301
bio topics amino
acid
changes
from
the
phOx-15 hca\n;-chrtingcrn~lint. The hlghcst afimty mcasuj cd was 1.1 n?~ - 3%-fr,ld highx than that of phO+lS. the initial antiho+ The take-home message Chain shuffling clearly provides a route to afftnity maturation ofphagrselected a&bodies irr ~ri/ro. The authors compare their or virr~ process with antibody maturation in tritJn. In both cases there are phases of sclection followed by generation of additional genetic diversity. In particular, the authors point to the known
kinetics of the immune response to conjugated phOx hapten in the mouse. Here too, somatic hypermutation of the V-genes Frlected in the primary immune response is known to increase antib6dy affinity by slowing the antigen ‘OK’ rate. Certainly the latest work is coming closer to ‘reproducing the immune system i;r I irm’. It remains to br dcmon=.trated that high-atfinity human antibodies to a real (protein) therapeutic target can be produced by this means. tfthis turns out to be the ca~c, hybridoma companies must begin to develop an affinity for molecular biologists.
Growth factors in wound healing
The process of normal wound hcaling in healthy mammals follows a complrx. co-ordinated sequence of steps which are now beginning m be understood at the molecular level. Grotih factors have been identified as playing a pivotal role in directing the migration and proliferation of cells and the deposition of extracellular matrix compolxnts during healing. The availability of recombinant growth factors, antagonist5 x:d inhibiton thus offers new opportunities for manipulating the hesling process. A recent conference* covered a wide range of aspects of treatmunt of wounds, fro-m improvements in the design and development of new materials for sutures and dressings, to the use of ultrasound, light and electrical currents to stimulate the repair of damaged tissue. Great emphasis was placed on the importance of growth factors, both as potential therapeutic agents, and as possible mediators by which tissues respond to other treatments.
Assessing therapeutic potential Many polypcptidc growth factors can now be synthesixd in sufficient quantity by recombinant DNA technoiogy for i,:-i+:.+: rf rb& use as therapeutics to be fcxible. W. Meyer&gold (&&rsdorf AC, Hamburg, Gemzany) listed six Icading growth factors judged to have therapeutic potentiai in wound healing. Thrsc are epidermal grow& factor (EGF), fibroblaqt growth facto1 {FCF), tr;r,sf;;rnlng gxwtii factor4 (TGF-a), transforming growth factor-p (TGF-@), insulinlike growth fzc%r {fC;F) and platelctderived growth factor (PDGF) (for a recent rev&m- see Ref. 1). M. Robson (Untwrsits 6f Texas, Medical Branch, Tk, USA) described the process by which his group assesses the tl~rrapeutic potential of a growth factor. Ideally, the molecular stmcture is first compared with those of previously characterized growth factors to see whether structural featurtv indicate that the molecule might have the desired activitv. The material is then ttzted in in I& tissue culture, folloxved by animal studies and. t!venNa&, dinical trials. PDGF, for csample, is a potent chemotactic. mitogcnir and activating agent for several ccfl types involved in snfi-tissue repair. 11: animals, the BB iscform of recom-
binant human PDGF (rhPDGF43B) accelerates normal tins.lc rLpair and rcstorx deficient repair. Based on thcac obscr,rations. a study \\vas initiated at the University of Texas with patients suffering Tom pressure ulcers. Either PDGF or placebo xvas apphrd topically to the ulcer da& for 25 day--:. Subjects receiving the I&.$est dose of PDGF (IO~O~gml-‘, 0.01 rtrlrn~r~ ulcer surface) showed a statistically signikmt incrcaw in their raw of wound closure compared to the groups rcccking lower d.xcs or placebo’. Animal stud& suggcstcd that basic fibroblast gowth iactor (bFC;F) might bc more cEectivc than PDGF in promoting wound closure, su a further study was initiated on patients with prcrssurc sores. using topical .-~~~kmon of rhrcc ditfcrcnt con~~mr
bio topics amino
acid
changes
from
the
phOx-15 hca\n;-chrtingcrn~lint. The hlghcst afimty mcasuj cd was 1.1 n?~ - 3%-fr,ld highx than that of phO+lS. the initial antiho+ The take-home message Chain shuffling clearly provides a route to afftnity maturation ofphagrselected a&bodies irr ~ri/ro. The authors compare their or virr~ process with antibody maturation in tritJn. In both cases there are phases of sclection followed by generation of additional genetic diversity. In particular, the authors point to the known
kinetics of the immune response to conjugated phOx hapten in the mouse. Here too, somatic hypermutation of the V-genes Frlected in the primary immune response is known to increase antib6dy affinity by slowing the antigen ‘OK’ rate. Certainly the latest work is coming closer to ‘reproducing the immune system i;r I irm’. It remains to br dcmon=.trated that high-atfinity human antibodies to a real (protein) therapeutic target can be produced by this means. tfthis turns out to be the ca~c, hybridoma companies must begin to develop an affinity for molecular biologists.
