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PubMed2006

Isolation of high-affinity single-chain antibodies against Mycobacterium avium subsp. paratuberculosis surface proteins from sheep with Johne's disease.

Johne's disease, caused by infection with Mycobacterium avium subsp. paratuberculosis, causes significant economic losses to the livestock farming industry. Improved investigative and diagnostic tools-necessary to understand disease processes and to identify subclinical infection-are much sought after. Here, we describe the production of single-chain antibodies with defined specificity for M. avium subsp. paratuberculosis surface proteins. Single-chain antibodies (scFv) were generated from sheep with Johne's disease by cloning heavy-chain and lambda light-chain variable regions and expressing these in fusion with gene III of filamentous phages. Two scFv clones (designated SurfS1.2 and SurfS2.2) were shown to be immunoreactive against M. avium subsp. paratuberculosis surface targets by flow cytometry, and immunoblotting identified specificity for a 34-kDa proteinase-susceptible determinant. Both antibodies were cross-reactive against Mycobacterium avium subsp. avium but nonreactive against Mycobacterium bovis or Mycobacterium phlei cells and were shown to be capable of enriching M. avium subsp. paratuberculosis cells by a factor of approximately 10(6)-fold when employed in magnetic bead separation of mixed Mycobacterium sp. cultures. Further, magnetic bead separation using SurfS1.2 and SurfS2.2 was capable of isolating as few as 10(3) M. avium subsp. paratuberculosis cells from ovine fecal samples, indicating the diagnostic potential of these reagents. Finally, inclusion of SurfS1.2 or SurfS2.2 in in vitro broth culture with M. avium subsp. paratuberculosis indicated that surface binding activity did not impede bacterial growth, although colony clumping was prevented. These results are discussed in terms of the potential use of single-chain phage display monoclonal antibodies as novel diagnostic reagents.

Animals↗
PubMed2004

Population differentiation in the Pacific white-sided dolphin Lagenorhynchus obliquidens inferred from mitochondrial DNA and microsatellite analyses.

We investigated genetic diversity and differentiation of the Pacific white-sided dolphin (Lagenorhynchus obliquidens) in Japanese coastal waters and offshore North Pacific by analyzing mitochondrial DNA and nuclear microsatellite variation. A total of 519 bp of the mitochondrial control region was sequenced and five microsatellite locus were genotyped for 59 individuals. A high level of haplotypic diversity (h=96.1%), moderate level of nucleotide diversity (pi=1.65%) and average expected heterozygosity (HE=0.66-0.76) were within an extent of those reported for other odontocetes. Consistent genetic difference between the samples from Japanese coastal Pacific-Sea of Japan and offshore North Pacific was indicated by analyses of molecular variance (AMOVAs) based on mtDNA and microsatellite variations, comparison of genetic variabilities, and geographical distributions of mtDNA haplotypes and microsatellite alleles. This result suggests that Pacific white-sided dolphins in each of the above two areas belong to different populations between which gene flow has been severely restricted. The low genetic diversity and mtDNA genealogy of the population in Japanese coastal waters suggest that it originated from a small population that colonized the Sea of Japan or that experienced population reduction when this Sea was isolated from the North Pacific during a glacial period in the Late Pleistocene.

Animals↗
PubMed2000

Variability of the F13B locus in South American populations.

A population study for the F13B locus was carried out in a total of 396 South American individuals. The analysis comprised new data from 5 Amerindian populations, existing data from 3 Amerindian populations, and I urban sample from La Plata, Argentina. In both pooled Amerindian and La Plata samples, 6 alleles were found. The individual Amerindian samples showed a lower number of alleles, changes in modal alleles, and restricted variability. Interpopulation comparisons revealed significant differences among samples from distinct geographical regions. Differences among the groups were also corroborated by the F(ST) statistic. Data support the hypothesis that genetic drift and gene flow influence Amerindian differentiation.

Argentina↗
PubMed1998

Ontogeny of the heavy chain immunoglobulin repertoire in fetal liver and bone marrow.

We studied the kinetics of maturation of B cell progenitors in the mouse embryo, from day 15 of development to birth, both in liver and bone marrow. The analysis of Ig heavy chain rearrangements at different time points of late fetal development shows that oligoclonal patterns of V(H)-D-J(H) rearrangements are detected by day 15 in fetal liver. The pattern is polyclonal and diverse by day 17; however, 80% of the rearrangements are nonproductive. In bone marrow, the pattern of rearrangements is less diverse at birth, although the percentage of nonproductive rearrangements approaches adult bone marrow levels (35-40%). After day 17 in fetal liver, there is a sudden reversal in the percentage of nonproductive rearrangements that reaches 33% at day 19 (birth). Maturation of B cells, as measured by the fraction of surface Ig+ in total B220+ cells and the presence of N sequence additions in V(H)-D-J(H) joints, occurs in the marrow before fetal liver. These results demonstrate that the lymphopoietic environment in fetal liver and bone marrow of animals at the same stage of development is functionally distinct.

