Daratumumab, a Novel Human Anti-CD38 Monoclonal Antibody for the Treatment of Chronic Lymphocytic Leukemia and B-Cell Non–Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3935-3935 ◽  
Author(s):  
Alba Matas-Céspedes ◽  
Anna Vidal-Crespo ◽  
Vanina Rodriguez ◽  
Gael Roue ◽  
Elias Campo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Lymphocytic Leukemia ◽  
Effector Cells ◽  
Non Hodgkin Lymphoma ◽  
Cd38 Expression

Abstract Abstract 3935 Daratumumab (DARA) is a human CD38 antibody with broad-spectrum killing activity. DARA induces killing of tumor cells, mainly via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) (de Weers M, J Immunol 2011). DARA is currently being evaluated in phase I/II clinical trials in patients with multiple myeloma. In these clinical studies the adverse events have been manageable and marked reductions in paraprotein and bone marrow plasma cells have been observed. In the present study, we have analyzed the potential of targeting CD38 using DARA in two types of B-cell non-Hodgkin lymphoma (B-NHL) (follicular lymphoma (FL) and mantle cell lymphoma (MCL)), and in chronic lymphocytic leukemia (CLL). Flow cytometry analysis demonstrated that MCL and CLL tumor cells show heterogeneous expression of CD38, while FL cells showed invariable high CD38 levels. CD38 has attracted special attention in CLL where high CD38 expression is a marker of bad prognosis (Hamblin et al, Blood 1999 and 2002) and is expressed preferentially in the proliferating fraction of the tumor (Damle RN, Blood 2007). In addition, we have recently shown that high CD38 expression in MCL was associated with resistance to the proteasome inhibitor bortezomib (Pérez-Galán P, Blood 2011). Here, we tested the cytotoxic activity of DARA in tumor cell lines and in fresh tumor cells obtained from patients. DARA did not induce CDC in MCL cell lines (MINO, REC, HBL2, JEKO), irrespective of CD38 expression levels. Also, FL cell lines (WSU-FSCCL, RL) expressing relatively high CD38 levels were insensitive to DARA-induced CDC. This low CDC was associated with high expression of the complement inhibitors CD55 and CD59. In addition, the number of CD38 molecules per cell in these MCL and FL cell lines was lower than that found on the CDC-sensitive Daudi Burkitt lymphoma cell line, suggesting a threshold for CD38-targeted CDC lysis. In the presence of PBMC effector cells obtained from healthy donors, DARA showed significant levels of ADCC in cells from MCL, FL and CLL. In CLL primary cases (n=8) tested, DARA (14–43% lysis) was generally superior or at least equally effective (mean+/−SD=28,78 +/− 9,78) in inducing ADCC as compared to the anti-CD20 antibodies ofatumumab (mean+/−SD=21,35 +/− 15,71) and rituximab (mean+/−SD=29,30 +/− 15,90). The immunomodulatory agent lenalidomide shows considerable single agent activity in MCL, FL and CLL. Interestingly, it has been shown that lenalidomide may be able to increase ADCC, probably via activation of NK cells. We therefore tested whether the combination of lenalidomide and DARA could enhance ADCC. Noteworthy, DARA-induced ADCC in MCL, FL cell lines and primary CLL cells was significantly (p<0,05) enhanced when effector cells were pretreated with the immunomodulatory agent lenalidomide (3 μM, 72 h) with DARA doses ranging from 0,01–1 μg/ml. Finally, CD38 is important for cell migration and adhesion, especially for CXCR4-CXCL12-induced migration of tumor cells (Vaisitti et al, Leukemia 2010). Our preliminary results suggest that in the CLL subtype with high CD38 and more migratory capacity DARA (10–30 μg/ml) inhibits CXCL12/SDF1α mediated migration up to 70%. These results are of high importance because inhibition of tumor cell trafficking to tissue sites as bone marrow and lymph nodes, may be clinically relevant, as increasing evidence indicates that tumor–microenvironment interactions may play an important role in drug resistance and contribute to clinical failures. We are currently validating this in vitro results in a CLL mouse model. Taken together, these results suggest that DARA may be a promising therapeutic agent both for MCL, FL and CLL, in which DARA exerts its effects mainly via ADCC and for CLL also via inhibition of migration of tumor cells. Interestingly, the cytotoxic activity of DARA by ADCC could be further augmented by addition of lenalidomide in these three models. Disclosures: Lammerts van Bueren: Genmab: Employment. Bakker:genmab: Employment. Parren:genmab: Employment. Perez-Galan:Genmab: Research Funding.

