A novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models
Abstract:
Concurrent KRAS LKB1 (STK11, KL) mutant Non-Small Cell Lung Cancers (NSCLC) is particularly difficult to treat and does not respond well to current immune checkpoint blockade (ICB) therapies. This is due to numerous mechanisms including low antigen presentation limiting T cell mediated killing. To activate anti-tumor immunity, we targeted tumor cell - natural killer (NK) cell interactions. We tested whether a novel antibody based therapeutic strategy that predominantly activates natural killer (NK) cells demonstrates efficacy in pre-clinical mouse models of KL NSCLC. NK cells rely on binding of ligands, such as Major Histocompatibility Complex (MHC) class I-related chain A or B (MICA/B), to the activating receptor NKG2D. Importantly MICA and MICB are widely expressed in elevated levels across NSCLC subtypes including KL lung cancers. Proteases with the tumor microenvironment (TME) can cleave these proteins rendering tumor cells less visible to NK cells. We therefore developed a MICA monoclonal antibody, AHA-1031, which utilizes two NK cell activating receptors. AHA1031 prevents ligand shedding without interfering with binding to NKG2D while targeting cancer cells to antibody mediated cell dependent cytotoxicity (ADCC). Our therapeutic novel antibody has significant monotherapy activity in KL cancer models including xenografts of human cell lines and patient derived xenografts. 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
A novel antibody therapy targeting Natural Killer (NK) cells shows promise for difficult-to-treat KRAS LKB1 (KL) mutant Non-Small Cell Lung Cancer (NSCLC). This approach activates anti-tumor immunity by stabilizing MICA/B ligands and inducing antibody-mediated cell-dependent cytotoxicity.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Concurrent KRAS LKB1 (KL) mutant Non-Small Cell Lung Cancer (NSCLC) presents significant treatment challenges, often showing poor response to immune checkpoint blockade (ICB) due to mechanisms like reduced antigen presentation.
- Natural Killer (NK) cells are crucial for anti-tumor immunity, recognizing target cells via activating receptors like NKG2D that bind ligands such as Major Histocompatibility Complex (MHC) class I-related chain A or B (MICA/B).
- Tumor microenvironment (TME) proteases can cleave MICA/B, diminishing NK cell recognition and anti-tumor activity in KL NSCLC.
Purpose of the Study:
- To evaluate a novel antibody-based therapeutic strategy designed to activate NK cells for treating KL NSCLC.
- To investigate the efficacy of a MICA monoclonal antibody (AHA-1031) in pre-clinical models of KL NSCLC.
Main Methods:
- Development of AHA-1031, a monoclonal antibody targeting MICA/B, designed to prevent ligand shedding and induce antibody-dependent cell-mediated cytotoxicity (ADCC).
- Testing the therapeutic efficacy of AHA-1031 as monotherapy in pre-clinical mouse models, including xenografts derived from human cell lines and patient samples of KL NSCLC.
- Assessing the antibody's mechanism of action, focusing on NK cell activation via MICA/B stabilization and ADCC induction.
Main Results:
- The novel antibody AHA-1031 demonstrated significant monotherapy activity in pre-clinical KL NSCLC models.
- The antibody effectively prevents MICA/B shedding, thereby enhancing NK cell-mediated anti-tumor responses.
- AHA-1031 successfully targets cancer cells for ADCC, contributing to its therapeutic efficacy.
Conclusions:
- Targeting NK cell interactions through MICA/B stabilization and ADCC induction represents a potent and alternative therapeutic strategy for KL NSCLC.
- The developed antibody-based therapy shows broad applicability across different tumor types due to the widespread shedding of MICA/B ligands.
