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Nils Lonberg
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ABSTRACT: Over the past two decades, technologies have emerged for generating monoclonal antibodies (MAbs) derived from human immunoglobulin gene sequences. These fully human MAbs provide an alternative to re-engineered, or de-immunized, rodent MAbs as a source of low immunogenicity therapeutic antibodies. There are now two marketed fully human therapeutic MAbs, adalimumab and panitumumab, and several dozen more in various stages of human clinical testing. Most of the drugs, including adalimumab and panitumumab, were generated using either phage display or transgenic mouse platforms. The reported clinical experience with fully human MAbs demonstrates that these two platforms are, and should continue to be, a significant source of active and well tolerated experimental therapeutics. While this body of reported clinical data does not yet provide a clear distinction between the platforms, the available descriptions of the drug discovery processes used to identify the clinical candidates highlight one difference. It appears that lead optimization is more commonly applied to phage display derived leads than transgenic mouse derived leads.
Current Opinion in Immunology 08/2008; 20(4):450-9. · 9.52 Impact Factor
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Nils Lonberg
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ABSTRACT: Laboratory mice provide a ready source of diverse, high-affinity and high-specificity monoclonal antibodies (mAbs). However, development of rodent antibodies as therapeutic agents has been impaired by the inherent immunogenicity of these molecules. One technology that has been explored to generate low immunogenicity mAbs for in vivo therapy involves the use of transgenic mice expressing repertoires of human antibody gene sequences. This technology has now been exploited by over a dozen different pharmaceutical and biotechnology companies toward developing new therapeutic mAbs, and currently at least 33 different drugs in clinical testing--including several in pivotal trials--contain variable regions encoded by human sequences from transgenic mice. The emerging data from these trials provide an early glimpse of the safety and efficacy issues for these molecules. Nevertheless, actual product approval, the biggest challenge so far, is required to fully validate this technology as a drug discovery tool. In the future, it may be possible to extend this technology beyond rodents and use transgenic farm animals to directly generate and produce human sequence polyclonal sera.
Nature Biotechnology 10/2005; 23(9):1117-25. · 23.27 Impact Factor
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Tibor Keler,
Ed Halk,
Laura Vitale,
Tom O'Neill,
Diann Blanset,
Steven Lee,
Mohan Srinivasan,
Robert F Graziano,
Thomas Davis, Nils Lonberg,
Alan Korman
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ABSTRACT: The immune modulatory molecule CTLA-4 (CD152), through interactions with the B7 costimulatory molecules, has been shown to be a negative regulator of T cell activation in various murine model systems. Abs that block CTLA-4 function can enhance immune responses that mediate potent antitumor activity. However, CTLA-4 blockade can also exacerbate autoimmune disease. The safety and activity of anti-CTLA-4 Abs in primates has not been addressed. To that end, we generated human Abs against CTLA-4 using transgenic mice expressing human Ig genes. A high affinity Ab (10D1) that blocked the binding of CTLA-4 to the B7-1 and B7-2 ligands and had cross-reactivity with macaque CTLA-4 was chosen for further development. Administration of 10D1 to cynomolgus macaques significantly enhanced Ab responses to hepatitis surface Ag and a human melanoma cell vaccine. Anti-self Ab responses as measured by immunoassays using lysate from melanocyte-rich tissues were elicited in those animals receiving the melanoma cell vaccine and anti-CTLA-4 Ab. Remarkably, chronic administration of 10D1 did not result in measurable polyclonal T cell activation, significant alteration of the lymphocyte subsets, or induce clinically observable autoimmunity. Repeated dosing of the 10D1 did not elicit monkey anti-human Ab responses in the monkeys. These observations support the development of CTLA-4 blockade for human immunotherapy.
The Journal of Immunology 01/2004; 171(11):6251-9. · 5.79 Impact Factor
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Isao Ishida,
Kazuma Tomizuka,
Hitoshi Yoshida,
Tomoyuki Tahara,
Nobuaki Takahashi,
Atsuko Ohguma,
Sonoko Tanaka,
Misako Umehashi,
Hiroaki Maeda,
Chikateru Nozaki,
Ed Halk, Nils Lonberg
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ABSTRACT: We have developed TransChromo (TC) technology, which enables the introduction of megabase-sized segments of DNA into cells. We have used this approach to derive mice that carry megabases of human DNA by the use of a human chromosome fragment (HCF) as a vector. TC technology has been applied to the construction of the TC Mouse,trade mark which incorporates entire human immunoglobulin (hIg) loci. TC Mouse expresses a fully diverse repertoire of hIgs, including all the subclasses of IgGs (IgG1-G4). Immunization of the TC Mouse with various human antigens produced antibody responses comprised of human antibodies. Furthermore, it was possible to obtain hybridoma clones expressing fully human antibodies specific for the target human antigen. However, because of the instability of the Igkappa locus-bearing HCF2, the efficiency of hybridoma production was less than one-tenth of that observed in normal mice. An instant solution to this problem was to cross-breed the Kirin TC Mouse carrying the HCF14, which was stable in mouse cells, with the Medarex YAC-transgenic mouse carrying about 50% of the hIgVkappa gene segments as a region that is stably integrated into the mouse genome. The resulting mouse, dubbed the KM Mouse, performed as well as normal mice with regard to immune responsiveness and efficiency of hybridoma production. Another application of TC technology is the production of polyclonal antibodies in large animals such as chickens and cows. To test the efficacy of human polyclonal antibodies derived from TC animals, feasibility studies were performed using antisera and purified gamma-globulin from TC mice immunized with Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), or Japanese encephalitis virus (JEV). The TC mouse-derived antisera and gamma-globulin showed a much higher titer and efficacy in terms of the neutralizing activity of the pathogens in vitro and in vivo than either human serum or gamma-globulin prepared from human blood.
Cloning and Stem Cells 02/2002; 4(1):91-102. · 2.66 Impact Factor
