Phase I Amount
$1,000,000
Breast cancer (BrCa) leads to ~685,000 deaths in women yearly worldwide (WHO). While patients with Hormone Receptor (HR) and Human Epidermal Growth Factor Receptor-2 (HER2)-driven cancers (HR+ and/or HER2+) have benefited from endocrine and HER2-targeted therapies, they still account for the majority of deaths. The HR and HER2 negative (HR-/HER2-) subtype, also known as Triple-negative breast cancer (TNBC), is the most aggressive and even more challenging to treat, leading to ~25% of deaths, despite a much lower incidence. More effective therapies are urgently needed. We identified the cell surface protein ADAM8 as an independent marker of poor BrCa patient outcome and a driver of tumor growth and spread. Using ADAM8-positive (ADAM8+) TNBC mouse models, we showed antibody (Ab)-based targeting of ADAM8 is an effective therapeutic (Tx) strategy [1]. Preliminary immunohistochemistry (IHC) of primary TNBCs revealed only a subset are ADAM8+ (17/50 or 34%), suggesting a diagnostic (Dx) will be needed to identify patients who can benefit from targeted therapy. We launched Adecto Pharmaceuticals to develop Dx and Tx products to improve the outcome of patients with ADAM8+ cancers. ADP2, our top Tx Ab, reduces pre-existing TNBC growth and spread, improves survival, and enhances response to standard-of-care chemotherapy. ADP2 was successfully humanized, and a lead candidate (AD100) selected ahead of IND-enabling studies. AD100 regimens could dramatically improve BrCa treatment. Here, we propose to develop an IHC-based Dx for ADAM8+ cancers as a companion to AD100 or a standalone prognostic for identification of patients at high risk of progressive disease. Currently, there is no Dx for detection of these tumors. Using a panel of highly specific anti-ADAM8 monoclonal Abs (mAbs) and Phase 1 SBIR funds, we (i) optimized IHC conditions and identified ADP2 as lead Dx Ab; (ii) developed a breast staining/scoring control cell line microarray (CCM) with 3 lines expressing low, medium or high ADAM8, and analyzed patient-derived xenograft samples; (iii) validated IHC assay and CCM, and established an ADAM8 scoring system, in primary BrCa samples (which completed all proposed aims). Consistent with earlier findings, ADP2 IHC showed 36.1% of TNBCs (22/61) were ADAM8+, and unexpectedly 32.8% of non-TNBC BrCas (115/351). A 10-year age-adjusted analysis of the HR+/HER2- subtype, with largest sample size, revealed ADAM8 score associated with poor survival, providing early support for a prognostic use of this assay. In this Direct to Phase 2 application, we propose to: 1) refine the ADP2 assay to permit accurate characterization of ADAM8 in any BrCa sample within ASCO/CAP guidelines; 2) verify ADAM8 positivity rates and study the prognostic value of the assay in BrCa; 3) test the predictive value of the assay for AD100 response using TNBC and HR+/HER2- mouse models; 4) complete CLIA validation of the assay by a clinical Dx contractor. Successful completion of the proposed aims will result in an ADAM8 IHC assay with CLIA standard operating protocols ready for testing in future clinical trials.
Public Health Relevance Statement: The ADAM8 cell surface protein is an independent prognostic indicator of poor breast cancer (BrCa) patient outcome, present in multiple BrCa subtypes and identified as a target for treatment. An ADAM8 immunohistochemistry (IHC)-based assay can i) identify patients for treatment with a novel ADAM8 antagonist antibody-based therapy, in development by Adecto, and ii) indicate prognosis, and thus direct treatment strategies with existing standard-of-care therapies to enhance survival of patients with BrCa that expresses ADAM8. Here, we propose to develop a CLIA-validated ADAM8 diagnostic IHC assay ready to enter clinical testing.
Project Terms: Age; ages; Antibodies; Monoclonal Antibodies; Clinical Treatment Moab; mAbs; Biological Assay; Assay; Bioassay; Biologic Assays; Biopsy; Breast; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Clinical Trials; Cox Proportional Hazards Models; Cessation of life; Death; Disease; Disorder; Female; Future; Growth; Generalized Growth; Tissue Growth; ontogeny; Hormone Receptor; Human; Modern Man; Immunohistochemistry; Immunohistochemistry Cell/Tissue; Immunohistochemistry Staining Method; Incidence; Lead; Pb element; heavy metal Pb; heavy metal lead; malignant stomach neoplasm; Gastric Body Cancer; Gastric Cancer; Gastric Cardia Cancer; Gastric Fundus Cancer; Gastric Pylorus Cancer; Malignant Gastric Neoplasm; Malignant Gastric Tumor; Stomach Cancer; gastric malignancy; malignant stomach tumor; stomach fundus cancer; stomach pylorus cancer; Manuals; Mus; Mice; Mice Mammals; Murine; Pathology; Patients; Predictive Value of Tests; Racial Group; Racial Stocks; Race; EGF Receptor; EGFR; ERBB Protein; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Epidermal Growth Factor-Urogastrone Receptors; HER1; TGF-alpha Receptor; Transforming Growth Factor alpha Receptor; Urogastrone Receptor; c-erbB-1; c-erbB-1 Protein; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; proto-oncogene protein c-erbB-1; Epidermal Growth Factor Receptor; Research; Risk; Risk Factors; Running; Specificity; Staining method; Stains; Stress; Testing; Time; Tissue Preservation; Woman; Work; Guidelines; base; improved; Image Analysis; Image Analyses; image evaluation; image interpretation; Clinical; Phase; prognostic; Cell Surface Proteins; Sample Size; Funding; Oncology Cancer; Oncology; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; Antibody Therapy; Normal Tissue; Normal tissue morphology; Pathologist; Companions; Hepatic Cancer; liver cancer; liver malignancy; malignant liver tumor; Malignant neoplasm of liver; Diagnostic; Protocol; Protocols documentation; System; Tumor Volume; Endocrine; computer imaging; digital imaging; Performance; tumor growth; novel; Colon Cancer; cancer in the colon; Colon Carcinoma; Sampling; response; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Progressive Disease; Age-Years; Breast Cancer Treatment; Contractor; Detection; Predictive Value; Reproducibility; American Society of Clinical Oncology; ASCO; Cancer Etiology; Cancer Cause; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Extracellular Domain; External Domain; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; Scheme; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Tumor-Derived; Validation; Monitor; follow-up; Active Follow-up; active followup; follow up; followed up; followup; sample fixation; Fixation; Development; developmental; Abraxane; triple-negative invasive breast carcinoma; TNBC; triple-negative breast cancer; digital; immunogenicity; Population; chemotherapy; mouse model; murine model; tumor; high risk; NOD/SCID mouse; standard of care; treatment strategy; effective therapy; effective treatment; Biological Markers; bio-markers; biologic marker; biomarker; Regimen; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; prognostic value; prognostic ability; prognostic power; prognostic utility; Breast Cancer cell line; Breast tumor cell line; Breast Cancer Patient; Breast Tumor Patient; companion diagnostics; improved outcome; CLIA certified; CLIA accredited; CLIA approved; CLIA compliant; CLIA licensed; cancer subtypes; cancer sub-types; lead candidate; predictive test; predictive assay; patient derived xenograft model; PDX model; Patient derived xenograft; detection assay; therapeutically effective; Prognosis; prognostic indicator; clinical prognostic; antagonist
