uPAR-Targeting Human Antibody for Treating Cancer and Fibrotic Diseases
Researchers at the University of Pittsburgh have developed two novel, high-affinity human VH domain antibodies (VH3 and VH115) that specifically target the urokinase-type plasminogen activator receptor (uPAR), a cell surface protein significantly overexpressed in multiple cancer types and implicated in fibrotic diseases. These single-domain antibodies represent a breakthrough in targeted therapeutic development, offering superior binding characteristics and versatility compared to traditional full-length antibodies.
Description
uPAR (CD87) is a glycosylphosphatidylinositol-anchored receptor that plays critical roles in cancer progression, including tumor cell proliferation, invasion, metastasis, and angiogenesis. High uPAR expression correlates with poor prognosis across various solid tumors, including breast, lung, colorectal, ovarian, prostate, pancreatic, liver, and gastric cancers, as well as melanoma and brain cancer. This technology comprises two fully human VH domain antibodies isolated from a phage-displayed library: - VH3: Exhibits an equilibrium dissociation constant (KD) of 17.1 nM and an affinity constant (kon) of 1.4 × 10⁻² ± 1.9 × 10⁻⁵ - VH115: Demonstrates a KD of 34.2 nM and kon of 2.4 × 10⁻³ ± 5.6 × 10⁻⁵ These binders have been engineered into VH-Fc fusion proteins, enhancing their half-life, avidity, and therapeutic potential. The VH-Fc format increased affinity by 2-fold for VH3 and maintained strong binding for VH115, while significantly improving stability and reducing aggregation tendencies. Key Technical Features: - Single-domain architecture enables superior tissue penetration - High specificity for human uPAR with no cross-reactivity to BSA - Demonstrated binding to multiple uPAR-expressing cell lines (293T, 293T-uPAR, A375 melanoma cells) - Engineered Fc fusion format for extended circulation time - Monomeric folding reduces manufacturing complexityApplications
1) Cancer Immunotherapy:The antibodies show significant therapeutic potential across multiple cancer types where uPAR is overexpressed in:
Solid Tumors:
Breast cancer, colorectal cancer, melanoma, brain cancer, lung cancer, ovarian cancer, prostate cancer, bladder cancer, liver cancer, gastric cancer, pancreatic cancer
Hematologic Malignancies: Acute myeloid leukemia, myeloma
Mechanism: Direct tumor cell targeting, potential for antibody-drug conjugate (ADC) development, CAR-T/CAR-NK cell engineering
2) Fibrotic Diseases:
uPAR's role in inflammation, angiogenesis, and tissue remodeling makes these antibodies applicable to:
Systemic sclerosis (SSc)
Idiopathic pulmonary fibrosis
Renal fibrosis
Ureteral fibrosis
Urethral fibrosis
Bladder fibrosis
Peyronie's disease
Liver cirrhosis
COPD
3) Senescence-Related Disorders:
uPAR is broadly induced during cellular senescence, suggesting applications in:
Fibrin-associated inflammation
Age-related liver fibrosis
Other senescence-associated pathologies
Advantages
Superior Binding CharacteristicsHigh-affinity binding (KD values of 17.1 nM and 34.2 nM)
Target different epitopes on uPAR, enabling potential combination strategies
Maintained specificity across diverse uPAR-expressing cell types
Enhanced Therapeutic Properties
VH-Fc fusion format extends half-life and improves pharmacokinetics
Reduced aggregation tendency compared to initial single-domain formats
Monomeric structure facilitates manufacturing and quality control
Versatile Platform Technology
Adaptable for multiple therapeutic modalities:
Antibody-drug conjugates (ADCs) with cytotoxic payloads
Bispecific T-cell engagers (BiTEs)
CAR-T and CAR-NK cell engineering
Chimeric antigen receptors
Small size enables superior tissue penetration compared to full-length antibodies
Human origin minimizes immunogenicity risk
Demonstrated Efficacy
Potent cytotoxicity against uPAR-expressing cancer cells in vitro
Domain-based bispecific T-cell engager (DbTE) format showed effective tumor cell killing
First reported uPAR-specific human VH domain antibodies as candidates for cancer immunotherapy
Broad Market Applicability
Addresses multiple high-burden diseases (cancer and fibrosis)
Applicable across numerous cancer types with validated uPAR expression
Potential for both therapeutic and diagnostic applications