Animals↗
PubMed2000

Isotype switch variants reveal clonally related subpopulations in diffuse large B-cell lymphoma.

Primary diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors accounting for approximately 40% of B-cell malignancies. The immunoglobulin (Ig) variable region genes have undergone rearrangement and are commonly somatically mutated. The majority show intraclonal variation which indicates that somatic mutation has continued after transformation. Typically, cells of DLBCLs express Ig of a single isotype, but there may be accompanying cells that express alternative isotypes. To probe the status of the isotype switch process in DLBCL, 4 cases of tumor-derived constant region transcripts of all isotypes were investigated. Following the identification of the VDJ sequences, the presence of the major isotype expected from immunohistochemical analysis was confirmed at the RNA level. Another 3-4 alternative isotypes were revealed in all cases, some of which could also be detected by immunohistochemistry. All cases were somatically mutated with an intraclonal variation. In 2 cases there were clearly distinct patterns of somatic mutation between isotypes, which was consistent with independent evolution of the tumor subpopulations. There was apparent clustering of mutational patterns into either an IgMD/IgG3/IgA set or an IgG1/IgA set, indicating that the switch to IgA can occur by different routes. Alternative isotype expression is evident in DLBCL at both the RNA and protein levels. The pattern of mutation indicates that switching is occurring in subpopulations of the tumor after malignant transformation. The findings support the concept that isotype switch events may be a feature of DLBCL.

Adult↗
PubMed2004

Limited effect of anthropogenic habitat fragmentation on molecular diversity in a rain forest skink, Gnypetoscincus queenslandiae.

To examine the effects of recent habitat fragmentation, we assayed genetic diversity in a rain forest endemic lizard, the prickly forest skink (Gnypetoscincus queenslandiae), from seven forest fragments and five sites in continuous forest on the Atherton tableland of northeastern Queensland, Australia. The rain forest in this region was fragmented by logging and clearing for dairy farms in the early 1900s and most forest fragments studied have been isolated for 50-80 years or nine to 12 skink generations. We genotyped 411 individuals at nine microsatellite DNA loci and found fewer alleles per locus in prickly forest skinks from small rain forest fragments and a lower ratio of allele number to allele size range in forest fragments than in continuous forest, indicative of a decrease in effective population size. In contrast, and as expected for populations with small neighbourhood sizes, neither heterozygosity nor variance in allele size differed between fragments and sites in continuous forests. Considering measures of among population differentiation, there was no increase in FST among fragments and a significant isolation by distance pattern was identified across all 12 sites. However, the relationship between genetic (FST) and geographical distance was significantly stronger for continuous forest sites than for fragments, consistent with disruption of gene flow among the latter. The observed changes in genetic diversity within and among populations are small, but in the direction predicted by the theory of genetic erosion in recently fragmented populations. The results also illustrate the inherent difficulty in detecting genetic consequences of recent habitat fragmentation, even in genetically variable species, and especially when effective population size and dispersal rates are low.

Animals↗
PubMed2006

When supercolonies collide: territorial aggression in an invasive and unicolonial social insect.

Some species of ants possess an unusual form of social organization in which aggression among nests is absent. This type of social organization, called unicoloniality, has been studied in only a handful of species and its evolutionary origins remain unclear. To date, no study has examined behavioural and genetic patterns at points of contact between the massive supercolonies that characterize unicoloniality. Since interactions at territory boundaries influence the costs of aggression and the likelihood of gene flow, such data may illuminate how supercolonies are formed and maintained. Here we provide field data on intraspecific territoriality for a widespread and invasive unicolonial social insect, the Argentine ant (Linepithema humile). We observed abrupt and well-defined behavioural boundaries at 16 contact zones between three different pairs of supercolonies. We visited nine of these zones weekly during a six-month period and observed consistent and intense intercolony aggression that resulted in variable, but often large, levels of worker mortality. Microsatellite variation along six transects across territory borders showed that F(ST) values were lower within supercolonies (0.08 +/- 0.01 (mean +/- SE)) than between supercolonies (0.29 +/- 0.01) and that this disparity was especially strong right at territory borders, despite direct and prolonged contact between the supercolonies. Matrix correspondence tests confirmed that levels of aggression and genetic differentiation were significantly correlated, but no relationship existed between geographic distance and either intraspecific aggression or genetic differentiation. Patterns of F(ST) variation indicated high levels of gene flow within supercolonies, but little to no gene flow between them. Overall, these findings are inconsistent with a model of relaxed ecological constraints leading to colony fusion and suggest that environmentally derived cues are not the prime determined of nestmate recognition in field populations of Argentine ants.

