Small numbers of monoclonal B cells with the phenotype of chronic lymphocytic leukemia (CLL) were detected by means of high-sensitivity flow cytometry in about 5% of adults with a normal blood count ...and about 14% of subjects with lymphocytosis. In the latter group, frank CLL ultimately developed in 15%. The principal features of these monoclonal B cells and the B cells of CLL were similar.
Small numbers of monoclonal B cells with the phenotype of chronic lymphocytic leukemia (CLL) were detected by means of high-sensitivity flow cytometry in about 5% of adults with a normal blood count and about 14% of subjects with lymphocytosis. In the latter group, frank CLL ultimately developed in 15%.
The incidence of chronic lymphocytic leukemia (CLL) is approximately 6 per 100,000 persons per year in North America.
1
The National Cancer Institute–sponsored Working Group guidelines for the diagnosis of CLL require a lymphocyte count of 5000 or more per cubic millimeter and a characteristic cell-surface phenotype of B cells: the presence of CD19, CD5, and CD23, weak expression of CD20 and CD79b, and either kappa or lambda immunoglobulin light chains.
2
High-sensitivity flow cytometry allows for the detection of B cells with a CLL phenotype in numbers as low as 1 per 10,000 normal leukocytes.
3
With this method, CLL-phenotype cells have . . .
Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo disease) is a neurodegenerative disorder caused by a deficiency in the lysosomal enzyme sulfamidase (SGSH), catabolizing heparan sulfate (HS). ...Affected children present with severe behavioral abnormalities, sleep disturbances, and progressive neurodegeneration, leading to death in their second decade. MPS I, a similar neurodegenerative disease accumulating HS, is treated successfully with hematopoietic stem cell transplantation (HSCT) but this treatment is ineffectual for MPS IIIA. We compared HSCT in MPS IIIA mice using wild-type donor cells transduced ex vivo with lentiviral vector-expressing SGSH (LV-WT-HSCT) versus wild-type donor cell transplant (WT-HSCT) or lentiviral-SGSH transduced MPS IIIA cells (LV-IIIA-HSCT). LV-WT-HSCT results in 10% of normal brain enzyme activity, near normalization of brain HS and GM2 gangliosides, significant improvements in neuroinflammation and behavioral correction. Both WT-HSCT and LV-IIIA-HSCT mediated improvements in GM2 gangliosides and neuroinflammation but were less effective at reducing HS or in ameliorating abnormal HS sulfation and had no significant effect on behavior. This suggests that HS may have a more significant role in neuropathology than neuroinflammation or GM2 gangliosides. These data provide compelling evidence for the efficacy of gene therapy in conjunction with WT-HSCT for neurological correction of MPS IIIA where conventional transplant is ineffectual.
Mucopolysaccharidosis type IIIB (Sanfilippo syndrome) is a lysosomal storage disease caused by a genetic defect in the production of α-
N-acetylglucosaminidase. This results in lysosomal and ...extracellular accumulation of the undegraded glycosaminoglycan (GAG) substrate, heparan sulphate. Affected patients show progressive CNS degeneration characterised by mental retardation, hyperactivity and seizures, with death usually in the mid teens to early twenties. Visceral organ storage is also present but is relatively mild compared to other MPS diseases storing similar substrates. No treatments currently exist for MPS IIIB.
Genistein is a broad spectrum protein tyrosine kinase inhibitor which acts on several different growth factor receptors, notably EGF and IGF receptors, both of which are important for proteoglycan synthesis. Recent work has shown that genistein can reduce GAG synthesis in patients’ fibroblasts
in vitro and there is evidence in patients to suggest that it may be an effective substrate reduction therapy agent for MPS III. Here we have tested the dose responses of MPS IIIB mice to daily sub-chronic dosing of genistein in half log increments compared to carrier over 8
weeks.
We show clear reductions in liver lysosome compartment size in both sexes and significant dose dependent improvements in total liver GAGs and hair morphology in male MPS IIIB animals following genistein treatment. Male MPS IIIB mice exhibited considerably more liver storage than females and responded better to treatment. No changes in total GAGs, lysosomal size or reactive astrogliosis in the brain cortex were observed after 8
weeks of treatment despite evidence that genistein can cross the blood brain barrier. This is the first demonstration of genistein treatment in MPS models
in vivo.
