Fully human antibodies against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Various subsequent manipulations can be performed to obtain either antibodies per se or analogs thereof.

Human antibodies derived from immunized xenomice

ObjectiveThe Working Group on Civilian Biodefense has developed consensus-based
recommendations for measures to be taken by medical and public health professionals
if botulinum toxin is used as a biological weapon against a civilian population.ParticipantsThe working group included 23 representatives from academic, government,
and private institutions with expertise in public health, emergency management,
and clinical medicine.EvidenceThe primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE
(1960–March 1999) and their professional collections for literature
concerning use of botulinum toxin as a bioweapon. The literature was reviewed,
and opinions were sought from the working group and other experts on diagnosis
and management of botulism. Additional MEDLINE searches were conducted through
April 2000 during the review and revisions of the consensus statement.Consensus ProcessThe first draft of the working group's consensus statement was a synthesis
of information obtained in the formal evidence-gathering process. The working
group convened to review the first draft in May 1999. Working group members
reviewed subsequent drafts and suggested additional revisions. The final statement
incorporates all relevant evidence obtained in the literature search in conjunction
with final consensus recommendations supported by all working group members.ConclusionsAn aerosolized or foodborne botulinum toxin weapon would cause acute
symmetric, descending flaccid paralysis with prominent bulbar palsies such
as diplopia, dysarthria, dysphonia, and dysphagia that would typically present
12 to 72 hours after exposure. Effective response to a deliberate release
of botulinum toxin will depend on timely clinical diagnosis, case reporting,
and epidemiological investigation. Persons potentially exposed to botulinum
toxin should be closely observed, and those with signs of botulism require
prompt treatment with antitoxin and supportive care that may include assisted
ventilation for weeks or months. Treatment with antitoxin should not be delayed
for microbiological testing.

https://jamanetwork.com/journals/JAMA/articlepdf/193600/jst00017.pdf

Botulinum Toxin as a Biological Weapon: Medical and Public Health Management

Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNFα, chemokines, and growth factors are expressed in diseased joints. The rationale that TNFα played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNFα antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNFα antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activcity of TNFα in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNFα monoclonal antibody (mAB), has prov...

Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?

Antibodies constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The generation of potent antibody therapeutics, which I review here, is an iterative design process that involves the generation and optimization of antibodies to improve their clinical potential.

Potent antibody therapeutics by design

The present invention relates to transgenic non-human animals that are engineered to contain human immunoglobulin gene loci. In particular, animals in accordance with the invention possess human Ig loci that include plural variable (V H and Vκ) gene regions. Advantageously, the inclusion of plural variable region genes enhances the specificity and diversity of human antibodies produced by the animal. Further, the inclusion of such regions enhances and reconstitutes B-cell development to the animals, such that the animals possess abundant mature B-cells secreting extremely high affinity antibodies.

Transgenic mammals having human Ig loci including plural VH and VK regions and antibodies produced therefrom

We describe a strategy for producing human monoclonal antibodies in mice by introducing large segments of the human heavy and κ light chain loci contained on yeast artificial chromosomes into the mouse germline. Such mice produce a diverse repertoire of human heavy and light chains, and upon immunization with tetanus toxin have been used to derive antigen–specific, fully human monoclonal antibodies. Breeding such animals with mice engineered by gene targeting to be deficient in mouse immunoglobulin (Ig) production has led to a mouse strain in which high levels of antibodies are produced, mostly comprised of both human heavy and light chains. These strains should provide insight into the adoptive human antibody response and permit the development of fully human monoclonal antibodies with therapeutic potential.

D. Garza

Papers

Antigen–specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs