Abstract
The monoclonal antibody (mAb) against CD20 known as Rituxan is widely used to treat autoimmune diseases and lymphomas. However, further application of Rituxan faces challenges of high production cost, which limits its availability in developing countries. Here, we report a new approach for large production of a recombinant anti-CD20 mAb in the milk of transgenic cattle (at a yield of up to ~6.8 mg/mL), with ~80% recovery rate and >99% purity. Crystallography study showed that our recombinant mAb is structurally nearly identical to Rituxan with only minor differences in N-linked glycosylation pattern. Functional study showed that, while our mAb shared similar target-cell binding capacities and complement-dependent cytotoxicity with Rituxan, our product exhibited a higher binding affinity for FcγRIIIα and a greater antibody-dependent cellular cytotoxicity. Accordingly, our recombinant mAb demonstrated a superior efficacy over Rituxan against B-cell lymphomas in severe combined immunodeficiency mice. Taken together, our data supports transgenic cattle as a novel model for cost-competitive, large-scale production of therapeutic antibodies.
Highlights
In 1997, Rituxan was approved by the US Food and Drug Administration (FDA) as the first therapeutic recombinant monoclonal antibodies to treat non-Hodgkin lymphoma[1]
The results showed that our recombinant monoclonal antibody (mAb) and Rituxan were both capable of eliciting strong antibody-dependent cell-mediated cytotoxicity (ADCC) activity against Raji cells in a dose-dependent manner (Fig. 4e)
As the first FDA-approved mAb, Rituxan has offered an effective treatment against most B-cell lymphoproliferative disorders over the past 30 years
Summary
In 1997, Rituxan was approved by the US Food and Drug Administration (FDA) as the first therapeutic recombinant monoclonal antibodies (mAb) to treat non-Hodgkin lymphoma[1]. Previous studies found that Rituxan acts through several mechanisms contributing to tumor clearance This includes complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and the direct induction of programmed cell death, which together can effectively reduce the circulating B-cell counts in patients with lymphoma[2,3]. Mammary gland bioreactors derived from transgenic animals have been considered as efficient and attractive systems for producing recombinant pharmaceutical proteins, because their extremely high production capacities with low manufacturing costs[9]. Eukaryotic proteins, those from mammalians, undergo complex post-translational modifications, such as glycosylation, which can widely vary among cell types and play a major role in protein functions[10,11]. This different glycosylation may contribute to the observed higher ADCC effects and in vivo therapeutic efficacy
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