Monoclonal B-cell lymphocytosis (MBL) is detectable in > 3% of the general population. Recent data are compatible, at least in a proportion of cases, with MBL being a progenitor lesion for chronic ...lymphocytic leukemia (CLL) and a surrogate for inherited predisposition. Common single nucleotide polymorphisms (SNPs) at 2q13 (rs17483466), 2q37.1 (rs13397985), 2q37.3 (rs757978), 6p25.3 (rs872071), 8q24.21 (rs2456449), 11q24.1 (rs735665), 15q21.3 (rs7169431), 15q23 (rs7176508), 16q24.1 (rs305061), and 19q13.32 (rs11083846) have been shown to confer a modest but significant increase in CLL risk. To examine the impact of these 10 SNPs on MBL, we analyzed 3 case-control series totaling 419 cases and 1753 controls. An association between genotype and MBL risk was seen for 9 SNPs, 6 of which were statistically significant: rs17483466 (odds ratio OR =1.27; P = .02), rs13397985 (OR = 1.40; P = 1.72 × 10−3), rs757978 (OR = 1.38; P = .02), rs872071 (OR = 1.27; P = 7.75 × 10−3), rs2456449 (OR = 1.31; P = 3.14 × 10−3), and rs735665 (OR = 1.63; P = 6.86 × 10−6). Collectively, these data provide support for genetic variation influencing CLL risk through predisposition to MBL.
Abstract 59▪▪This icon denotes an abstract that is clinically relevant.
Monoclonal B-cell Lymphocytosis with a CLL-phenotype (CLL-type MBL) is detected in over 10% of individuals undergoing ...investigation of a lymphocytosis. The risk of developing progressive CLL requiring treatment is approximately 1% per year. However, monoclonal B-cells can now be readily detected at a level above 1 cell/μL in over 3.5% of adults with normal blood counts, & using highly sensitive techniques in over 20% of elderly individuals. There is currently no reported outcome data for such individuals. The aim of this study was to determine whether individuals with normal blood counts and very low count MBL had any increase in mortality or risk of developing a haematological malignancy. We obtained ethical approval to undertake a linked anonymised investigation of low count MBL cases identified in previous studies. In 2003, 1520 peripheral blood samples from haematologically normal 60–80 year old hospital outpatients were screened & MBL was detected in 105 individuals (78 CLL-type, 27 CD5-negative). Follow-up data is available for 40 CLL-type MBL, 17 CD5-negative MBL & 126 age-matched controls screened for MBL at the same time from the same source with no evidence of abnormal B-cells. After a median follow-up of 65 months (range 0.2–72 months) there have been 51 deaths: 23% (9/40) CLL-type MBL, 35% (6/17) CD5-negative MBL & 29% (36/126) controls. The presence of MBL was not associated with a significantly different overall survival (Log-rank P=0.82). The yearly mortality rate (with 95% CI) was 4.8% (2.5–9.2%) for patients with CLL-type MBL vs. 6.8% (4.7–9.8%, P=0.76) for matched controls. The yearly mortality rate (with 95% CI) was 5.2 % (2.6–10.3%) for patients with a CD5-negative MBL vs. 6.4% (2.6–15.3%) for matched controls. A non-haematological malignancy was detected in 30 cases: 20% (8/40) CLL-type MBL, 6% (1/17) CD5-negative MBL & 17% (21/126) controls. The presence of MBL was also not associated with a significantly risk of developing a non-haematological malignancy (Log-rank P=0.65). Three individuals who had a low level of CLL-type MBL detectable with a normal blood count have been subsequently referred for investigation of a haematological malignancy at 8, 21 and 50 months after initial testing. Two were for referred for investigation of a paraprotein: in both cases the paraprotein isotype was different to the immunoglobulin expressed by the CLL-phenotype cells and neoplastic plasma cells were detected. The third was referred for investigation of a lymphocytosis. In all cases CLL cells were detectable, representing 5-25% of leucocytes. All three individuals are alive with a stable B-lymphocyte count below 5,000/μL and none have required treatment for progressive CLL or myeloma where applicable. One individual who had CD5-negative MBL detected was investigated for a suspected lymphoproliferative disorder 41 months after screening but bone marrow & peripheral blood investigation did not demonstrate any abnormality & the CD5-negative MBL was no longer detectable. One individual from the control group developed MDS. We therefore demonstrate that the presence of a low level of MBL in hospital patients with a normal blood count has no influence on survival or development of non-haematological malignancies compared to age-matched controls. None of the individuals have developed progressive CLL but 7.5% (3/40) cases of low-count CLL-type MBL have shown an expansion of CLL cells over time and been identified clinically through independent referral. The higher rate of detection of MBL or a paraprotein in this group may reflect the closer monitoring applied to regular hospital attenders. These represent the first data concerning outcome for individuals with low levels (<1,500/μL) of CLL-phenotype cells or monoclonal CD5-negative B-cells. The results suggest an increased probability of developing an asymptomatic B-cell abnormality that is routinely detectable but there is no increased risk over a five year period of mortality or development of a B-cell malignancy that requires treatment.
