Michael-Paul Robinson, a graduate student in Chemical & Biomolecular Engineering, studies a slide in a lab in Olin Hall.

Michael-Paul Robinson, a graduate student in Chemical & Biomolecular Engineering, studies a slide in a lab in Olin Hall.

September 30, 2015

Cornell Researchers Engineer Antibodies From E. Coli

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By SNEHA KABARIA

A team of Cornell chemical engineers in partnership with New England Biolabs have developed a method to efficiently produce antibodies in the cytoplasm in E. coli bacteria, leading to a new drug development platform.

The research was led by co-senior author Prof. Matthew DeLisa, chemical engineering, and first author Michael-Paul Robinson ’16 grad. Robinson is part of the Cornell Sloan and Colman Fellowship Program, which supplied funding for the project.

The research, which has been ongoing for approximately five years, was published in a paper entitled “Efficient expression of full-length antibodies in the cytoplasm of engineered bacteria” in Nature Communications on Aug. 17.

According to DeLisa, antibodies are specialized immune proteins that bind to antigens, substances the body recognizes as alien, and hence counteract specific antigens within the body. Anti­bodies are used for a wide variety of purposes among which are as vaccines, therapeutic drugs and testing for the presence of specific molecules in research.

“Right now the fastest growing class of new drugs are monoclonal antibodies,” DeLisa said. “Antibodies have quickly taken over as the modality for treating diseases.”

According to Robinson, there is a high demand for large amounts of antibodies to be available quickly.

“There has been a lot of interest in producing antibodies rapidly and less expensively,” Robinson said. “Currently the process can take anywhere from a month to a year.”

Cheaper and faster production can also be used to allow for better distribution and production of important antibodies for people in the developing world who currently may not have ready access to medications.  The new research in particular allows the processing of more complex proteins than before.

Michael-Paul Robinson, a graduate student in Chemical & Biomolecular Engineering, studies a slide in a lab in Olin Hall.

Michael-Paul Robinson grad studies a slide in a lab in Olin Hall.

The research was done using a specific highly engineered strain of E. coli named SHuffle, according to DeLisa. This strain has modifications in the genome that allow the disulfide bonds, which are essential to antibody formation, to be produced in the cytoplasm of the bacteria. Normally different components of enzymes are assembled in separate compartments of the cell, which make them hard to extract without huge inputs of energy.

“Anytime you have to transport something somewhere it costs energy. So what we thought is that if you could produce antibodies and assemble them in the same compartment then you could more efficiently make them,” Robinson said. “But the compartment that the proteins is made in, the cytoplasm, is actually not favorable to disulfide bonds. So our contribution was that we engineered a strain in which the disulfide bond in the antibody assembly was favorable.”

Utilizing recombinant DNA technology to remove certain genetic segments from the DNA sequence, the research team was able to produce protein strands that assembled into correctly folded antibodies, according to DeLisa. The team was able to demonstrate the effective production of few full-length antibodies using their modifications, including those against influenza and those which are considered blockbuster drugs.

“A fully humanized antibody was able to be made quite well in a bacterial system,” DeLisa said. “A system such as ours that can produce one monoclonal antibody has the potential of producing all of them because structurally antibodies are very similar, though they have subtle differences that give them specificity to their respective target antigens.”

“We think that this could be a powerful technology because you have your protein synthesis and assemblage all in the same compartment,” Robinson added.

According to Robinson, producing monoclonal antibodies in E. coli offers some advantages over being produced in Chinese hamster ovary (CHO) cell as has often been done previously. They are quicker, less susceptible to contamination and more cost-effective.

As of now, the research has focused upon the expression and creation of a select few antibodies to demonstrate the effectiveness of the new technology. In the long term, the aim of the research is to develop new platforms upon which to conduct drug discovery of novel antibodies not found in nature to work against diseases.

“For us, our interest is in not only being able to produce antibodies, but being able to engineer antibodies,” Robinson said.

The team also sees the possibility to one day scale up the production process for use by biotechnology and pharmaceutical industries, according to DeLisa.

“[We anticipate that] drug companies who are developing antibodies against new targets will want to use our technology as a way to manufacture a known antibody sequence more cost-effectively and faster,” he said.

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