scholarly journals Targeted delivery of interferon-alpha via fusion to anti-CD20 results in potent antitumor activity against B-cell lymphoma

Blood ◽  
2010 ◽  
Vol 115 (14) ◽  
pp. 2864-2871 ◽  
Author(s):  
Caiyun Xuan ◽  
Kristopher K. Steward ◽  
John M. Timmerman ◽  
Sherie L. Morrison
Keyword(s):  
B Cell ◽  
Interferon Alpha ◽  
Targeted Delivery ◽  
Fusion Proteins ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Type I ◽  
B Cell Malignancies ◽  
Anti Cd20 ◽  
Tumor Eradication

Abstract The anti-CD20 antibody rituximab has substantially improved outcomes in patients with B-cell non-Hodgkin lymphomas. However, many patients are not cured by rituximab-based therapies, and overcoming de novo or acquired rituximab resistance remains an important challenge to successful treatment of B-cell malignancies. Interferon-alpha (IFNα) has potent immunostimulatory properties and antiproliferative effects against some B-cell cancers, but its clinical utility is limited by systemic toxicity. To improve the efficacy of CD20-targeted therapy, we constructed fusion proteins consisting of anti-CD20 and murine or human IFNα. Fusion proteins had reduced IFNα activity in vitro compared with native IFNα, but CD20 targeting permitted efficient antiproliferative and proapoptotic effects against an aggressive rituximab-insensitive human CD20+ murine lymphoma (38C13-huCD20) and a human B-cell lymphoma (Daudi). In vivo efficacy was demonstrated against established 38C13-huCD20 grown in syngeneic immunocompetent mice and large, established Daudi xenografts grown in nude mice. Optimal tumor eradication required CD20 targeting, with 87% of mice cured of rituximab-insensitive tumors. Gene knockdown studies revealed that tumor eradication required expression of type I IFN receptors on the tumor cell surface. Targeting type I IFNs to sites of B-cell lymphoma by fusion to anti-CD20 antibodies represents a potentially useful strategy for treatment of B-cell malignancies.

scholarly journals Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5191-5201 ◽  
Author(s):  
Stephen A. Beers ◽  
Ruth R. French ◽  
H. T. Claude Chan ◽  
Sean H. Lim ◽  
Timothy C. Jarrett ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Type I ◽  
Type Ii ◽  
Antigenic Modulation ◽  
Lymphatic Leukemia ◽  
Human B Cells ◽  
Anti Cd20

Abstract Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcγ receptor–expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

Differential Patterns of Gene Expression and CD20 Localisation by the Type II Anti-CD20 Antibody Obinutuzumab (GA101) Compared with the Type I Antibody Rituximab Suggests Binding to Functionally Distinct CD20 Subpopulations on B-Cell Lymphoma Cell Lines,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3721-3721
Author(s):  
Gerhard Niederfellner ◽  
Olaf Mundigl ◽  
Alexander Lifke ◽  
Andreas Franke ◽  
Ute Baer ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mechanisms Of Action ◽  
Type I ◽  
Type Ii ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 3721 The anti-CD20 antibody rituximab has become central to the treatment of B-cell malignancies over the last decade. Recently, it has been shown that anti-CD20 antibodies can be divided into two types based on their mechanisms of action on B cells. Rituximab is a type I antibody that redistributes CD20 into lipid rafts and promotes complement-dependent cytotoxicity (CDC), while the type II, glycoengineered antibody GA101 has lower CDC activity but higher antibody-dependent cellular cytotoxicity and direct cell death activity. In preclinical studies GA101 was superior to rituximab in B-cell killing in vitro, depletion of B cells from whole blood, and inhibition of tumour cell growth in lymphoma xenograft models. GA101 is currently being evaluated in Phase II/III trials, including comparative studies with rituximab. To investigate the differences in direct effects of GA101 and rituximab on B-cell lymphoma signaling, we have analysed the effects of antibody binding on gene expression in different B-cell lines using a GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix). Rituximab and GA101 rapidly induced gene expression changes in SUDHL4 and Z138 cells, including regulation of genes associated with B-cell-receptor activation such as EGR2, BCL2A1, RGS1 and NAB2. The effects on gene expression differed markedly between different cell lines and between the two antibodies. SUDHL4 cells showed pronounced changes in the gene expression pattern to rituximab treatment, while Z138 cells, which represent a different B-cell stage, showed less pronounced changes in gene expression. The reverse was true for GA101, suggesting not only that the signaling mediated by CD20 differs in different cell lines, but also that in a given cell line the two types of antibodies bind CD20 molecules with different signaling capacity. For each cell line, gene expression induced by other type I antibodies (LT20, 2H7, MEM97) was more like rituximab and that induced by other type II antibodies (H299/B1, BH20) was more like GA101 in terms of the number of genes regulated and the magnitude of changes in expression. Unbiased hierarchical clustering analysis of gene expression in SUDHL4 could discriminate type I from type II antibodies, confirming that the two classes of antibody recognised CD20 complexes with inherently different signalling capacities. By confocal and time-lapse microscopy using different fluorophores, rituximab and GA101 localised to different compartments on the membrane of lymphoma cells. GA101/CD20 complexes were relatively static and predominantly associated with sites of cell–cell contact, while rituximab/CD20 complexes were highly dynamic and predominantly outside areas of contact. These findings suggest that type II antibodies such as GA101 bind distinct subpopulations of CD20 compared with type I antibodies such as rituximab, accounting for the differences in mechanisms of action and anti-tumour activity between these antibodies. Disclosures: Niederfellner: Roche: Employment. Mundigl:Roche: Employment. Lifke:Roche: Employment. Franke:Roche: Employment. Baer:Roche: Employment. Burtscher:Roche: Employment. Maisel:Roche: Employment. Belousov:Roche: Employment. Weidner:Roche: Employment. Umana:Roche: Employment, Patents & Royalties. Klein:Roche: Employment, Equity Ownership, Patents & Royalties.