An Fc-Engineered Humanized Anti-CD40 Monoclonal Antibody, XmAb5485, Exhibits Potent Activity in Vitro and in Vivo against Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 881-881 ◽  
Author(s):  
Eugene A. Zhukovsky ◽  
Holly Horton ◽  
Matthias Peipp ◽  
Erik Pong ◽  
Matthew Bernett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Lymphocytic Leukemia ◽  
Non Hodgkin Lymphoma

Abstract CD40, a transmembrane glycoprotein belonging to the tumor necrosis factor receptor family, is an attractive target for cancers of lymphoid origin since it is expressed on most mature B-cell malignancies, some early B-cell acute lymphocytic leukemias, and multiple myeloma. Finding efficient therapies for multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and rituximab-refractory Non-Hodgkin Lymphoma (NHL) represents an unmet need. Several anti-CD40 antibodies, both agonistic and antagonistic, have demonstrated objective responses in early clinical NHL trials and thus validated this antigen as a target for lymphoproliferative diseases. Here we present the characterization of a novel Fc-engineered and humanized anti-CD40 antibody, XmAb®5485, that was generated using our XmAb antibody engineering technology. This antibody is highly cytotoxic against lymphoma, leukemia and multiple myeloma cell lines as well as primary cancer cells. XmAb5485 is characterized by: i) increased affinity for Fc gamma receptors (FcgR), ii) improved effector function, and iii) significantly increased antitumor potency. We investigated several direct and indirect (Fc-mediated) mechanisms of antibody-mediated cytotoxicity in vitro. The potency (EC50) of XmAb5485 in antibody-dependent cell-mediated cytotoxicity (ADCC) increased up to 150-fold relative to the native non Fc-engineered version (anti-CD40 IgG1) of the antibody in a screen of Burkitt’s lymphoma [BL], CLL and MM-derived cell lines. In the same cell lines, ADCC potency and maximal efficacy (% lysis) of XmAb5485 were also superior to that of rituximab: 74- and 1.3-fold higher in CLL, 12.5- and 1.4-fold higher in BL, and 190- and 1.9-fold higher in MM. In a MM cell line with low density of CD40 expression (~3500 per cell) XmAb5485 facilitated efficient ADCC whereas anti-CD40 IgG1 was virtually ineffective. Furthermore, using a BL cell line (Ramos) XmAb5485 displayed antibody-dependent cellular phagocytosis (ADCP) with potency and efficacy increased relative to rituximab (15- and 1.6-fold) and anti-CD40 IgG1 (5- and 1.2-fold). XmAb5485 also exhibited anti-proliferative apoptotic activity that was similar to that of rituximab. Ex vivo, XmAb5485 mediated potent ADCC of multiple primary patient-derived CLL, MCL, and plasma cell leukemia (PCL, an aggressive form of MM) cells, with substantially increased potency and efficacy relative to rituximab; in contrast, anti-CD40 IgG1 displayed minimal or no activity in these primary tumor cells. In vivo, in an established large (210–350 mm3) sc Ramos tumor xenograft model, 6 mg/kg XmAb5485 cured 80% of mice of detectable tumors and displayed statistically significant superiority over anti-CD40 IgG1. In contrast, only 7% of animals in the rituximab cohort were cured. In summary, our data suggest that XmAb5485, an anti-CD40 Fc variant antibody engineered for increased effector function, is a promising next-generation immunotherapeutic for leukemias, lymphomas, and multiple myeloma.

scholarly journals FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 338-343 ◽  
Author(s):  
Xing Du ◽  
Satoshi Nagata ◽  
Tomoko Ise ◽  
Maryalice Stetler-Stevenson ◽  
Ira Pastan
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Hairy Cell Leukemia ◽  
Surface Membrane ◽  
Lymphocytic Leukemia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Non Hodgkin Lymphoma

