Currently approved immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, most patients do not respond to these treatments because of primary or acquired resistance. Identifying new immune regulators and developing therapeutics targeting such molecules is a current focus in immuno-oncology. We have found that the secreted phospholipase A2 PLA2G2D is highly expressed in various human tumors and positively correlated with that of classic checkpoints such as CTLA-4, PD-1, and PD-L1. PLA2G2D potently diminishes dendritic cell function, suppresses T cell activity, and promotes macrophage M2 polarization. Accordingly, studies using genetically-engineered loss- or gain-of-function mice demonstrate that PLA2G2D strongly enhances tumor growth, indicating that PLA2G2D is a novel, targetable checkpoint for tumor immunotherapy. We have generated more than 700 anti-PLA2G2D monoclonal antibodies, and using a series of in vitro biochemical and immune cell functional assays we have identified 39 leading function-blocking candidates. This proposal seeks to evaluate the anti-tumor efficacy of the 5 most functionally potent drug candidates (which do not cross-react with mouse PLA2G2D), alone and in combination with existing ICIs, using syngeneic tumor models in transgenic PLA2G2D-humanized mice. We will also assess how anti-PLA2G2D changes the tumor immune profile and histologically evaluate PLA2G2D protein expression in various human tumors using our drug candidate (Aim 1). The best drug candidate identified in Aim 1 will then be subjected to non-GLP maximum tolerated dose toxicity and toxicokinetic evaluation in cynomolgus monkeys (Aim 2). Collectively, the successful execution of this proposal will enable us to nominate our final lead molecule and begin IND-enabling studies as part of a follow-up phase II SBIR proposal. Ultimately, an efficacious therapeutic anti-PLA2G2D antibody will comprise a new treatment for patients resistant to currently available ICIs.
Public Health Relevance Statement: PROJECT NARRATIVE The clinical success of immune checkpoint inhibitors (ICIs) represents a transformative advancement in cancer therapy, however >70% of patients fail to respond and new treatments promoting anti-tumor immunity are still urgently needed. PLA2G2D, a member of the secreted phospholipase A2 family, has emerged as an important negative immune regulator and a novel checkpoint suppressing anti-tumor immunity. This project seeks to identify the best anti-PLA2G2D monoclonal antibody drug candidate for development as a novel immunotherapy to benefit patients resistant to current ICIs.
Project Terms: Animals; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anti-Inflammatory Agents; Antibodies; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; Autoimmunity; Autoimmune Status; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Response Modifiers; Biomodulators; Immune Mediators; Immune Mediators/Modulators; Immune Regulators; immunomodulatory biologics; Biology; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Malignant neoplasm of cervix uteri; Cervical Cancer; Cervix Cancer; Malignant Cervical Neoplasm; Malignant Cervical Tumor; Malignant Neoplasm of the Cervix; Malignant Tumor of the Cervix; Malignant Tumor of the Cervix Uteri; Malignant Uterine Cervix Neoplasm; Malignant Uterine Cervix Tumor; Uterine Cervix Cancer; Dendritic Cells; Veiled Cells; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Exhibits; Family; Genetic Engineering; Genetic Engineering Biotechnology; Genetic Engineering Molecular Biology; Recombinant DNA Technology; genetically engineered; Grant; Human; Modern Man; Natural Immunity; Innate Immunity; Native Immunity; Non-Specific Immunity; Nonspecific Immunity; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Inflammation; Lead; Pb element; heavy metal Pb; heavy metal lead; Lymphocyte; Lymphatic cell; Lymphocytic; lymph cell; Macaca fascicularis; Crab-Eating Macaque; Crab-Eating Monkey; Cynomolgus Monkey; Cynomolgus macaque; M