Aggression↗
PubMed2005

Geographical distance and physical barriers shape the genetic structure of Eurasian red squirrels (Sciurus vulgaris) in the Italian Alps.

Red squirrels (Sciurus vulgaris) are widely distributed throughout Eurasia, occurring in many types of coniferous and mixed-deciduous forests. In fragmented landscapes, small and partly isolated populations with low immigration rates show reduced genetic diversity, but reforestation can increase gene flow and restore levels of genetic variation in a few decades. No studies have so far investigated the genetic structure of red squirrel in large, continuous forests. The Italian Alps are presently characterized by almost continuous, recently reconnected forest habitats, that were affected by deep landscape changes during last glaciations but remained mostly unchanged between 10 000 and 200 years bp, when forest cover was heavily reduced. In this study we analyse patterns of genetic variability of red squirrels in and between seven sites distributed over 250 km of Alpine habitat, using mitochondrial DNA (mtDNA) and microsatellites. We use isolation-by-distance (IBD) models to investigate the relative importance that past (Pleistocene glaciations) and recent (fragmentation, bottlenecks) events had on the present genetic situation. Both nuclear and mtDNA data indicate a significant differentiation among study sites and a significant correlation between genetic and geographical distance only over a large scale. No recent bottlenecks are recorded through microsatellites and demographic models strongly support equilibrium between gene flow and drift; however, mtDNA suggests that there may have been local demographic crashes, probably in correspondence with the 19th-century forest fragmentation. These findings indicate that local landscape factors other than geographical distance per se, such as barriers of unsuitable habitat, affect gene flow and determine differentiation.

Animals↗
PubMed2005

Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis.

BACKGROUND: For clinically relevant proangiogenic therapy, it would be essential that the growth of the whole vascular tree is promoted. Vascular endothelial growth factor (VEGF) is well known to induce angiogenesis, but its capability to promote growth of larger vessels is controversial. We hypothesized that blood flow remodels vascular growth during VEGF gene therapy and may contribute to the growth of large vessels. METHODS AND RESULTS: Adenoviral (Ad) VEGF or LacZ control gene transfer was performed in rabbit hindlimb semimembranous muscles with or without ligation of the profound femoral artery (PFA). Contrast-enhanced ultrasound and dynamic susceptibility contrast MRI demonstrated dramatic 23- to 27-fold increases in perfusion index and a strong decrease in peripheral resistance 6 days after AdVEGF gene transfer in normal muscles. Enlargement by 20-fold, increased pericyte coverage, and decreased alkaline phosphatase and dipeptidyl peptidase IV activities suggested the transformation of capillaries toward an arterial phenotype. Increase in muscle perfusion was attenuated, and blood vessel growth was more variable, showing more sprouting angiogenesis and formation of blood lacunae after AdVEGF gene transfer in muscles with ligated PFA than in normal muscles. Three-dimensional ultrasound reconstructions and histology showed that the whole vascular tree, including large arteries and veins, was enlarged manifold by AdVEGF. Blood flow was normalized and enlarged collaterals persisted in operated limbs 14 days after AdVEGF treatment. CONCLUSIONS: This study shows that (1) blood flow modulates vessel growth during VEGF gene therapy and (2) VEGF overexpression promotes growth of arteries and veins and induces capillary arterialization leading to supraphysiological blood flow in target muscles.

Adenoviridae↗
PubMed2006

Point mutations in the melanocortin-4 receptor cause variable obesity in mice.

