FRL5 Antibody

Structure and Function of FCRL5

FCRL5 is a 120 kDa protein with nine Ig-like domains in its extracellular region, a transmembrane segment, and intracellular tyrosine motifs (ITAM/ITIM) that modulate B-cell activation . Key features include:

• Binding Affinity: Binds IgG with varying affinities (IgG1/IgG4: ~1 µM KD; IgG3: weaker; IgG2: variable) .

• Isoforms: Alternate splicing generates truncated variants (1, 6, or 8 domains) .

• Expression: Restricted to B-lineage cells; upregulated in Epstein-Barr virus (EBV)-transformed B cells and B-cell malignancies (hairy cell leukemia, chronic lymphocytic leukemia, multiple myeloma) .

Antibody-Drug Conjugate (ADC) in Multiple Myeloma

DFRF4539A, an anti-FCRL5 ADC, combines a humanized IgG1 monoclonal antibody (MFRF3266A) with monomethyl auristatin E (MMAE), a microtubule-disrupting agent .

Mechanism of Action:

• Targeting: FCRL5 is enriched on malignant plasma cells vs. normal tissues .

• Internalization: ADC binds FCRL5, undergoes lysosomal degradation, releasing MMAE to disrupt microtubule networks .

Pharmacokinetics:

• Linear Exposure: Total antibody and conjugate-MMAE concentrations increased proportionally with dose .

• Half-Life: Not explicitly reported, but PK profiles were consistent across schedules .

Efficacy in Relapsed/Refractory Multiple Myeloma

DFRF4539A showed limited clinical activity:

• Response Rates: 5% partial responses, 3% minimal responses, 46% stable disease .

• Resistance: Lack of efficacy attributed to tumor heterogeneity or insufficient drug delivery .

FCRL5 as a Biomarker

• Overexpression: Elevated in multiple myeloma and B-cell lymphomas, correlating with EBV-driven malignancies .

• Diagnostic Utility: Soluble FCRL5 levels are elevated in B-cell leukemia patients .

IgG Binding Domains

• Critical Domains: FCRL5 domains 1 and 3 are essential for IgG interactions .

• Glycosylation Dependency: Full binding requires intact IgG with both Fab arms and Fc regions .

Therapeutic Potential Beyond ADCs

• Immunomodulation: FCRL5 ligation inhibits B-cell receptor signaling, suggesting potential for combination therapies (e.g., with anti-CD20 agents) .

• Targeted Delivery: FCRL5’s restricted expression and internalization capacity make it a candidate for payload delivery in other B-cell malignancies .