FCRL1 (Fc receptor–like 1) is a cell-surface membrane protein belonging to FCRL family and is preferentially expressed on B cells. To evaluate FcRL1 as an immunotherapy target for B-cell malignancies, we prepared anti-FCRL1 mAbs without cross-reactivity to other FCRL family proteins and analyzed FCRL1 protein expression on malignant cells from patients and on B-cell lines. Frequent FCRL1 expression was observed by flow cytometry on 12 B-cell non-Hodgkin lymphoma (B-NHL) cell lines and many patient samples: 12 of 14 chronic lymphocytic leukemia (CLL), 7 of 7 follicular lymphoma (FL), 13 of 17 hairy cell leukemia (HCL), and 2 of 3 mantle cell lymphoma (MCL). Two recombinant immunotoxins, E3(Fv)-PE38 and E9(Fv)-PE38, were constructed. Both immunotoxins bound to FCRL1-positive cells with similar affinities (3.4 and 3.2 nM) and were cytotoxic to cell lines, but E9(Fv)-PE38 was 4- to 20-fold more cytotoxic than E3(Fv)-PE38. The concentrations that inhibited response by 50% (IC50s) of E9(Fv)-PE38 on 11 different FCRL1-positive cell lines ranged from 1.0 ng/mL to 90 ng/mL and correlated with the FCRL1 expression levels. Our results suggest that anti-FCRL1 immunotoxin E9(Fv)-PE38 exhibits remarkably specific cytotoxicity and merits further evaluation for the treatment of FCRL1-positive malignancies, including CLL, HCL, FL, MCL, and other B-NHL.

Unrelated Donor Marrow Transplantation for B-Cell Chronic Lymphocytic Leukemia After Using Myeloablative Conditioning: Results From the Center for International Blood and Marrow Transplant Research

2005 ◽  
Vol 23 (24) ◽  
pp. 5788-5794 ◽  
Author(s):  
Steven Z. Pavletic ◽  
Issa F. Khouri ◽  
Michael Haagenson ◽  
Roberta J. King ◽  
Philip J. Bierman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Cell Chronic Lymphocytic Leukemia

Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

scholarly journals Emergence of a B-cell lymphoblastic lymphoma in a patient with B-cell chronic lymphocytic leukemia: evidence for the single-cell origin of the two tumors

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 797-804
Author(s):  
V Pistoia ◽  
S Roncella ◽  
PF Di Celle ◽  
M Sessarego ◽  
G Cutrona ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Peripheral Blood ◽  
Chromosomal Abnormalities ◽  
Cell Clone ◽  
Lymphoblastic Lymphoma ◽  
Lymphocytic Leukemia ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Chain Gene

A patient is described who presented with a chronic lymphocytic leukemia (CLL) and later developed a lymphoblastic lymphoma. The cells from the CLL were typical mature B lymphocytes as could be assessed by morphologic, cytochemical, and surface marker analyses. The cells from the lymphoblastic lymphoma were immature B cells that expressed CD10, CD20, and HLA-DR markers, but not surface Ig or cytoplasmic mu chains, and were negative for terminal deoxynucleotidyl transferase (TdT). The cells of two continuous cell lines, obtained from the bone marrow and the peripheral blood of the patient, had the same phenotype as the lymphoblastic lymphoma cells, did not contain the Epstein-Barr virus genome, and displayed malignant features in vitro, including the capacity to form colonies in agar. The two cell lines also shared identical chromosomal abnormalities, a finding which suggests that they derived from the same malignant cell already present in vivo. Such chromosomal abnormalities were not seen in the karyotype of the peripheral blood cells at the onset of the disease. Analysis of the Ig heavy chain genes using a DJ-specific probe showed the very same monoclonal rearrangement in the cells from the B-CLL, the lymphoblastic lymphoma and the two cell lines, thus demonstrating their common clonal origin. By contrast, a monoclonal rearrangement of the lambda chain gene locus was found in the B-CLL cells only, a finding consistent with their exclusive capacity to express surface IgM lambda. This patient represents a rare case in whom a chronic lymphoproliferative disorder with mature malignant cells transforms into a lymphoblastic lymphoma characterized by cells frozen at a very early maturational stage. The possible mechanisms leading to such transformation within the same cell clone are discussed.

scholarly journals COMPARISON OF CHROMOSOMAL REARRANGEMENTS IN BONE MARROW CELLS AND BLAST TRANSFORMED B-CELLS IN RELAPSE OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA/ SMALL LYMPHOCYTIC LYMPHOMA