Mutations in the melanocortin-4 receptor (MC4R) are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure. As part of independent N-ethyl- N-nitrosourea (ENU) mutagenesis screens, two obesity mutants, Fatboy and Southbeach, were isolated. Mapping revealed linkage to the melanocortin-4 receptor (Mc4r) and sequencing found single amino acid changes in Mc4r for each line. Expression of the mutant receptors in HEK 293 cells revealed defects in receptor signaling. The mutated Fatboy receptor (I194T) shows an increase in the effective concentration necessary for 50% of maximal signaling (EC(50)) when stimulated with alpha-MSH. Based on competitive binding, I194T is expressed on the cell surface at lower levels than the nonmutated receptor. In contrast, Southbeach (L300P) displays minimal receptor signaling when stimulated with the natural ligand alpha-MSH or the synthetic agonist NDP-alpha-MSH. Cell surface binding is absent, which usually indicates a lack of cell surface expression. However, antibody binding to Flag-tagged receptors by flow cytometry analysis and immunofluorescence demonstrates that L300P is translocated to the plasma membrane at a level comparable to the wild-type receptor. These results indicate a correlation with remaining receptor activity and the severity of the obesity in the mice homozygous for the mutations. Southbeach has less receptor activity and becomes more obese. These mutants will serve as good models for the variability in phenotype in humans carrying mutations in the MC4R gene.

Alkylating Agents↗
PubMed1983

Patterns of genetic variability in the serum proteins of the Kenyan vervet monkey (Cercopithecus aethiops).

An electrophoretic survey of 13 serum proteins was carried out on samples drawn from 340 vervet monkeys (Cercopithecus aethiops) living in 30 troops from four different localities in central and southern Kenya. The proportion of polymorphic loci is 0.17 and the average heterozygosity is 0.05. The group specific component, prealbumin carboxylesterase, and transferrin are all polymorphic. The analysis of the patterns of gene diversity show that a large part of the genic variation exists within individual troops and among neighboring troops from the same trapping locality. Only a small proportion of the overall genetic variability occurs between the populations at the different trapping localities which are separated by between 80 and 380 km. The migration of young males from their natal troops is a likely mechanism of gene flow among the vervet populations. Gene flow appears to be sufficient to prevent high levels of geographic variation in the gene frequencies at these loci, but is insufficient to prevent the occasional fixation of alleles in some local populations.

Alkaline Phosphatase↗
PubMed2003

Phylogeography of the rock partridge (Alectoris graeca).

We used mitochondrial DNA control-region and microsatellite data to infer the evolutionary history and past demographic changes in 332 rock partridges (Alectoris graeca) sampled from throughout the species' distribution range, with the exception of the central Balkans region. Maternal and biparental DNA markers indicated concordantly that rock partridge populations are structured geographically (mtDNA phiST = 0.86, microsatellite FST = 0.35; RST = 0.31; P < 0.001). Phylogenetic analyses of 22 mtDNA haplotypes identified two major phylogroups (supported by bootstrap values = 93%), splitting partridges from Sicily vs. all the other sampled populations at an average Tamura-Nei genetic distance of 0.035, which corresponds to 65% of the average distance between closely related species of Alectoris. Coalescent estimates of divergence times suggested that rock partridges in Sicily were isolated for more than 200000 years. This deep subdivision was confirmed by multivariate, Bayesian clustering and population assignment analyses of microsatellite genotypes, which supported also a subdivision of partridges from the Alps vs. populations in the Apennines, Albania and Greece. Partridges in the Apennines and Albania-Greece were probably connected by gene flow since recently through a late Pleistocene Adriatic landbridge. Deglaciated Alps were probably colonized by distinct and, perhaps, not yet sampled source populations. Bottleneck and mismatch analyses indicate that rock partridges have lost variability through past population declines, and did not expand recently. Deglaciated areas could have been recolonized without any strong demographic expansion. Genetic data partially supported subspecies subdivisions, and allowed delimiting distinct conservation units. Rock partridges in Sicily, formally recognized as A. g. whitakeri, met the criteria for a distinct evolutionary significant unit.

Animals↗
PubMed2004

Mate recognition in a freshwater fish: geographical distance, genetic differentiation, and variation in female preference for local over foreign males.

It often is assumed that more distant allopatry should reflect reduced rates of contemporary gene flow and/or greater divergence in mate recognition systems. This assumption, however, is rarely tested and may not always be appropriate. Here we investigated female preference for local and foreign males in a morphologically variable Australian freshwater fish, the Pacific blue-eye Pseudomugil signifer. Using a multidisciplinary approach that combined molecular phylogeography with conventional mate choice experiments, we found female blue-eyes spent more time in association with local males only when the alternative was a foreigner from a geographically and genetically more distant population. When offered the choice between two foreign males, females associated more with males from the population that was more closely adjacent to their own. Our results suggest that female preference for local over foreign males in blue-eyes may depend on how genetically and geographically separated populations are from one another.

