BY Chester BisbeeSpecial To BioWorld Today
Destruction is most successful when targeted well. This applies to"smart" bombs as well as human therapeutics. Sometimes smartbombs go astray; more often, human therapeutics go astray. Duringtheir wanderings in the bloodstream, drugs find their way to siteswhere they are useless or worse yet, dangerous. The end result is anunwanted dilution of effects, at best, and toxic side effects, at worst.
However, until recently, specific targeting of therapeutics was only aclinician's dream. But with the identification of more cell-specificreceptors and antigens, came the uncovering of receptor ligands andthe development of antibodies specific to these important cell surfacemolecules. This, in turn, led to the use of these ligands andantibodies as targeting devices that homed in on designated cellswhere they dropped the payloads of drugs that had been linked tothem.
But even targeted toxins have major problems; they lack specificityand often destroy cells that are innocent bystanders. In today's issueof Science, a big step forward in customizing these toxins isreported. In a paper entitled "Biotherapy of B-cell precursorleukemia by targeting genistein to CD19-associated tyrosinekinases," Fatih Uckun and his colleagues from the University ofMinnesota described the use of genistein, a tyrosine kinase-specificinhibitor, linked to monoclonal antibodies against CD19, a B-cellspecific receptor, to destroy B-cell precursor leukemia.
Uckun, a pediatric oncologist, used this targeted therapeutic, calledB43-Gen immunoconjugate, to treat B-cell precursor leukemia thathad been introduced into severe combined immunodeficient (SCID)mice. As reported in their article, all untreated SCID mice died ofdisseminated human B-cell precursor leukemia between 24 and 61days after inoculation. In contrast, all mice treated with CD19antibody-genistein conjugate remained alive without clinicalevidence of leukemia for more than four months. This was true evenfor mice that received less than 10 percent of the maximum tolerateddose of targeted therapeutic.
Long-term surviving mice were examined at 142 days after the initialinjection of B-cell precursor leukemia cells. No evidence ofleukemic cells infiltrating mouse tissues was seen. Polymerase chainreaction-based assays for the presence of human genes that, bydefinition, could only be associated with these human leukemic cellswere negative. Uckun was able to estimate that less than .001 percentof the injected cells could have remained in the SCID mice at 20weeks after inoculation.
Uckun's strategy for specifically targeting cancer cells and reducingthe death of innocent bystander cells is described in the Sciencearticle. The CD19 receptor found on B lineage cells is physically andfunctionally associated with Src protooncogene family proteintyrosine kinases (PTK). They form transmembrane CD19 receptor-PTK complexes that transmit CD19 receptor surface interactions todownstream intracellular signaling pathways. When Uckun's B43-Gen immunoconjugate complex binds to the CD19 receptor, itundergoes antibody-induced internalization, making genistein locallyavailable to bind to PTKs. The final result of this binding isapoptotic, or programmed, B-cell precursor leukemia cell death,which results from PTKs involvement in apoptosis in hematopoieticcells.
According to Uckun, this therapeutic gives an additional level ofspecificity. "As with other current technology, only cells expressingthe receptor are targeted. But unlike other toxin-linked systems, onlythe associated enzyme is inhibited. Since genistein is a relativelyweak inhibitor, it only affects the tightly coupled Src family PTK's.Once the inhibitor diffuses away, it has little effect."
As he explained to BioWorld Today, "This is very different frommost of the fusion toxins being commercially developed becausereleased molecules can cause widespread toxicity and antibodyproduction against them."
Targeted Cancer Biotherapy Development
Uckun told BioWorld Today, "We are very excited about validatingthe ability to target intracellular signal transduction. We haveprogressed to toxicology studies in mice and monkeys. Our B43-Genimmunoconjugate shows no toxicity in these systems. We are alsoabout to report on its effectiveness against lymphoma."
Uckun's biotherapy group has already filed an investigational newdrug (IND) application for the use of another targetedimmunoconjugate on B-cell leukemias and lymphomas. Thistherapeutic uses the more common generalized toxin technologywith pokeweed toxin at the business end of the immunoconjugate.Phase I and II trials have already been done and they are moving intonationwide testing in children. Uckun reported that "we will seek asupplemental IND in about three months for the use of our genisteintoxin conjugate in a Phase I 17-institute study."
Paul Gaynon, a pediatric oncologist at the University of Wisconsin,told BioWorld, that "Fatih Uckun has been instrumental in educatingclinicians about what is going on in these systems at the basicscience level. He has fostered a very productive interchange betweenthose of us who see the patients and those who work in the lab."
Gaynon said that while Uckun has no company affiliation yet, hesuspects that will come in time. "The problem here is that while thepotential for scientific advancement is great, many of the patientpopulations being treated are small. So, for now the commercialpotential is limited, but somewhere down the line one of Uckun'sagents will treat a larger market and then the company interest willbe there." n
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