No relevant conflicts of interest to declare.
INTRODUCTION: CLL is a disorder with a wide variation in outcome. Patients with adverse cellular features are often refractory to treatment and have a short overall survival. Individuals with ...CLL-type MBL are unlikely to require treatment and in most cases will eventually die of an unrelated cause. Many factors that predict a poor outcome have been identified, including stage, IGHV mutation status, ZAP-70 expression, and deletions of chromosomes 17p (TP53) and/or 11q23 (ATM). Deletions and mutations in TP53 are generally not presenting features and appear to require clonal evolution. One hypothesis is that the degree of intraclonal variation in genes targeted by the somatic hypermutation machinery, e.g. IGHV and BCL6, may predict the potential for clonal evolution. We have previously tested 66 antigens for their capacity to differentiate proliferating CLL cells, resting CLL cells and normal B-cells and identified 30 potentially relevant markers, including common markers such as CD38 and less frequently used markers such as the Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1).
AIM: To compare the expression of relevant cell surface markers with the degree of intraclonal variation in the IGHV and BCL6 genes and to determine if these markers can be used to differentiate CLL-type MBL and CLL with or without adverse biological features.
METHODS: The cell surface phenotype was assessed by 6-colour cytometry in 133 patients: 22 CLL with deletion 17p or 11q23, 69 CLL with no adverse prognostic chromosomal abnormalities, and 42 MBL. Surface phenotype was also compared with IGHV mutation status in a cohort of 29 CLL patients (16 ≤2% IGHV mutation, 13 >2% IGHV mutation). These antigens were also assessed using 4-colour flow cytometry in 20 cases (4 MBL, 16 CLL) and compared with IGHV & BCL6 mutation status and degree of intraclonal variation (defined as the proportion of mutations that were detected in a single clone only), and with ZAP-70 (AF488-1E7.2) expression.
RESULTS: CLL cases with ≤2% IGHV mutation showed increased expression of CD38 (6.8 fold, p 0.02), CD49d (4.9-fold, P = 0.04), IgD (2.0-fold, P = 0.05), ZAP-70 (1.5-fold, P=0.04) and decreased expression of LAIR-1 (6.2-fold, P = 0.003) in comparison to CLL cases with >2% IGHV mutation. CLL cases with deletions of 17p and 11q23 showed decreased expression of CCR6 (1.7-fold, P = 0.0001), IgD (1.3-fold, P = 0.03) and LAIR-1 (7.1-fold, P<0.0001) in comparison to CLL cases without deletion 17p/11q23. CLL cases showed increased expression of CD23 (1.4-fold, P = 0.04), CD25 (1.3-fold, P = 0.05) and CD62L (1.7-fold, P = 0.04) in comparison to MBL. Cases with ≤2% overall IGHV mutation showed a similar degree of intraclonal variation as cases with >2% overall IGHV mutation in both IGHV (median 0.075% vs. 0.049% unique mutations, P>0.05) and BCL6 (median 0.10% vs. 0.095% unique mutations, P>0.05). However, there was an inverse relationship between BCL6 and IGHV intraclonal variation and cases with the highest levels of BCL6 intraclonal variation showed significantly decreased expression of CD39 (1.9-fold, P = 0.04) and LAIR1 (4.7-fold, P = 0.019).