fascicularis; M. fascicularis; Macrophage; MÏ; melanoma; Malignant Melanoma; Transgenic Mice; Mus; Mice; Mice Mammals; Murine; Patients; Phospholipase A2; EC 3.1.1.4; Lecithinase A2; PLA2; lecithinase A; phosphatidase; phosphatidolipase; phosphatidylcholine 2 acylhydrolase; Phospholipase; Lecithinases; Pilot Projects; pilot study; Polyunsaturated Fatty Acids; Proteins; Publishing; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Generations; CD3; CD3 Complex; CD3 molecule; OKT3 antigen; T3 Antigens; T3 Complex; T3 molecule; CD3 Antigens; Chronic; Clinical; Phase; Histologically; Histologic; Biochemical; Medical; Series; Evaluation; Blood Serum; Serum; anti-cancer immunotherapy; anticancer immunotherapy; immune-based cancer therapies; immunotherapy for cancer; immunotherapy of cancer; cancer immunotherapy; Malignant Head and Neck Neoplasm; head/neck cancer; malignant head and neck tumor; Head and Neck Cancer; Toxicokinetics; Therapeutic; restraint; Malignant neoplasm of pancreas; Malignant Pancreatic Neoplasm; Pancreas Cancer; Pancreatic Cancer; pancreatic malignancy; Knowledge; Immune; Immunes; experience; success; tumor growth; lipid mediator; Transgenic Organisms; transgenic; Toxic effect; Toxicities; novel; member; Modality; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; Modeling; Sampling; cross reactivity; protein distribution; Myeloid Cells; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; neoplasm immunotherapy; anti-tumor immune therapy; anti-tumor immunotherapy; antitumor immune therapy; antitumor immunotherapy; tumor immune therapy; tumor immunotherapy; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Ovary Cancer; ovarian cancer; Malignant neoplasm of ovary; protein expression; CTLA4 gene; CD152; CD152 Antigen; CD152 Gene; CTLA 4; CTLA-4 Gene; CTLA4; CTLA4-TM; Cytotoxic T-Lymphocyte Protein 4; Cytotoxic T-Lymphocyte-Associated Antigen 4; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocyte-Associated Serine Esterase-4; cytotoxic T-lymphocyte antigen 4; CD8B1 gene; CD8; CD8B; CD8B1; LYT3; programmed cell death protein 1; PD 1; PD-1; PD1; programmed cell death 1; programmed death 1; sle2; systemic lupus erythematosus susceptibility 2; Affinity; Data; Immunooncology; immune-oncology; immuno oncology; immunology oncology; oncoimmunology; in vivo; New Agents; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Tumor Immunity; anti-tumor immunity; antitumor immunity; cancer immunity; Tumor Promotion; Genetically Engineered Mouse; GEM model; GEMM model; genetically engineered mouse model; genetically engineered murine model; follow-up; Active Follow-up; active followup; follow up; followed up; followup; Development; developmental; pre-clinical; preclinical; determine efficacy; efficacy analysis; efficacy assessment; efficacy determination; efficacy examination; evaluate efficacy; examine efficacy; efficacy evaluation; Population; resistant; Resistance; MAb Therapeutics; monoclonal antibody drugs; therapeutic mAbs; Therapeutic Monoclonal Antibodies; clinical applicability; clinical application; gain of function; therapeutic target; tumor; candidate identification; drug candidate; CT-26; CT26; anti-tumor effect; antitumor effect; B7-H1; B7H1; CD274; PD-L1; PDL-1; PDL1; Programmed Cell Death 1 Ligand 1; Programmed Death Ligand 1; programmed cell death protein ligand 1; protein death-ligand 1; programmed cell death ligand 1; humanized mice; humanized mouse; clinical development; immune check point; immunecheckpoint; immune checkpoint; Checkpoint inhibitor; immune check point inhibitor; Immune checkpoint inhibitor; PD-1 antibody; PD1 antibody; anti-PD-1 Ab; anti-PD-1 antibodies; anti-PD-1 monoclonal antibodies; anti-PD1 Ab; anti-PD1 monoclonal antibodies; anti-programmed cell death protein 1 antibodies; anti-programmed death-1 antibody; anti-PD1 antibodies; aPD-1; aPD1; anti programmed cell death 1; anti-PD1; anti-programmed cell death protein 1; antiPD-1; antiPD1; aPD-1; aPD1; anti-PD-1; Teff cell; effector T cell; Keytruda; pembrolizumab