Growth factors in wound healing
The process of normal wound hcaling in healthy mammals follows a complrx. co-ordinated sequence of steps which are now beginning m be understood at the molecular level. Grotih factors have been identified as playing a pivotal role in directing the migration and proliferation of cells and the deposition of extracellular matrix compolxnts during healing. The availability of recombinant growth factors, antagonist5 x:d inhibiton thus offers new opportunities for manipulating the hesling process. A recent conference* covered a wide range of aspects of treatmunt of wounds, fro-m improvements in the design and development of new materials for sutures and dressings, to the use of ultrasound, light and electrical currents to stimulate the repair of damaged tissue. Great emphasis was placed on the importance of growth factors, both as potential therapeutic agents, and as possible mediators by which tissues respond to other treatments.
Assessing therapeutic potential Many polypcptidc growth factors can now be synthesixd in sufficient quantity by recombinant DNA technoiogy for i,:-i+:.+: rf rb& use as therapeutics to be fcxible. W. Meyer&gold (&&rsdorf AC, Hamburg, Gemzany) listed six Icading growth factors judged to have therapeutic potentiai in wound healing. Thrsc are epidermal grow& factor (EGF), fibroblaqt growth facto1 {FCF), tr;r,sf;;rnlng gxwtii factor4 (TGF-a), transforming growth factor-p (TGF-@), insulinlike growth fzc%r {fC;F) and platelctderived growth factor (PDGF) (for a recent rev&m- see Ref. 1). M. Robson (Untwrsits 6f Texas, Medical Branch, Tk, USA) described the process by which his group assesses the tl~rrapeutic potential of a growth factor. Ideally, the molecular stmcture is first compared with those of previously characterized growth factors to see whether structural featurtv indicate that the molecule might have the desired activitv. The material is then ttzted in in I& tissue culture, folloxved by animal studies and. t!venNa&, dinical trials. PDGF, for csample, is a potent chemotactic. mitogcnir and activating agent for several ccfl types involved in snfi-tissue repair. 11: animals, the BB iscform of recom-
binant human PDGF (rhPDGF43B) accelerates normal tins.lc rLpair and rcstorx deficient repair. Based on thcac obscr,rations. a study \\vas initiated at the University of Texas with patients suffering Tom pressure ulcers. Either PDGF or placebo xvas apphrd topically to the ulcer da& for 25 day--:. Subjects receiving the I&.$est dose of PDGF (IO~O~gml-‘, 0.01 rtrlrn~r~ ulcer surface) showed a statistically signikmt incrcaw in their raw of wound closure compared to the groups rcccking lower d.xcs or placebo’. Animal stud& suggcstcd that basic fibroblast gowth iactor (bFC;F) might bc more cEectivc than PDGF in promoting wound closure, su a further study was initiated on patients with prcrssurc sores. using topical .-~~~kmon of rhrcc ditfcrcnt con~~mr
