Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models
Ryan R Kowash1,2, Manoj Sabnani3, Laura T Gray3
1Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
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.
Insights
Targeting MICA/B with the novel antibody AHA-1031 offers a promising therapy for KRAS LKB1 mutant NSCLC by activating natural killer (NK) cells and inducing antibody-dependent cellular cytotoxicity (ADCC). This approach shows significant tumor inhibition and immune cell activation in preclinical models.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Concurrent KRAS LKB1 mutant non-small cell lung cancer (NSCLC) exhibits poor response to current immune checkpoint blockade therapies.
- Targeting Major Histocompatibility Complex class I-related chain A or B (MICA/B) presents an alternative strategy by activating natural killer (NK) cells.
Purpose of the Study:
- To investigate the potential of MICA/B as a therapeutic target in NSCLC.
- To develop and evaluate a novel antibody, AHA-1031, for its ability to stabilize MICA/B and enhance anti-tumor immunity.
Main Methods:
- Analysis of MICA/B expression and shedding in NSCLC cell lines and patient data using flow cytometry and ELISA.
- Engineering of AHA-1031, an antibody-dependent cellular cytotoxicity (ADCC)-enhanced MICA/B monoclonal antibody designed to prevent ligand shedding.
- In vitro and in vivo evaluation of AHA-1031 efficacy in KL mutant NSCLC cell lines and patient-derived xenograft models, including immune cell profiling.
Main Results:
- NSCLC cell lines and patient samples show high MICA/B expression and shedding.
- AHA-1031 effectively binds to MICA/B, prevents shedding, stabilizes cell surface expression, and induces potent ADCC in vitro.
- AHA-1031 monotherapy demonstrated significant tumor growth inhibition and increased immune cell infiltrates, including activated NK cells, in preclinical KL mutant NSCLC models without observable toxicity.
Conclusions:
- MICA/B stabilization and ADCC induction via AHA-1031 represent a potent therapeutic strategy for KL mutant NSCLC.
- The broad MICA/B shedding across various tumors suggests universal applicability of this therapeutic approach.
