"We have a very powerful product-generational tool here," saidJonathan MacQuitty, chairman and CEO of GenPharm International.

The aforesaid product is a large and proliferating population of mice,he told BioWorld Today, "way beyond our capacity to use it."

They are not, however, beyond the capacity of "a variety ofpharmaceutical companies, and at least one biotech firm,"MacQuitty, added, "which have strong interests in particular kinds ofhuman antibodies and human antigens." These customers are takingquantities of mice off his hands, in research collaborations withGenPharm, of Mountain View, Calif.

The transgenic rodents have swapped their murine humoral immunesystems for the human equivalent. That is, they are born and bredwith a repertoire of incipient B cells primed to churn out human _not humanized _ antibodies, programmed against a wide spectrum ofhuman antigens.

"We're working on a number of different antigenic targets,"MacQuitty said, "and haven't at this point finalized our clinicalstrategy. Our first product will go into clinicals by the end of 1997,"he added. "It might be an antibody targeting CD4+ T cells, to treatrheumatoid arthritis, or it might be another one.

"We already are in monkey studies with a number of our humanantibodies," he said.

GenPharm's director of molecular biology, Nils Lonberg, is seniorauthor of a paper in the July Nature Biotechnology, which reports"High-avidity human IgGk monoclonal antibodies from a novelstrain of minilocus transgenic mice."

His article describes the generation of all-human CD4+ T cells fromthe mice, "for which the human therapeutic use," he told BioWorldToday, "is treating autoimmune diseases.

"The difference between our methodology and those pursued byother groups," Lonberg said, "is two-fold: One is that, because we donot start with a mouse antibody we do not leave any mouse residues.All of the residues in our antibodies are human, which should provideincreased safety and efficacy."

He explained: "There should be less of an immune response by thepatient to the antibody, and that should provide for a longercirculating half-life, and ability to repeat the dose." (Many currentantibody treatments can be given only once, because the patientdevelops an immune reaction to the molecule's mouse residues.)

"The second difference," Lonberg continued, "is that because of theway we make the antibody, we get a large variety of potentialantibody candidates to test preclinically. Also, we get them in theirfinal form, so we can then choose the best one."

Lonberg contrasts this method with other current efforts to humanizeantibodies: "In humanizing an antibody," he said, "you have to makea bet on a mouse antibody, that you can turn it into a successfulhuman one with the right characteristics. We go directly to the humanantibody."

The entire human gene locus that encodes the humoralimmunoglobulins spans a whopping 4-plus megabases of the genome.Of this super-sequence, 1.3 megabases serve the entire heavy-chainantibody locus, and 1.9 the kappa light chain.

"We have put into our mice," Lonberg pointed out, "pieces of DNAthat are smaller. Yet these miniloci contain sufficient geneticinformation." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.