Transgenic Animals: 

A major obstacle in the clinical use of monoclonal antibodies in humans is that such antibodies are usually mouse antibodies and thus recognized as foreign, inducing an anti-isotype response. Thus efforts are underway to try and produce human monoclonal antibodies.

Transgenic mice: One approach is to incorporate genes encoding human antibody within mice. Scid-human mice, for example, contain human B and T cells and following immunization of such mice, activated human B cells can be isolated and used to produce human monoclonal antibodies. It has also been described that the monozygous deletion of the antibody heavy chain joining rejgion (JH) gene in chimeric and germ-line mutant mice results in complete inhibiition of endogenous antibody production. Transfer of the human germ line immunoglobulin gene array in such germ line mutant mice will result in the production of human antibodies upon anitgen challenge (Jakbovits, Proc. Natl. Acad. Sci, USA, 90: 2551 (1993).

Rajpal (US 13/857,867) discloses generating human monoclonal antibodies to human IL-6 using human Ig transgenic mouse strains which express human antibodies that are indistinguishable from antibodies isolated form humans. In brief, the transgenic mice strains were immunized with human IL-6splenocytes and/or lymph node lymphocytes isolated from mice producing anti-IL-6 antibodies were fused to mouse myeloma cells, cells were cultured and then supernatants from individual wells were screen for the present of human gamma, kappa antibodies and then screen for human anti-IL-6 monoclonal IgG antibodies, followed by cloning and sequencing of the anti-IL-6 antibodies. Amino acid substitution variants of the anti-IL-6 antibody 9C8 in the heavy chain variable domain were made at various positions including 68 (N68T) either singly or in combination both in the context of an IgG1 or an IgG2 format. Amino acid substitution variants of the anti-IL-6 antibody 9C8 in the light chain variable domain were made at 92 (K92N) both as an IgG1 or an IgG2 format. 

Commerical transgenic mice systems include HuMAB Mouse® (Medares, Inc., ) KM Mouse® (Medarex, Inc.) and XenoMouse®(Amgen) (Ramasubramanyan (US 13/829989) 

Transgenic chickens: Zhu show that a mAb produced in the tubular gland cells of the chicken oviduct is secreted ito egg white to yield eggs containing miligram quantities of the antibody. (Nature Biotechnology, 23(9), 2005. 

Antibody production in birds:

When compared with other immunogloical hosts, such as mice, rats and rabbits, chicken have various advantages. First,chickens can geenrate antibodies agaisnt conserved mammlain molecules because molecules that are less immunogenic in mammals might be immunogenic in chickens due to their genetic distance. Second, chicken antibodies agasint human antigens may cross-react with mosue homologues. In fact, a lot of chicken mAbs agaisnt PrP reacts with human, mouse, sheep and govine PrP. This is an important property for developmetn of therpaetuic antibodeis becasue they must be evaluated in mouse models before clinical application, and thus they are required to recognie both the human antigens and mouse homologues. Theird, chicken mAbs are easily generated by hybridoma technology. Lastly, chicken antiobdies can be easily humanized and the resulting antibodies retain both high specificity and affinity for the antigen when compared with parental antibodies. (Nishibori, “Humanization of checken monoclonal antibody using a phage-display system” (2006) Molecular immunology. 43; 634-642. 

Avian Influenze A virus M2 protein immunization:

Sinkells, Virology Journal 2013, 10: 206 (2013) discloses giving chicken a primer-boost vacination with recombinant M2 protein construct and determining specific antibody responses in serum before vaccination and after vaccination. 

Chicken Egg Yolk Immunoglobulin:

–Chiken immunized with Rotavirus:

Sarker (J Pediatric Gastoenterology and Nutrition, 32: 19-25, 2001). disclsoes that hyperimmune egg yolk given to children with known rotairus diarrhea was significantly reduced. 

Mammalain Expression Systems: 

Bansal disclsoes cloning of heavy and light chain variable domains into BioAtla’s proprietary mammalian expression system. 

Chinese haster ovary (CHO) cell based systems remain by far the most common mammalian cell line in use for mAb production. (Gary Wash “Biopharmaceutical benchmarks 2018” Nature Biotechnology, 36(12), 2018)

Adaptor molecule Act 1 (Act1) deficient B cells: 

Li (US20070028316) discloses methods of producing a hybridoma which expresses a monoclonal antibody that is specifically directed to an antigen by introudcing the antigen into a transgenic non-human mammal whose genome includes a disruption of the Act1 gene. The antibodies which specifically bind to the antigen are produced in the mammal and B cells are isolated and a B celss which expresses an antibody that specifically recognizes the antigen is selected. The selected B cell is fused with an immortal cell, thereby producing a hybrodoma that expressed a monoclonal that is specifically directed to the antigen. The invention is based on the discovery that a genetic deficiency in the adapter molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, hyper humoral immune respones and production of autoantibodies.