Bispecific three-chain antibody-like molecules
A bispecific, tri-chain antibody technology, applied in the field of bi-specific tri-chain antibody-like molecules and bi-specific tri-chain polypeptides, can solve problems such as short half-life of immunogenicity
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[0085] 1. Bispecific triabody-like molecule (TCA)
[0086] The present invention discloses novel specific antibody-like molecules (binding polypeptides) which are useful, for example, in the treatment and / or diagnosis of human diseases. The novel bispecific antibody-like molecules consist of three polypeptide chains and are called triabodies (TCAs). Two of such polypeptide chains comprise at least part of the antibody heavy and light chains required to form the antigen binding domain and at least one antibody heavy chain constant region sequence, i.e. CH1 and / or CH2 and / or CH3 regions and / or CH4 region sequence. In certain embodiments, the heavy chain sequence may also include a hinge region. In one embodiment, the two polypeptide chains are a heavy chain and a light chain of a monoclonal antibody that specifically binds to the first antigen.
[0087] The third polypeptide chain is a heavy chain only antibody comprising an Fc portion comprising a CH2 and / or CH3 and / or CH4...
Embodiment 1
[0146] Example 1 : Generation of genetically engineered rats expressing heavy chain-only antibodies
[0147] Construction of modified human Ig loci on YAC and BAC .
[0148] The human IgH locus was constructed and assembled in several parts, which included modifying and joining the rat C region gene, and then joining the rat C region gene in the human V H 6-D-J H downstream of the area. will then have independent person V H The two BACs [BAC3 and BAC6] of the gene cluster are associated with the encoded assembled human V H 6-D-J H - BAC co-injection of fragments of rat C).
[0149] For rat, three BACs [N12, M5 and I8] of the constant region were identified. These BACs were trimmed separately, and a 170 bp homology arm matching the 5' end of the trimmed M5 was added to the 3' end of the trimmed N12, and a 100 bp homology arm matching the 5' end of the trimmed I8 Added to the 3' end of the trimmed M5. Taken together, these modified BACs contain most of the rat cons...
Embodiment 2
[0175] Example 2: Production of Antigen-Specific Heavy Chain Only Antibodies in Rats
[0176] To generate antigen-specific heavy chain-only antibodies in rats, genetically engineered rats expressing heavy chain-only antibodies were immunized in various ways.
[0177] Immunization with inactivated virus
[0178] Influenza viruses with a variety of different hemagglutinin and neuraminidase genes were provided by the Immunology and Pathogenesis Branch, Influenza Division, CDC, Atlanta, GA. The virus stock solution was propagated in the allantoic cavity of 10-day-old embryonated eggs, and purified by ultracentrifugation through a 10%-50% sucrose gradient. Viruses were resuspended in phosphate buffered saline and inactivated by treatment with 0.05% formalin at 4°C for 2 weeks. Inactivated virus and alumn solution (Pierce) were mixed at a ratio of 3:1 and incubated at room temperature for 1 hour before immunization. Genetically engineered rats expressing heavy chain-only anti...
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