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1.  A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies 
Background
CD19 is a B cell lineage specific surface receptor whose broad expression, from pro-B cells to early plasma cells, makes it an attractive target for the immunotherapy of B cell malignancies. In this study we present the generation of a novel humanized anti-CD19 monoclonal antibody (mAb), GBR 401, and investigate its therapeutic potential on human B cell malignancies.
Methods
GBR 401 was partially defucosylated in order to enhance its cytotoxic function. We analyzed the in vitro depleting effects of GBR 401 against B cell lines and primary malignant B cells from patients in the presence or in absence of purified NK cells isolated from healthy donors. In vivo, the antibody dependent cellular cytotoxicity (ADCC) efficacy of GBR 401 was assessed in a B cell depletion model consisting of SCID mice injected with healthy human donor PBMC, and a malignant B cell depletion model where SCID mice are xenografted with both primary human B-CLL tumors and heterologous human NK cells. Furthermore, the anti-tumor activity of GBR 401 was also evaluated in a xenochimeric mouse model of human Burkitt lymphoma using mice xenografted intravenously with Raji cells. Pharmacological inhibition tests were used to characterize the mechanism of the cell death induced by GBR 401.
Results
GBR 401 exerts a potent in vitro and in vivo cytotoxic activity against primary samples from patients representing various B-cell malignancies. GBR 401 elicits a markedly higher level of ADCC on primary malignant B cells when compared to fucosylated similar mAb and to Rituximab, the current anti-CD20 mAb standard immunotherapeutic treatment for B cell malignancies, showing killing at 500 times lower concentrations. Of interest, GBR 401 also exhibits a potent direct killing effect in different malignant B cell lines that involves homotypic aggregation mediated by actin relocalization.
Conclusion
These results contribute to consolidate clinical interest in developing GBR 401 for treatment of hematopoietic B cell malignancies, particularly for patients refractory to anti-CD20 mAb therapies.
doi:10.1186/1756-8722-7-33
PMCID: PMC4021825  PMID: 24731302
B cell malignancies; GBR 401; Anti-CD19 monoclonal antibody; ADCC; Therapeutic antibody
2.  Pneumocystis jirovecii Genotype Associated with Increased Death Rate of HIV-infected Patients with Pneumonia 
Emerging Infectious Diseases  2013;19(1):21-28.
Comorbidities might predict presence of specific fungal genotypes.
doi:10.3201/eid1901.120140
PMCID: PMC3557975  PMID: 23260763
Pneumocystis jirovecii pneumonia; Pneumocystis jirovecii dihydropteroate synthase; DHPS; HIV; homosexuality; intravenous drug use; dihydropteroate synthase mutations; opportunistic infection; immunocompromised; virus; fungus; fungi; fungal; sulfa resistance; sulfamethoxazole/trimethoprim; SMX/TMP; dapsone; pentamidine; atovaquone; antimicrobial drugs; antibiotic; antifungal drugs
3.  Molecular Evidence of Pneumocystis Transmission in Pediatric Transplant Unit 
Emerging Infectious Diseases  2005;11(2):330-332.
We describe an outbreak of Pneumocystis jirovecii pneumonia in a pediatric renal transplant unit, likely attributable to patient-to-patient transmission. Single-strand conformation polymorphism molecular typing showed that 3 affected patients had acquired the same 2 strains of Pneumocystis, which suggests interhuman infection. An infant with mitochondriopathy was the probable index patient.
doi:10.3201/eid1102.040820
PMCID: PMC3320462  PMID: 15752458
Pneumocystis jirovecii; pneumonia; PCP; pediatric renal transplantation; single-strand conformation polymorphism; inter-human transmission; dispatch
4.  Mutations of Pneumocystis jirovecii Dihydrofolate Reductase Associated with Failure of Prophylaxis 
Antimicrobial Agents and Chemotherapy  2004;48(11):4301-4305.