In Vivo Eradication of a Rituximab-Resistant Human CD20+ B Cell Lymphoma by Rituximab-CpG Oligodeoxynucleotide Conjugate Is Mediated by Natural Killer Cells and Complement.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 723-723
Author(s):  
David J Betting ◽  
Kamran Kafi ◽  
Reiko E Yamada ◽  
Kristopher K Steward ◽  
Tove Olafsen ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
B Cell ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Killer Cells ◽  
Anti Cd20 ◽  
Tumor Eradication

Abstract Abstract 723 The anti-CD20 monoclonal antibody rituximab exerts its anti-tumor effects against B cell non-Hodgkin's lymphoma (NHL) via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and apoptosis induction. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG ODN) are potent activators of ADCC and T cell immunity, and have been studied for anti-NHL effects when administered by systemic or intratumoral (i.t.) routes. We have used an aggressive human CD20-expressing syngeneic murine B cell lymphoma (38C13-huCD20) that is resistant to single agent rituximab to study techniques for improving antibody efficacy. We recently reported that combining rituximab with i.t. (but not systemic) CpG promotes eradication of 7-day established rituximab-resistant 38C13-huCD20 lymphoma from 42% of mice (D. Betting et al, J. Immunotherapy 2009). Six doses of i.t. CpG (50 μg days 7, 8, and 9 and 25 μg days 11, 13, and 15) were required to achieve tumor eradication in this setting. Both natural killer cells and complement participated in the cure of tumors by rituximab plus i.t CpG, by increasing tumor cell sensitivity to ADCC and complement lysis, and by augmenting the cytotoxicity of ADCC effectors. To overcome the need for repeated i.t. injections, eliminate the need for an accessible tumor site, and allow for more direct targeting of CpG to tumor cells, we chemically linked CpG to rituximab using a cleavable linker. The conjugate retained both antibody binding activity to human CD20 and potent CpG biologic activity, demonstrated via upregulation of costimulatory molecules on cultured lymphoma cells and activation of bone marrow-derived dendritic cells. Just 2 injections of rituximab-CpG conjugate (containing 50 μg CpG, days 7 and 9) achieved eradication of 7-day established tumors from 100% of mice, while injection of rituximab-control ODN or trastuzumab-CpG conjugates had no therapeutic effects. Treatment with equivalent doses of rituximab plus i.v. or i.t. CpG prolonged survival slightly, but did not result in tumor eradication. In vivo depletion of NK cells or complement nearly eliminated tumor eradication effects. In contrast, in vivo depletion of macrophages, or CD4+ or CD8+ T cells had no significant effects on tumor eradication by rituximab-CpG, indicating that adaptive T cell immunity did not contribute to elimination of tumor during rituximab-CpG conjugate therapy. As CpGs can stimulate leukocytes to secrete alpha interferon (αaIFN), which can inhibit the growth of B cell lymphomas, we sought to determine whether αaIFN played a significant role in tumor control after rituximab-CpG therapy. 38C13-huCD20 tumor cells rendered deficient in αaIFN receptor (IFNAR) by lentiviral transduction with shRNA were nearly as sensitive to rituximab-CpG as wild-type IFNAR+ 38C13-huCD20 cells, indicating no role for direct αaIFN tumor cytotoxicity in eradication of 38C13-huCD20. In conclusion, natural killer cells and complement, but not T cells, macrophages, or αaIFN, are critical to the efficacy of rituximab-CpG conjugate in efficiently eradicating an established human CD20+ B cell lymphoma that is fully resistant to single-agent rituximab. Further pre-clinical studies of anti-CD20-CpG conjugates against B cell lymphomas are thus warranted. Anti-CD20-CpG conjugates may represent a novel treatment modality for human NHL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Imaging the mechanisms of anti-CD20 therapy in vivo uncovers spatiotemporal bottlenecks in antibody-dependent phagocytosis

