Paper in Frontiers in Immunology Describes Trimer Design and Development of Production CHO Cell Lines That Generate Properly Folded HIV-1 Env Trimers to Support Goal of Developing an Effective HIV Vaccine
Geneva, Switzerland, May 31, 2018 – The International AIDS Vaccine Initiative (IAVI) and Selexis SA announced today the publication of their collaborative work describing an improved and more robust approach for generating commercially-viable manufacturing levels of clinical grade, properly folded HIV-1 Env trimers for vaccine generation. Extensive research has established that development of an effective HIV-1 vaccine will require production of a complete HIV-1 Env gp120/gp41 trimer, which is a very difficult-to-express protein complex. Within HIV-infected cells, the Env protein, is synthesized as a gp160 precursor and processed into a trimer containing gp120 and gp41 heterodimers (six subunits total: three gp120 subunits and three gp41 subunits). All six subunits within the trimer are required for appropriate protein folding and viral entry into cells.
In the Frontiers in Immunology paper, entitled “Cleavage-independent HIV-1 trimers from CHO cell lines elicit robust autologous tier 2 neutralizing antibodies,” IAVI and Selexis researchers, along with their collaborators from The Scripps Research Institute and the Universities of Oxford and Southampton, describe the two-pronged strategy they used to significantly improve productivity levels of properly folded and glycosylated HIV-1 Env trimers from CHO cells.
“With more than two million people newly acquiring the HIV virus each year, we are pleased to be able to contribute to this very important work. Clearly, a vaccine against the HIV virus remains a vital global public health need and is a major challenge for researchers and industry,” said Yemi Onakunle, PhD, vice president, licensing and business development, Selexis SA. “It is extremely rewarding to be able to leverage the Selexis SUREtechnology Platform to overcome the secretion bottlenecks associated with HIV envelope protein trimer production.”
The first prong of the productivity-enhancing strategy eliminated the need for a cleavage event to generate gp120 and gp41 from gp160. IAVI developed a construct whereby gp120 and gp41 are expressed as a single protein separated by a flexible peptide linker. These proteins assemble into a native-like conformation, which is more stable than the non-covalent association of cleaved gp120 and gp41. The second prong of the strategy was to utilize Selexis’ SUREtechnology Platform™ to boost expression levels and Selexis’ SURE CHO-Mplus Libraries™ to drive more robust and effective folding, assembly and maturation through the secretory pathway of the HIV-1 Env trimer antigens. Utilizing this approach, the authors report generating three manufacturing CHO cell lines each producing approximately 1.8 g/L of properly folded HIV-1 Env trimer, a thirty-fold increase over conventional approaches.
“This study demonstrates the establishment of a stable CHO cell line producing homogeneous HIV cleavage-independent trimers that, following vaccination, rapidly elicit strain-specific neutralizing antibodies in preclinical models, without generating non-neutralizing antibodies associated with in vivo unfolding. These data suggest the utility of these native-like viral spike mimics for clinical development,” said Richard Wyatt, PhD, professor of immunology, IAVI's Neutralizing Antibody Center, The Scripps Research Institute.
Analysis of the HIV-1 Env trimers determined that they were properly glycosylated and that 90% of the produced trimers contained the closed, native-like conformation structure. The trimers were stable at 4oC for at least two months and, significantly, these trimers displayed favorable antigenic properties, including eliciting robust neutralizing antibodies when injected into animal models. As a result of these successes, IAVI and Selexis are currently generating Env trimers from other HIV clades utilizing this strategy as part of the larger effort to address HIV viral diversity in vaccine development.
About Selexis SA
Selexis SA is a pioneering life sciences company and a global leader in mammalian (suspension-adapted CHO-K1) cell line generation, providing unparalleled proprietary technology and the highly-specialized expertise that is necessary to translate scientific innovation into life-saving medicines for patients. Selexis’ SUREtechnology Platform™ facilitates the rapid, stable, and cost-effective production of virtually any recombinant protein and provides seamless integration of the bioproduction continuum, spanning discovery to commercialization. With more than 100 partners worldwide, more than 100 drug products in clinical development and three commercial products utilizing Selexis-generated cell lines, the Company has a history of empowering scientists and biopharmaceutical companies around the world to realize the full potential of their research. More information is available at www.selexis.com.
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