents ligand shedding without interfering with binding to natural killer group 2D while targeting cancer cells via superior ADCC. We performed in vitro assays using ELISA and flow cytometry-based assays to confirm that our antibody potently binds to and stabilizes MICA/B expression across lung cancer and other solid tumor cell lines. Additionally, we used two KL mutant NSCLC cell lines and a KL mutant patient-derived xenograft (PDX) model to demonstrate in vivo antitumor efficacy and flow cytometry analysis for immune cell activation profiling.Results NSCLC cell lines exhibit high MICA/B expression and secrete soluble MICA/B in vitro. Soluble MICA/B is also detected in patient blood samples. AHA-1031 binds to the α3 domain of MICA/B, preventing shedding and targeting tumor cells to ADCC. AHA-1031 exhibits high affinity and specificity to MICA/B, preventing MICA/B shedding in tumor lines and inducing ADCC in vitro. Our antibody also effectively binds and stabilizes MICA/B expression in additional tumor types and demonstrates broad specificity. We show that in two KL mutant NSCLC xenograft models and a KL mutant PDX model, treatment with AHA-1031 monotherapy significantly inhibits tumor growth compared with vehicle-treated animals with no observable toxicity. Tumor tissues from treated mice exhibit significantly increased immune cell infiltrates and activated NK cell populations.Conclusions Activating NK cells through MICA/B stabilization and inducing ADCC offers an alternative and potent therapy option in KL tumors. MICA/B are shed across different tumors making this therapeutic strategy universally applicable. |
| format | Article |
| id | doaj-art-124a929bd35b44ebb30dd5b73950cf53 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-124a929bd35b44ebb30dd5b73950cf532025-01-07T08:15:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-009867Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer modelsShohei Koyama0Yujiro Naito1John D Minna2David E Gerber3Ryan R Kowash4Manoj Sabnani5Laura T Gray6Qing Deng7Nusrat U A Saleh8Luc Girard9Kentaro Masahiro10Zhiqian Lucy Liu11Hemanta Baruah12Esra A Akbay13Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center Japan, Kashiwa, JapanDepartment of Respiratory Medicine and Clinical Immunology, Osaka University, Suita, JapanSimmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USASimmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USADepartment of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USAAakha Biologics, Frisco, Texas, USAAakha Biologics, Frisco, Texas, USASimmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USADepartment of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USASimmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USADepartment of Respiratory Medicine and Clinical Immunology, Osaka University, Suita, JapanAlloy Therapeutics Inc, Lexington, Massachusetts, USAAakha Biologics, Frisco, Texas, USADepartment of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USABackground Concurrent KRAS LKB1 (STK11, KL) mutant non-small cell lung cancers (NSCLC) do not respond well to current immune checkpoint blockade therapies, however targeting major histocompatibility complex class I-related chain A or B (MICA/B), could pose an alternative therapeutic strategy through activation of natural killer (NK) cells.Methods Expression of NK cell activating ligands in NSCLC cell line and patient data were analyzed. Cell surface expression of MICA/B in NSCLC cell lines was determined through flow cytometry while ligand shedding in both patient blood and cell lines was determined through ELISA. We engineered an antibody-dependent cellular cytotoxicity (ADCC) enhanced MICA/B monoclonal antibody, AHA-1031, which prevents ligand shedding without interfering with binding to natural killer group 2D while targeting cancer cells via superior ADCC. We performed in vitro assays using ELISA and flow cytometry-based assays to confirm that our antibody potently binds to and stabilizes MICA/B expression across lung cancer and other solid tumor cell lines. Additionally, we used two KL mutant NSCLC cell lines and a KL mutant patient-derived xenograft (PDX) model to demonstrate in vivo antitumor efficacy and flow cytometry analysis for immune cell activation profiling.Results NSCLC cell lines exhibit high MICA/B expression and secrete soluble MICA/B in vitro. Soluble MICA/B is also detected in patient blood samples. AHA-1031 binds to the α3 domain of MICA/B, preventing shedding and targeting tumor cells to ADCC. AHA-1031 exhibits high affinity and specificity to MICA/B, preventing MICA/B shedding in tumor lines and inducing ADCC in vitro. Our antibody also effectively binds and stabilizes MICA/B expression in additional tumor types and demonstrates broad specificity. We show that in two KL mutant NSCLC xenograft models and a KL mutant PDX model, treatment with AHA-1031 monotherapy significantly inhibits tumor growth compared with vehicle-treated animals with no observable toxicity. Tumor tissues from treated mice exhibit significantly increased immune cell infiltrates and activated NK cell populations.Conclusions Activating NK cells through MICA/B stabilization and inducing ADCC offers an alternative and potent therapy option in KL tumors. MICA/B are shed across different tumors making this therapeutic strategy universally applicable.https://jitc.bmj.com/content/13/1/e009867.full |
| spellingShingle | Shohei Koyama Yujiro Naito John D Minna David E Gerber Ryan R Kowash Manoj Sabnani Laura T Gray Qing Deng Nusrat U A Saleh Luc Girard Kentaro Masahiro Zhiqian Lucy Liu Hemanta Baruah Esra A Akbay Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models Journal for ImmunoTherapy of Cancer |
| title | Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models |
| title_full | Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models |
| title_fullStr | Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models |
| title_full_unstemmed | Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models |
| title_short | Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models |
| title_sort | novel and potent mica b antibody is therapeutically effective in kras lkb1 mutant lung cancer models |
| url | https://jitc.bmj.com/content/13/1/e009867.full |
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