Most drugs used for prevention and treatment of Pneumocystis jirovecii pneumonia target enzymes involved in the biosynthesis of folic acid, i.e., dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Emergence of P. jirovecii drug resistance has been suggested by the association between failure of prophylaxis with sulfa drugs and mutations in DHPS. However, data on the occurrence of mutations in DHFR, the target of trimethoprim and pyrimethamine, are scarce. We examined polymorphisms in P. jirovecii DHFR from 33 patients diagnosed with P. jirovecii pneumonia who were receiving prophylaxis with a DHFR inhibitor (n = 15), prophylaxis without a DHFR inhibitor (n = 11), or no prophylaxis (n = 7). Compared to the wild-type sequence present in GenBank, 19 DHFR nucleotide substitution sites were found in 18 patients with 3 synonymous and 16 nonsynonymous mutations. Of 16 amino acid changes, 6 were located in positions conserved among distant organisms, and five of these six positions are probably involved in the putative active sites of the enzyme. Patients with failure of prophylaxis, including a DHFR inhibitor, were more likely to harbor nonsynonymous DHFR mutations than those who did not receive such prophylaxis (9 of 15 patients versus 2 of 18; P = 0.008). Analysis of the rate of nonsynonymous versus synonymous mutations was consistent with selection of amino acid substitutions in patients with failure of prophylaxis including a DHFR inhibitor. The results suggest that P. jirovecii populations may evolve under selective pressure from DHFR inhibitors, in particular pyrimethamine, and that DHFR mutations may contribute to P. jirovecii drug resistance.
doi:10.1128/AAC.48.11.4301-4305.2004
PMCID: PMC525445  PMID: 15504856
5.  Molecular Evidence of Interhuman Transmission of Pneumocystis Pneumonia among Renal Transplant Recipients Hospitalized with HIV-Infected Patients 
Emerging Infectious Diseases  2004;10(10):1766-1773.
Molecular evidence indicates that P. jirovecii may be nosocomially transmitted to severely immunosuppressed patients.
Ten Pneumocystis jirovecii pneumonia (PCP) cases were diagnosed in renal transplant recipients (RTRs) during a 3-year period. Nosocomial transmission from HIV-positive patients with PCP was suspected because these patients shared the same hospital building, were not isolated, and were receiving suboptimal anti-PCP prophylaxis or none. P. jirovecii organisms were typed with the multitarget polymerase chain reaction–single-strand conformation polymorphism method. Among the 45 patients with PCP hospitalized during the 3-year period, 8 RTRs and 6 HIV-infected patients may have encountered at least 1 patient with active PCP within the 3 months before the diagnosis of their own PCP episode. In six instances (five RTRs, one HIV-infected patient), the patients harbored the same P. jirovecii molecular type as that found in the encountered PCP patients. The data suggest that part of the PCP cases observed in this building, particularly those observed in RTRs, were related to nosocomial interhuman transmission.
doi:10.3201/eid1010.040453
PMCID: PMC3323259  PMID: 15504262
Epidemiology; Pneumocystis carinii; Pneumocystis jirovecii; interhuman transmission; cluster analysis; sulfa drug resistance; dihydropteroate synthase; single-strand conformation polymorphism; PCP; research
6.  Sulfa Resistance and Dihydropteroate Synthase Mutants in Recurrent Pneumocystis carinii Pneumonia 
Emerging Infectious Diseases  2003;9(7):864-867.
Failure of sulfa or sulfone prophylaxis is associated with mutations in Pneumocystis carinii gene coding for dihydropteroate synthase (DHPS). The DHPS genotype was analyzed in AIDS patients who had two separate episodes of P. carinii pneumonia. The results suggest that DHPS mutations can be selected de novo within patients by the pressure of a sulfa or sulfone drug.
doi:10.3201/eid0907.020753
PMCID: PMC3023424  PMID: 12890330
Pneumocystis carinii; pneumonia; fungal typing; drug resistance; drug pressure; mutation; dihydropteroate synthase; AIDS; dispatch
7.  Rapid PCR–Single-Strand Conformation Polymorphism Method To Differentiate and Estimate Relative Abundance of Pneumocystis carinii Special Forms Infecting Rats 
Journal of Clinical Microbiology  2001;39(12):4563-4565.
A rapid method that uses PCR–single-strand conformation polymorphism analysis of the intron of the nuclear 26S rRNA gene was shown to differentiate the two Pneumocystis carinii special forms that infect rats, P. carinii f. sp. carinii and P. carinii f. sp. ratti. The method also provides a means for estimation of the relative abundance of the two special forms in the case of a coinfected rat. The results suggest that the method described will help to further standardize the immunosuppressed rat model of P. carinii infection and, thus, contribute to a better understanding of P. carinii infection in humans.
doi:10.1128/JCM.39.12.4563-4565.2001
PMCID: PMC88588  PMID: 11724884

Results 1-7 (7)