CONCLUSIONS: There were no markers or marker combinations that could discriminate MBL from CLL. The key differences were decreased expression of markers that are expressed during cell cycle, i.e. CD23, and adhesion markers such as CD62L and CD49d. These markers show sequential changes with disease stage, supporting the hypothesis that cellular interactions are central to the accumulation and expansion of CLL cells. However, the marker most consistently associated with adverse biological features is LAIR1, which is weak or negative in CLL with ≤2% IGHV mutation, high levels of intraclonal variation and TP53 or ATM deletions. LAIR-1 is an inhibitory receptor involved in regulating classs-witching. LAIR1 is strongly expressed in normal circulating peripheral B-cells. As with other prognostic markers, expression is a continuous variable and therefore a suitable cutoff will need to be identified. However, fluorochrome-conjugated antibodies are readily available and expression on CLL cells is stable for several days in EDTA samples which should minimise inter-laboratory analytical variation. LAIR1 expression in CLL is more closely associated with IGHV mutation status than CD38 or ZAP-70 expression. LAIR1 is a promising prognostic marker that appears to be central to the development of aggressive CLL as there is a strong association between downregulation of LAIR1, intraclonal heterogeneity in BCL6 and development of TP53 and ATM deletions.
Recently published data has identified the type-1 membrane glycoprotein CD200 as a potential therapeutic target in the treatment of CLL. CD200 has been reported to be expressed at significantly ...higher levels in CLL compared to normal mature B cells. CD200 has an immunosuppressive function and it's expression by CLL cells may be involved in disease progression by exerting an immunomodulatory effect facilitating escape from host immune responses. In order to further evaluate the clinical and laboratory utility of this antibody the expression of CD200 has been assessed in a range of specimens. We have assessed CD200 expression in 41 CLL patients (36 peripheral blood and 5 bone marrow) and 12 normal samples (5 peripheral blood, 5 bone marrow, 2 lymph node biopsies). Biological features were assessed in 24 known CLL patients (male to female ration 3:1, median age 70 years), 15 untreated and 9 post treatment. Patients were defined as being poor risk if they were ZAP-70+, had deletions of p53, ATM and/or unmutated IgVH genes. Using these criteria 50% of cases were defined as good risk, and 50% as poor risk. Leucocytes were isolated from the specimens by ammonium chloride lysis and an aliquot of 1x106 cells were analysed by 6 colour flow cytometry using the FACS Canto and analysed using FACS Diva software (Becton Dickinson, UK). The level of expression of CD200 above an isotype control was reported for Lymphocytes, Monocytes, Granulocytes, Mature B cells, Germinal centre B cells, Plasma cells and CLL cells. Mean fluorescence intensities were also recorded for each of these groups (table 1). This data shows that CD200 is expressed above control levels by the majority of CLL cells, expression levels were not significantly different between patients with poor and good risk disease (median mfi 1921 and 1677 respectively p=0.42). CD200 was not increased in normal CD5+ B-cells. The very weak expression seen in non-CLL leucocytes may be an artefact of the lower background fluorescence of the control antibody relative to the CD200. Expression levels of CD200 relative to control were to the same magnitude as CD52 and several fold higher than CD20 expression levels, suggesting that CD200 is potentially an excellent target for immunotherapy. In conclusion our data shows that CD200 expression is uniformly higher in CLL than in any other peripheral blood or bone marrow leucocytes. The level of expression appears to be unaffected by prognostic risk factors, suggesting that treatments which target CD200 would be applicable in all patients with CLL. In addition, the lack of CD200 expression on normal leucocytes, particularly on T-cells, is potentially important. The uniformly increased expression of this molecule in CLL also makes this a potential marker for diagnostic and minimal residual disease assays.