2021 ◽  
Vol 7 (8) ◽  
pp. eabd6167
Author(s):  
Capucine L. Grandjean ◽  
Zacarias Garcia ◽  
Fabrice Lemaître ◽  
Béatrice Bréart ◽  
Philippe Bousso
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Critical Path ◽  
B Cell Lymphoma ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Fluorescent Reporter ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Partial Depletion

Anti-CD20 antibody (mAb) represents an effective strategy for the treatment of B cell malignancies, possibly involving complement activity, antibody-dependent cellular cytotoxicity and phagocytosis (ADP). While ADP by Kupffer cells deplete circulating tumors, mechanisms targeting non-circulating tumors remain unclear. Using intravital imaging in a model of B cell lymphoma, we establish here the dominance and limitations of ADP in the bone marrow (BM). We found that tumor cells were stably residing in the BM with little evidence for recirculation. To elucidate the mechanism of depletion, we designed a dual fluorescent reporter to visualize phagocytosis and apoptosis. ADP by BM-associated macrophages was the primary mode of tumor elimination but was no longer active after one hour, resulting in partial depletion. Moreover, macrophages were present at low density in tumor-rich regions, targeting only neighboring tumors. Overcoming spatiotemporal bottlenecks in tumor-targeting Ab therapy thus represents a critical path towards the design of optimized therapies.

scholarly journals Correlations between baseline 18F-FDG PET tumour parameters and circulating DNA in diffuse large B cell lymphoma and Hodgkin lymphoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Pierre Decazes ◽  
Vincent Camus ◽  
Elodie Bohers ◽  
Pierre-Julien Viailly ◽  
Hervé Tilly ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Fdg Pet ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Circulating Dna ◽  
Tumour Burden ◽  
B Cell Malignancies ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background 18F-FDG PET/CT is a standard for many B cell malignancies, while blood DNA measurements are emerging tools. Our objective was to evaluate the correlations between baseline PET parameters and circulating DNA in diffuse large B cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). Methods Twenty-seven DLBCL and forty-eight cHL were prospectively included. Twelve PET parameters were analysed. Spearman’s correlations were used to compare PET parameters each other and to circulating cell-free DNA ([cfDNA]) and circulating tumour DNA ([ctDNA]). p values were controlled by Benjamini–Hochberg correction. Results Among the PET parameters, three different clusters for tumour burden, fragmentation/massiveness and dispersion parameters were observed. Some PET parameters were significantly correlated with blood DNA parameters, including the total metabolic tumour surface (TMTS) describing the tumour–host interface (e.g. ρ = 0.81 p < 0.001 for [ctDNA] of DLBLC), the tumour median distance between the periphery and the centroid (medPCD) describing the tumour’s massiveness (e.g. ρ = 0.81 p < 0.001 for [ctDNA] of DLBLC) and the volume of the bounding box including tumours (TumBB) describing the disease’s dispersion (e.g. ρ = 0.83 p < 0.001 for [ctDNA] of DLBLC). Conclusions Some PET parameters describing tumour burden, fragmentation/massiveness and dispersion are significantly correlated with circulating DNA parameters of DLBCL and cHL patients. These results could help to understand the pathophysiology of B cell malignancies.

