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BsAb Generation by Genetic Engineering

With our comprehensive bispecific antibodies (BsAbs) production platform and extensive experience in antibody manufacture, Creative Biolabs offers custom genetic engineered BsAbs development services, enabling clients to adjust the format, valency, flexibility and half-life of BsAbs to achieve the desired BsAbs profile.

Genetic engineering is a powerful technology for the artificial manipulation, modification, and recombination of DNA or other nucleic acid molecules, for purpose of modifying an organism or population of organisms. Recently, the development in genetic engineering has promoted the creation of second-generation bispecific molecules of different sizes and binding strengths. Moreover, genetic engineering enables to produce recombinant BsAbs of defined composition, and with enhanced stability and producibility by modulation of valency and size. Genetic engineering BsAbs are manly produced via the recombinant DNA technology.

Recombinant DNA Technology

Recombinant DNA (or rDNA) is achieved by combining DNA from two or more sources. Generally, the process often refers to combining the DNA of different organisms, which is based on the capacity of cut, and re-join DNA molecules at points identified by specific sequences of nucleotide bases called restriction sites. DNA fragments are cut out of their natural position in the chromosome through restriction enzymes and then inserted into other chromosomes or DNA molecules by enzymes called ligases. Recombinant DNA technology has dramatically impacted several fields – from medicine to agriculture. They have also helped produce progresses in medicine, for example, treatments for cancer, production of recombinant proteins, vaccines, as well as BsAbs.

Schematic diagram of the design and three-dimensional model of the bispecific tetravalent Ab format.

Figure 1. Schematic diagram of the design and three-dimensional model of the bispecific tetravalent Ab format. Part A shows the overall structure of the designed BsAbs bearing Fab of mAb1 and mAb2. Part B shows the structural modeling of the bispecific construct with WT hinge; H chain in blue and L chains in yellow. (Golay, J., 2016)

Genetic Engineering BsAbs

Recombinant BsAbs can be able to be divided into two groups: 1) those containing solely the variable domains from two or more parental antibodies; 2) those with additional constant immunoglobulin domains or nonimmunoglobulin domains, such as proteins, scaffold, etc. Usually, the variable domains can be obtained from existing hybridomas, isolated from antibody libraries or antibody sequencing.

Small recombinant BsAbs devoiding of all constants are assembled from the variable domains of two antibodies, VH and VL. Fv fragments can be converted into different molecules by genetically joining the Fv moieties with different linkers. Tandem scFv and bispecific Diabody are the representatives. Besides the bispecific and bivalent molecules, Fv moieties can also assemble to form tetravalent molecules, TandAb. The addition of constant domains allows for the heterodimerization and the formation of bispecific, multivalent antibodies. A variety of techniques including knobs-into-holes (KIH), charge pair, crossover, etc., facilitate the higher purity and great developability of BsAbs.

With our well-established genetic engineering platform, the experienced scientists here at Creative Biolabs are dedicated to help you develop therapeutic BsAbs. We also provide other various services regarding BsAbs development. Please feel free to contact us for more information and a detailed quote.

References

1. Golay, J.; et al. Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies. The Journal of Immunology. 2016, 196(7): 3199-3211.
2. Zhang, X.; et al. The development of bispecific antibodies and their applications in tumor immune escape. Experimental Hematology & Oncology. 2017, 6(1): 12.

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