Table 1Cell TypeMedian %CD200+ (range)Mean MFICLL96.60 (65.2–100)2773.23Mature B cells23.89 (6.06–36.75)69.29Germinal Centre B cells35.60 (2.7–48)871.86Plasma Cells42.50 (2.8–80.9)1939.5T cells0.25 (0.11–0.48)7.73Monocytes3.65 (0.23–6.31)31.86Granulocytes4.47 (0.13–13.25)34.63CD200 Expression in CLL is consistently higher than in normal leucocytes
A monoclonal B-cell Lymphocytosis (MBL) is detected in the peripheral blood of around 3% of otherwise healthy adults, the majority of these have a CLL immunophenotype. We have previously demonstrated ...that the cells in MBL are indistinguishable from good risk CLL, sharing the same immunophenotypic profile, genetic aberrations and IgVH gene usage. MBL exerts an increasing burden on haematology clinics with over 100 new patients diagnosed per annum in our regional haemato-oncology laboratory. This is largely as a result of the increased tendency to investigate patients with a mild lymphocyosis although <1% of patients show progression to CLL per year. Immunoglobulin VH gene mutational status is the gold standard marker for predicting disease progression in early stage A CLL. The aim of this study was to determine if IgVH mutational status predicts outcome in MBL. DNA was extracted from 72 presentation MGG stained blood films from patients diagnosed with MBL between 1995 and 2000 (37 male, 35 female median age 71 years) using a modified version of the QIAamp mini kit protocol for dried blood spots (Qiagen GmbH). In addition DNA was extracted from leucocytes prepared from ammonium-chloride lysed whole blood (<24hrs old) from MBL patients (n=20). DNA was then amplified using BIOMED-2 IgH primers for FR1 or FR2. The products of the PCR were purified from 2% agarose gels and used for direct sequencing of the IgH genes. DNA was successfully amplified from 67/72 archived samples and 20/20 fresh samples. Direct sequencing has been performed on 32/67 archive cases and 20/20 fresh cases to date. Rearranged VH segments were identified in a total of 47/52 cases (27 archive, 20 fresh) using IgBlast (www.ncbi.nlm.nih.gov/BLAST/IgBlast). Rearrangements with more than 2% deviation from the germline sequence were considered somatically hypermutated (SHM). Gene usage in fresh MBL reflected the bias seen in indolent CLL with a predominance of VH4-34 and VH3-7 and no evidence of VH1-69. This was mirrored in archived material with 11/27 cases utilising VH4-34 (n=6) or VH3-7 (n=5) and no cases using VH1-69. The median level of SHM in fresh MBL samples was 5.7% (range 1.3–13.7%). All archived samples analysed showed deviation from germline sequences of greater than 2% (median 6.5% range 2.7–3.2%). Follow-up data from archived samples revealed that 7 patients showed resolution of their lymphocytosis, with persistent but decreasing levels of CLL-phenotype cells. 10 patients had stable lymphocyte counts, with CLL phenotype cells present at levels between 5,000 and 10,000/μL. 9 patients had persistently increasing lymphocyte counts, in all cases CLL cells were present at levels >10,000/μL and included 3 patients who progressed to a clinical stage requiring treatment. VH gene usage was different in each of these 3 patients was with VH3-7, VH4-34 and VH5-51 identified, the levels of SHM were 5.8, 4.0 and 5.3% respectively. Follow-up data shows that a deletion of ATM was detected at progression in one of these patients. In conclusion, we show that MBL is predominantly mutated and that progression to CLL is independent of mutational status. Other prognostic markers, particularly assessment of chromosomal aberrations, may be informative but this would probably require cell selection to increase sample purity. Our data suggests that current prognostic markers are not effective at predicting outcome in MBL and periodic monitoring is required.
A monoclonal B-cell lymphocytosis (MBL) is detectable in approximately 3% of the general adult population. In most cases the abnormal cells have a phenotype and genotype that is indistinguishable ...from indolent CLL. Individuals presenting with an MBL count over 500 cells per microlitre progress to CLL requiring treatment at a rate of approximately 1% per year. The relationship between MBL and CLL therefore appears to be similar to that of MGUS and myeloma. Intraclonal variation (ICV) in the immunoglobulin heavy chain gene (IgVH) gene occurs in approximately half of MGUS patients but is not present in myeloma. The majority MGUS patients that progress to myeloma lack intraclonal variation at the MGUS stage suggesting that clonal selection is a critical pathway for disease progression in myeloma. The aim of this study was to compare the rate of intraclonal variation in MBL and CLL and determine whether low rates of ICV are associated with progressive disease. DNA was extracted from ammonium-chloride lysed blood samples from individuals with CLL-phenotype MBL (n=20) and CLL with progressive disease (n=10). IgVH and BCL6 PCR products were directly sequenced and also cloned and at least 10 clones sequenced. Intraclonal variation was defined as the number of unique sequences as a percentage of total clones sequenced. Unmutated CLL