Animals↗
PubMed2005

Chromosomal evidence of incipient speciation in the Afrotropical malaria mosquito Anopheles funestus.

The analysis of chromosomal polymorphism of paracentric inversions in anopheline mosquitoes has often been instrumental to the discovery of sibling species complexes and intraspecific genetic heterogeneities associated with incipient speciation processes. To investigate the population structure of Anopheles funestus Giles (Diptera: Culicidae), one of the three most important vectors of human malaria in sub-Saharan Africa, a three-year survey of chromosomal polymorphism was carried out on 4,638 karyotyped females collected indoors and outdoors from two villages of central Burkina Faso. Large and temporally stable departures from Hardy-Weinberg equilibrium due to significant deficits of heterokaryotypes were found irrespective of the place of capture, and of the spatial and temporal units chosen for the analysis. Significant linkage disequilibrium was observed among inversion systems on independently assorting chromosomal arms, indicating the existence of assortative mating phenomena. Results were consistent with the existence of two chromosomal forms characterized by contrasting degrees of inversion polymorphism maintained by limitations to gene flow. This hypothesis was supported by the reestablishment of Hardy-Weinberg and linkage equilibria when individual specimens were assigned to each chromosomal form according to two different algorithms. This pattern of chromosomal variability is suggestive of an incipient speciation process in An. funestus populations from Burkina Faso.

Animals↗
PubMed2005

Patterns of speciation in endemic Mexican Goodeid fish: sexual conflict or early radiation?

Currently there is much interest in the potential for sexual selection or conflict to drive speciation. Theory proposes that speciation will be accelerated where sexual conflict is strong, particularly if females are ahead because mate choice will accentuate divergence by limiting gene flow. The Goodeinae are a monophyletic group of endemic Mexican fishes with an origin at least as old as the Miocene. Sexual selection is important in the Goodeinae and there is substantial interspecific variability in body morphology, which influences mate choice, allowing inference of the importance of female mate choice. We therefore used this group to test the relationship between sexual dimorphism and speciation rate. We quantified interspecific variation in sexual dimorphism amongst 25 species using a multivariate measure of total morphological differentiation between the sexes that accurately reflects sexual dimorphism driven by female mate choice and also used a mtDNA-based phylogeny to examine speciation rates. Comparative analyses failed to support a significant association between sexual dimorphism and speciation rate. In addition, variation in the time course of speciation throughout the whole clade was also examined using a similar tree containing 34 extant species. A constant rates model for the growth of this clade was rejected, but analyses instead indicated a decline in the rate of speciation over time. These results support the hypothesis of an early expansion of the group, perhaps due to an early radiation influenced by the key innovation of live bearing, or the prevalence of Miocene volcanism. In general, support for the role of sexual selection in generating patterns of speciation is proving equivocal and we argue that vicariance biogeography and adaptive radiations remain the most likely determinants of major patterns of diversification of continental organisms.

Animals↗
PubMed2003

Evaluation of interphase fluorescence in situ hybridization for the t(14;18)(q32;q21) translocation in the diagnosis of follicular lymphoma on fine-needle aspirates: a comparison with flow cytometry immunophenotyping.