Phase 3 trial (GCT3013-05) of epcoritamab versus standard of care in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS7569-TPS7569
Author(s):  
Catherine Thieblemont ◽  
Michael Roost Clausen ◽  
Anna Sureda Balari ◽  
Pier Luigi Zinzani ◽  
Christopher Fox ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Group Performance ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Standard Of Care ◽  
Phase 3 ◽  
Cycle Number ◽  
Car T ◽  
Anti Cd20

TPS7569 Background: Patients (pts) with DLBCL who are refractory to/or have relapsed (R/R) after treatment with chemotherapy and anti-CD20 monoclonal antibody (mAb) have a poor prognosis. There is a need for new treatment options to improve outcomes. Epcoritamab, a novel subcutaneous (SC) bispecific antibody, binds to CD3 on T-lymphocytes and CD20 on B-cell non-Hodgkin lymphoma (NHL) cells to induce potent and selective killing of malignant CD20+ B-cells. In an ongoing phase 1/2 dose-escalation trial in heavily pretreated pts with B-cell NHL (N = 68), epcoritamab demonstrated a tolerable safety profile and substantial single-agent anti-tumor activity, with a complete response (CR) rate of 55% and an overall response rate (ORR) of 91% in pts with R/R DLBCL (at ≥48 mg doses; n = 12) (NCT04663347; Hutchings, ASH, 2020). Furthermore, all 4 evaluable R/R DLBCL pts previously treated with chimeric antigen receptor T-cell (CAR-T) therapy achieved an objective response with 2 achieving CR. These encouraging data support the potential for epcoritamab to improve clinical outcomes in pts with R/R DLBCL. Here we describe the phase 3 trial of epcoritamab versus standard of care (SOC) treatments in pts with R/R DLBCL (NCT04628494). Methods: GCT3013-05 is a randomized, open-label, worldwide, multicenter, phase 3 study designed to evaluate the efficacy of epcoritamab versus investigator’s choice of SOC with R-GemOx (rituximab, gemcitabine, oxaliplatin) or BR (bendamustine, rituximab) in adults with R/R disease of one the following CD20+ B-cell NHL histologies: I) DLBCL, not otherwise specified including de novo DLBCL or DLBCL histologically transformed from follicular lymphoma; II) “double-hit” or “triple-hit” DLBCL (high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations); or III) follicular lymphoma grade 3B. Other key eligibility criteria include: ≥1 line of prior chemotherapy that included treatment with an anti-CD20 mAb, Eastern Cooperative Oncology Group performance status 0–2, and prior failure of/ineligibility for autologous stem cell transplantation. Prior CAR-T therapy is allowed. A total of 480 pts will be randomized 1:1 to receive either SC epcoritamab at the recommended phase 2 dose (28-day cycles; weekly, biweekly, or monthly schedule depending on cycle number) until disease progression or unacceptable toxicity; or up to 4 cycles of biweekly treatment with intravenous (IV) R-GemOx (8 doses); or up to 6 cycles of IV BR (6 doses; dosing every 3 weeks). The primary endpoint is overall survival. Key secondary endpoints include progression-free survival, ORR, duration of response, time to response, and safety. The study is currently enrolling in Australia, Belgium, Denmark, France, Spain, and will open for enrollment in additional countries. Clinical trial information: NCT04628494.

scholarly journals Construction of Anti-CD20 Single-Chain Antibody-CD28-CD137-TCRζ Recombinant Genetic Modified T Cells and its Treatment Effect on B Cell Lymphoma

2015 ◽  
Vol 21 ◽  
pp. 2110-2115 ◽  
Author(s):  
Fei Chen ◽  
Chuming Fan ◽  
Xuezhong Gu ◽  
Haixi Zhang ◽  
Qian Liu ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Treatment Effect ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Anti Cd20

Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin's B-cell lymphoma

1997 ◽  
Vol 25 (2) ◽  
pp. 705-708 ◽  
Author(s):  
D. R. Anderson ◽  
A. Grillo-López ◽  
C. Varns ◽  
K. S. Chambers ◽  
N. Hanna
Keyword(s):  
Cancer Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Anti Cancer ◽  
Cd20 Antibody ◽  
Anti Cd20

scholarly journals Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies

Blood ◽  
2019 ◽  
Vol 133 (16) ◽  
pp. 1742-1752 ◽  
Author(s):  
Andres Forero-Torres ◽  
Radhakrishnan Ramchandren ◽  
Abdulraheem Yacoub ◽  
Michael S. Wertheim ◽  
William J. Edenfield ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
B Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Janus Kinase ◽  
B Cell Malignancies ◽  
Once Daily ◽  
Grade 3

Abstract This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (&gt;2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment (∼9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861.

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