was defined as having <2% difference in the predominant IgVH clone sequence from germline. The median IgVH mutation rate in the MBL group was 7.4% (range 1.3–13.7%) and in the progressive CLL group 0.6% (range 0–11.3%). Intraclonal variation was observed in both groups of patients: the median number of unique clones was 2/10 (range 0–7/10) in MBL patients and 3/10 (range 0–5/10) in CLL patients. Intraclonal variation was generally restricted to 1 or 2 point mutations in each sequence and for the VH gene the replacement/silent (R/S) ratio of mutations was 1.7 in the framework regions and 3.3 in the complementarity-determining regions. Independent of disease category, unmutated CLL/MBL had a higher degree of intraclonal variation than mutated CLL with a median ICV for unmutated cases of 31% and for mutated cases of 20%. The proportion of patients showing complete clonal homogeneity was lower for unmutated CLL/MBL (14%) than mutated CLL/MBL (27%). The BCL6 gene, which is also mutated during the canonical somatic hypermutation process, showed similar results with a greater degree of intraclonal variation in unmutated CLL/MBL. The results demonstrate that intraclonal variation is a frequent occurrence in both MBL and CLL particularly when non-immunoglobulin genes are also considered. Clonal heterogeneity is either independent of, or inversely related to, the immunoglobulin mutation status demonstrating that both mutated and unmutated CLL have undergone (or are continuing to undergo) somatic hypermutation. The mechanisms of disease progression in MBL/CLL are clearly biologically distinct from MGUS/Myeloma and this data provides strong evidence for an antigen-driven selection process in CLL. Disease progression in CLL may therefore be the result of continued activity of the somatic hypermutation machinery, demonstrated by AID expression in some patients. Coupled with a selective pressure to maintain the immunoglobulin gene this process may result in the selection of CLL clones with transforming mutations in non-immunoglobulin genes.
Antibody-drug conjugates (ADCs), antibodies linked to potent cytotoxic drugs via specialized chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to ...neoplastic cells while reducing side effects. We have previously shown that ADCs targeted to CD79b are highly effective in xenograft models of non-Hodgkin's lymphoma. Here we report the development of an ADC consisting of a humanized anti-CD79b antibody (hu-anti-CD79b) conjugated to monomethylauristatin E (MMAE) through engineered cysteines (THIOMABS) by a maleimidocaproyl-valinecitrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker (hu-anti-CD79b-thioMAb-MC-vc-PAB-MMAE) that is designed to be cleaved by cathepsins. To determine the potential of this ADC, hu-anti-CD79b-thioMAb-MC-vc-PAB-MMAE (referred to as anti-CD79b-vcMMAE henceforth), as a therapeutic for NHL we interrogated its potency across a large panel of NHL cell lines. Strikingly, anti-CD79b-vcMMAE has very potent activity across a large panel of NHL cell lines in vitro with 68% (23 out of 34) cell lines having greater than 50% reduction in cell viability. Quantitative FACS across the cell line panel revealed that of the 11 insensitive cell lines, 9 had negligible surface CD79b, suggesting a threshold effect in that below a specific level of antigen on the cell surface resulted in cells being insensitive to anti-CD79b-vcMMAE. Within the sensitive cell lines, there was not a direct correlation per se with anti-CD79b-vcMMAE IC50 values and cell surface expression levels and this prompted us to investigate other potential molecular parameters. Gene expression profiling and gene set enrichment analysis revealed that genes predominantly involved in antigen processing and presentation and genes induced by IFN-gamma were significantly enriched in the less sensitive cell lines to CD79b-vcMMAE. Classifying our NHL cell lines as GCB or ABC subtypes by gene expression revealed that both ABC and GCB were responsive. In addition, the activity of anti-CD79b-vcMMAE was very potent in p53 mutant as well as p53 wild-type cell lines. Since the pre-clinical evidence suggests that anti-CD79b-vcMMAE will be a very promising drug candidate for NHL and we have established that cell surface expression is perhaps the best predictor of response, we wished to determine the prevalence of expression of CD79b on the cell surface of primary human lymphoma and CLL samples to estimate a patient population that may gain benefit. Strikingly, CD79b was detected in all cases of CLL, MZL, HCL, DLBCL, FL, and MCL. Furthermore, CD79b expression was detected in all cases that had relapsed from prior chemotherapy regimens, highlighting the clinical relevance of this target and potential therapeutic utility of anti-CD79b-vcMMAE. To assess the potential of anti-CD79b-vcMMAE in vivo we compared its efficacy to R-CHOP in three xenograft models of NHL. In all three models, a single dose of anti-CD79b-vcMMAE resulted in complete sustained tumor remission and was more effective than R-CHOP. These data suggest that anti-CD79b-vcMMAE could be broadly efficacious as a treatment for NHL.
PDF
