Abstract The envelope protein E2 is involved in hepatitis C virus (HCV) entry into host cells. The proteolytic activity of antibodies (Abs) offers a novel neutralizing mechanism by permanent inactivation of multiple epitopes by a single Ab molecule. We studied the proteolytic cleavage of E2 linked to a glutathione S-transferase tag (E2-GST) by Abs purified from human sera. IgM but not IgG class Abs hydrolyzed recombinant E2 determined by an electrophoresis assay, consistent with previous observations that Ab catalysis is an innate immune function subject to deterioration over the course of adaptive B lymphocyte differentiation. To determine the feasibility of engineering HCV E2-specific proteolytic Abs, we cloned hybrid human IgGs composed of light chains with promiscuous proteolytic activity (clones GG63, HK13 and HK14; isolated from a lupus phage library) and the heavy chain of an HCV E2-specific Ab (clone CBH-7; isolated from an HCV infected subject). The hybrid Abs hydrolyzed E2-GST with little or no activity in the wildtype control Ab. The hybrid Abs displayed the ability to bind 125I-E2, confirming that the heavy chain subunit can imparts specificity for E2. These observations suggest the feasibility of harnessing the natural proteolytic activity of Abs to developing catalytic reagents with potential immunotherapeutic utility.