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Transgenic Goat Can Produce Improved Version of siltuximab on a Large Scale

Studies have confirmed that transgenic goats can produce composite monoclonal antibodies (Mab) in milk. After further incubation, the researchers found that a modified version of the monoclonal antibody siltuximab (siltuximab) was produced in goat milk, which can improve the efficacy and safety is relatively higher.

 

Monoclonal antibodies (mAbs) are a class of important biopharmaceutical drugs for the treatment of serious human diseases. Most therapeutic monoclonal antibodies are produced in cultured mammalian cells, but the production process is costly and its effectiveness is limited. Goats provide an alternative platform for the mass production of therapeutic monoclonal antibodies (mAbs). At present, the most advanced clinical anti-EGFR human/mouse chimeric monoclonal antibody, siltuximab, is commercially produced under the Erbitux brand and approved for anti-cancer treatment.

 

Recently, a study led by the Ruakura Research Center of the New Zealand National Academy of Agricultural and Pastoral Sciences showed that goats produce an improved siltuximab, which has the potential to improve efficacy and better safety compared to Erbitux treatment. In addition, studies have confirmed that transgenic goats are a good platform for the mass production of therapeutic monoclonal antibodies. The research was published on the preprint website bioRxiv.

 

The researchers isolated 23 cell clones from two independent transfection activities carried out in different time periods in the laboratory, and after PCR identification, these two transgenes had stable integration.

 

To determine whether different transgenic lines express g siltuximab in their milk, the founders of nine transgenic lines were hormone-induced into lactation and milked for up to 30 days. Two transgenic lines (GL8.3 and GN118) with very high LC and HC transgene copy numbers cannot secrete lactate. The researchers chose (GN388 and GN451) for further characterization and further development and application in subsequent experiments. Both genotypes are stable, and the production of siltuximab is as high as 10g/L.

 

The study found that the monoclonal antibody gsiltuximab produced by goats has two obvious advantages compared with the current Erbitux products:

 

The goat mammary gland did not modify g siltuximab with highly immunogenic α-Gal epitope. In contrast, α-Gal is present in the current Erbitux product, which has been shown to cause adverse reactions in some patients caused by an immune response to α-Gal. Compared with Erbitux, this will increase the safety of gsiltuximab treatment.

 

The effectiveness of gsiltuximab has improved. The mechanism of action of Erbitux is mainly to block the dimerization and activation of receptors by interfering with the binding of EGF to the extracellular domain of EGFR. Antibody-dependent cellular cytotoxicity (ADCC) can provide a mechanism to enhance the effectiveness of Erbitux, but it has not yet been developed. The gsiltuximab samples showed increased binding to CD16, indicating that they increased ADCC activity. This was directly demonstrated by the monoclonal antibody produced by goat line GN451, which has the highest CD16 binding affinity.

 

In summary, mAb is easily obtained in milk and can be effectively purified to meet an important prerequisite for commercial production. Compared with Erbitux, gsiltuximab has similar functions and can also provide more effective treatment options. Therefore, the production of these animal species with high yield capacity can provide a cost-effective new and improved version of siltuximab, and there is no α-Gal problem, and it will also improve efficiency due to the enhancement of ADCC.

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