BACKGROUND: Diagnosing lymphoproliferative disorders on fine-needle aspiration (FNA) can be challenging due to variable cellularity and lack of architecture. Ancillary studies often are required for diagnosis. Follicular lymphoma (FL) is characterized by a monoclonal B-cell proliferation with coexpression of CD19/CD10 and a t(14;18)(q32;q21) reciprocal translocation, resulting in the immunoglobulin heavy chain/BCL-2 fusion gene. These features also can be found, with much lower frequency, in diffuse large B-cell lymphoma (DLBCL) of follicle center cell origin. The objective of the current study was to compare the accuracy in detecting FL and DLBCL of follicle center cell origin by interphase fluorescence in situ hybridization (I-FISH) versus flow cytometry immunophenotyping (FCM) on FNAs. METHODS: Concurrent testing by FISH for t(14;18)(q32;q21) and FCM was performed on 84 FNAs, including 40 FLs and 44 non-FLs (de novo DLBCLs, mantle cell lymphomas, small lymphocytic lymphomas/chronic lymphocytic leukemias [SLLs/CLLs], small B-cell lymphomas, and reactive lymphoid hyperplasias). The final diagnosis was rendered based on the combined information from cytomorphology, FCM, FISH, immunocytochemical staining for Ki-67, monoclonality for kappa and lambda light chains, and, if available, corresponding tissue biopsy, cytogenetic analysis, and polymerase chain reaction analysis. RESULTS: Among 40 FLs, FISH produced positive results for the t(14;18) translocation in 85.0%, negative results in 7.5%, and insufficient results in 7.5%; whereas, with FCM, 75% of cases exhibited a CD19-positive (CD19+)/CD10+ population (28 monoclonal, 2 nonclonal), 12.5% of cases exhibited a CD19+/CD10-negative population (3 monoclonal, 2 nonclonal), and 12.5% of cases were insufficient. All of nonclonal results from FCM and all of the insufficient results from FCM analysis exhibited unequivocal t(14;18) translocation by FISH. In contrast, the three negative results and the three insufficient results from FISH were monoclonal and CD19+/CD10+ on FCM. The results from FISH and FCM were concordant in 75% cases. Of 44 non-FLs, FISH produced positive results for the t(14;18) translocation in 5 DLBCLs and 2 SLLs/CLLs. The latter showed single fusion signals just above the cutoff level. All cases in the non-FL group that failed to show clonality or had insufficient results from FCM were DLBCLs. Among 17 DLBCLs, FISH detected a t(14;18) translocation in 29.4%, whereas FCM demonstrated a CD19+/CD10+ population in 23.5%. CONCLUSIONS: I-FISH for the t(14;18)(q32;q21) translocation provided high overall accuracy in detecting FLs on FNAs. This test can be used for diagnosing or monitoring FL on FNAs when cellularity is limited or when FCM results are noncontributory. For detecting a follicle center cell origin in DLBCLs, I-FISH for the t(14;18) translocation appeared to be slightly more sensitive than FCM for the CD19+/CD10+ immunophenotype.

Chromosomes, Human, Pair 14↗
PubMed2003

A test for deviation from island-model population structure.

The neutral island model forms the basis for several estimation models that relate patterns of genetic structure to microevolutionary processes. Estimates of gene flow are often based on this model and may be biased when the model's assumptions are violated. An appropriate test for violations is to compare FST scores for individual loci to a null distribution based on the average FST taken over multiple loci. A parametric bootstrap method is described here based on Wright's beta-distribution to generate null distributions of FST for each locus. These null distributions account for error introduced by sampling populations, individuals and loci, and also biological sources of error, including variable alleles/locus and inbreeding. Confidence limits can be obtained directly from these distributions. Significant deviations from the island model may be the result of selection, deviations from the island model's migration pattern, nonequilibrium conditions, or other deviations from island-model assumptions. Only strong biases are likely to be detected because of the inherently large sampling variation of FST. Nevertheless, a coefficient, Nb, describing bias in the spread of the beta-distribution in units comparable to the gene flow parameter, Nm, can be obtained for each locus. In samples from populations of the butterfly Coenonympha tullia, the loci Idh-1, Mdh-1, Pgi and Pgm showed significantly lower FST than expected.

Animals↗
PubMed1994

Chimeric anti-ganglioside GM2 antibody with antitumor activity.

Ganglioside GM2, which is one of the major gangliosides expressed on the cell surface of human tumors of neuroectodermal origin, has been focused on as a target molecule for passive immunotherapy. GM2 is thought to be one of the T-cell-independent antigens and to elicit only IgM antibody responses in rodents and humans. We have previously established two murine anti-GM2 monoclonal antibodies with high specificity and strong binding activity, KM696 and KM697, both of which are of the IgM class. Variable heavy and light chain complementary DNAs of these two murine monoclonal antibodies were cloned and used in the construction of mouse/human IgG1 chimeric antibodies, KM966 and KM967, respectively, in this study. One of the chimeric antibodies, KM966, retained strong and specific reactivity with GM2 and showed the similarity of the binding activity with tumor cell lines to that of the original murine monoclonal antibody. Indirect immunofluorescence staining of tumor cell lines with the chimeric KM966 revealed that the antigen was expressed in substantial amounts on pulmonary tumor cells and leukemia cells as well as neuroectodermal origin tumor cells. When human serum and human peripheral blood mononuclear cells were used as effectors in complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity, respectively, chimeric KM966 was fully effective in killing GM2-expressing tumor cells. In addition, i.v. injection of chimeric KM966 markedly suppressed the establishment of human tumor xenografts in nude mice. Taken together, chimeric KM966 is the first antibody of the human IgG class to ganglioside GM2 and has strong antitumor activity both in vitro and in vivo. It is likely that chimeric KM966 will be a useful agent for passive immunotherapy of human cancer.

Amino Acid Sequence↗