2017 ◽  
Vol 39 (2) ◽  
pp. 141-144
Author(s):  
S V Andreieva ◽  
K V Korets ◽  
O E Ruzhinska ◽  
I M Skorokhod ◽  
O G Alkhimova
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Rearrangements ◽  
Lymphocytic Leukemia ◽  
Banding Technique ◽  
Small Lymphocytic Lymphoma ◽  
Detection Frequency ◽  
Cell Chronic Lymphocytic Leukemia

Aim: The genetic mechanisms of resistance to chemotherapy in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) are not clear. We aimed to determine the peculiarities of abnormal karyotype formation in bone marrow (BM) cells and peripheral blood (PB) blast transformed B-cells in relapse of B-CLL/SLL. Materials and Methods: Cytogenetic GTG banding technique and molecular cytogenetic in interphase cells (i-FISH) studies of BM cells and PB blast transformed B-lymphocytes were performed in 14 patients (10 males and 4 females) with B-CLL/SLL. Results: The results of karyotyping BM and PB cells revealed the heterogeneity of cytogenetic abnormalities in combined single nosological group of B-CLL/SLL. In PB B-cells, chromosome abnormalities related to a poor prognosis group were registered 2.5 times more often than in BM cells. Additional near tetraploid clones that occurred in 57.1% cases were the peculiar feature of BM cell karyotypes. Chromosomal rearrangements characteristic of the group of adverse cytogenetic prognosis were revealed in all cases from which in 2 cases by karyotyping BM cells, in 6 cases in PB B-cells and in 8 cases by the i-FISH method in BM cells, i.e. their detection frequency was 3 times higher in PB B-cells and 4 times higher when analyzing by i-FISH in BM cells. Conclusions: Mismatch in abnormal karyotypes in BM and PB B-cells by the presence of quantitative and structural chromosomal rearrangements may be indicative of simultaneous and independent processes of abnormal clone formation in the lymph nodes and BM hematopoietic cells. Accumulation the information about previously unidentified chromosomal rearrangements in relapse of the disease may help to understand the ways of resistance formation to chemotherapy.

scholarly journals Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms

2021 ◽  
Vol 12 ◽  
Author(s):  
Erwan Dumontet ◽  
Stéphane J. C. Mancini ◽  
Karin Tarte
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Therapeutic Option ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Niche Adaptation ◽  
Functional Features

B-cell non-Hodgkin lymphoma (B-NHL) evolution and treatment are complicated by a high prevalence of relapses primarily due to the ability of malignant B cells to interact with tumor-supportive lymph node (LN) and bone marrow (BM) microenvironments. In particular, progressive alterations of BM stromal cells sustain the survival, proliferation, and drug resistance of tumor B cells during diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The current review describes how the crosstalk between BM stromal cells and lymphoma tumor cells triggers the establishment of the tumor supportive niche. DLBCL, FL, and CLL display distinct patterns of BM involvement, but in each case tumor-infiltrating stromal cells, corresponding to cancer-associated fibroblasts, exhibit specific phenotypic and functional features promoting the recruitment, adhesion, and survival of tumor cells. Tumor cell-derived extracellular vesicles have been recently proposed as playing a central role in triggering initial induction of tumor-supportive niches, notably within the BM. Finally, the disruption of the BM stroma reprogramming emerges as a promising therapeutic option in B-cell lymphomas. Targeting the crosstalk between BM stromal cells and malignant B cells, either through the inhibition of stroma-derived B-cell growth factors or through the mobilization of clonal B cells outside their supportive BM niche, should in particular be further evaluated as a way to avoid relapses by abrogating resistance niches.

Cytokine-Release Syndrome in Patients With B-Cell Chronic Lymphocytic Leukemia and High Lymphocyte Counts After Treatment With an Anti-CD20 Monoclonal Antibody (Rituximab, IDEC-C2B8)

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2217-2224 ◽  
Author(s):  
U. Winkler ◽  
M. Jensen ◽  
O. Manzke ◽  
H. Schulz ◽  
V. Diehl ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Tumor Cells ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Anti Cd20 ◽  
Cell Chronic Lymphocytic Leukemia

Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin’s lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 × 109/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 × 109/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 × 109/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 × 109/L peripheral tumor cells (P= .0017). Due to massive side effects in the first patient treated with 375 mg/m2 in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m2 dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 × 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.

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