Phase 1 first-in-human clinical trial of AG01, a recombinant monoclonal antibody to progranulin/glycoprotein 88 (PGRN/GP88), to determine the safety, tolerability, pharmacokinetics, and preliminary anti-tumor response in subjects with advanced solid tumor malignancies.
Background: GP88/PGRN is the largest member of the granulin/epithelin family. We demonstrated GP88’s role as an autocrine growth & survival factor in breast cancer (BC): in ER+BC cells, GP88 stimulates proliferation & confers resistance to anti-estrogen therapy & aromatase inhibitors;GP88 is expressed in 80% of invasive ductal carcinomas & is negative in normal mammary tissue; GP88 tumor expression is a prognostic indicator of recurrence & death in BC pts; Elevated GP88 serum level in metastatic BC patients (pts) is associated with disease progression. PGRN/GP88 is overexpressed in several other solid tumors (non-small cell lung carcinoma, colorectal, bladder, ovarian, prostate & brain). In advanced NSCLC & prostate pts, elevated serum PGRN/GP88 have been found. These results make GP88/PGRN an ideal therapeutic & diagnostic target in BC and other solid tumors. An anti-human PGRN/GP88 monoclonal antibody (AG01) inhibiting PGRN/GP88 action was developed & expressed as recombinant antibody in CHO cells. Pharmacology, GMP manufacturing, formulation, stability studies & GLP toxicology studies in non-human primates were done. The IND application was cleared by the FDA to proceed with the first-in-human (FIH) AG01 study in adult subjects with advanced solid tumors. Methods: This IRB approved FIH study, will be conducted in 2 stages, dose escalation (1A) and dose expansion (1B). The 1A part is ongoing, with the 1 + (3+3) design. In the 1A part the AG01 is administered intravenously (IV) over 90 min. every 14 days +/- 1 day, 1 cycle = 28days, DLT assessments occur in the first 28 days of treatment. Five dose levels of AG01 & a -1 level are planned (level -1-0.5mg/kg, & 1mg/kg, 2mg/kg, 4mg/kg, 6mg/kg, 8 mg/kg). In 1A part of the study, initially an accelerated titration design (1pt/dose level) was utilized to guide dose progression & estimation of the maximum tolerated and/or administered dose (MTD/MAD). Eligibility criteria for 1A part include pts with advanced relapsed/refractory solid tumor malignancies who failed 1 or more standard of care (SOC) therapies or for whom no SOC treatment exists or is not tolerated, at least 1 RECIST1.1 measurable lesion, ECOG < = 2, Life expectancy > = 12wks, adequate organ & bone marrow function, willing to sign informed consent & follow study procedures. Primary objective (1A) is to determine the MTD and/or MAD of AG01. Secondary objectives: to determine the recommended phase 2 dose (RP2D), safety, tolerability, the PKs, immunogenicity & the preliminary anti-tumor activity of AG01. Exploratory objectives: to determine PGRN/GP88 expression in tumor tissue & PGRN/ GP88 blood levels (A&G’s IHC & ELISA test). This study is registered at NCT05627960. The study is supported by NCI grants NCI R44 CA224718 & CA162629.
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Author Details
Katherine Tkaczuk
University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
Abstract Details
Meeting
2025 ASCO Annual Meeting
Session Type
Poster Session
Session Title
Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
Track
Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology
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