scholarly journals Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicity

Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4393-4402 ◽  
Author(s):  
Ekkehard Mössner ◽  
Peter Brünker ◽  
Samuel Moser ◽  
Ursula Püntener ◽  
Carla Schmidt ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Effector Cell ◽  
Antibody Therapy ◽  
Cell Depletion ◽  
Type Ii ◽  
B Cell Depletion ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Cd20 Antibody

AbstractCD20 is an important target for the treatment of B-cell malignancies, including non-Hodgkin lymphoma as well as autoimmune disorders. B-cell depletion therapy using monoclonal antibodies against CD20, such as rituximab, has revolutionized the treatment of these disorders, greatly improving overall survival in patients. Here, we report the development of GA101 as the first Fc-engineered, type II humanized IgG1 antibody against CD20. Relative to rituximab, GA101 has increased direct and immune effector cell-mediated cytotoxicity and exhibits superior activity in cellular assays and whole blood B-cell depletion assays. In human lymphoma xenograft models, GA101 exhibits superior antitumor activity, resulting in the induction of complete tumor remission and increased overall survival. In nonhuman primates, GA101 demonstrates superior B cell–depleting activity in lymphoid tissue, including in lymph nodes and spleen. Taken together, these results provide compelling evidence for the development of GA101 as a promising new therapy for the treatment of B-cell disorders.

GA101, a Novel Humanized Type II CD20 Antibody with Glycoengineered Fc and Enhanced Cell Death Induction, Exhibits Superior Anti-Tumor Efficacy and Superior Tissue B Cell Depletion In Vivo.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2348-2348 ◽  
Author(s):  
Pablo Umana ◽  
Moessner Ekkehard ◽  
Bruenker Peter ◽  
Klingner Gabriele ◽  
Puentener Ursula ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Cell Depletion ◽  
Type Ii ◽  
B Cell Depletion ◽  
Cynomolgus Monkeys ◽  
High Affinity ◽  
Cd20 Antibody

Abstract GA101 is a novel monoclonal antibody of IgG1 type which binds with high affinity and selectivity to the extracellular domain of the human CD20 antigen on B cells. In contrast to rituximab which is a chimeric antibody and recognizes a type I epitope, GA101 is humanized and recognizes a type II epitope which is also localized in the extracellular loop of CD20. The recognition of the type II epitope together with a modification of the elbow hinge region results in enhanced direct non-caspase dependent cell death induction, and concomitant reduction in CDC upon binding to CD20. In addition, using GlycoMab technology, the Fc-region of GA101 was glycoengineered to contain bisected, afucosylated carbohydrates. As a result GA101 has increased affinity for the low and high affinity FcγRIIIa receptor expressed on natural killer cells, macrophages and monocytes. Consequently, GA101 mediated a 5–50 fold enhanced induction of effector cell mediated ADCC. In B-cell depletion assays with whole blood from healthy donors, an assay combining all mechanisms of action, GA101 was significantly more potent and efficacious in depleting B cells than rituximab. In preclinical NHL testing these properties translated into superior anti-tumoral efficacy of GA101 in direct comparison to rituximab against a number of aggressive NHL xenograft models. In cynomolgus monkeys the induction of B cell depletion mediated by GA101 and subsequent B cell recovery were investigated. GA101 induced complete, rapid and long-lasting B cell depletion both in peripheral blood and in lymphoid tissue e.g. spleen and lymph nodes. The efficacy of GA101 (10 and 30 mg/kg) at depleting B cells in different lymphoid tissues of cynomolgus monkeys was compared with that of rituximab (10 mg/kg) following 2 i.v. doses administered on days 0 and 7. Notably, GA101 showed statistically superior depletion of total B cells from lymph nodes compared to Rituximab from day 9 to 35 onwards with B cell numbers decreased by over 95%. These results demonstrated that GA101 was more efficacious at depleting B cells from lymph nodes and spleen of cynomolgus monkeys compared to rituximab. Compared to existing antibodies, GA101 constitutes the first type II CD20 antibody engineered for increased ADCC with significantly enhanced efficacy in a variety of preclinical models. Based on these data it is assumed that the combination of the recognition of a type II epitope together with improved ADCC potency might translate into superior efficacy in the clinical treatment of CD20 positive malignant diseases.

scholarly journals The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy

2004 ◽  
Vol 199 (12) ◽  
pp. 1659-1669 ◽  
Author(s):  
Junji Uchida ◽  
Yasuhito Hamaguchi ◽  
Julie A. Oliver ◽  
Jeffrey V. Ravetch ◽  
Jonathan C. Poe ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Effector Cell ◽  
Fc Receptor ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Antibody Immunotherapy ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Cd20 Antibodies

Anti-CD20 antibody immunotherapy effectively treats non-Hodgkin's lymphoma and autoimmune disease. However, the cellular and molecular pathways for B cell depletion remain undefined because human mechanistic studies are limited. Proposed mechanisms include antibody-, effector cell–, and complement-dependent cytotoxicity, the disruption of CD20 signaling pathways, and the induction of apoptosis. To identify the mechanisms for B cell depletion in vivo, a new mouse model for anti-CD20 immunotherapy was developed using a panel of twelve mouse anti–mouse CD20 monoclonal antibodies representing all four immunoglobulin G isotypes. Anti-CD20 antibodies rapidly depleted the vast majority of circulating and tissue B cells in an isotype-restricted manner that was completely dependent on effector cell Fc receptor expression. B cell depletion used both FcγRI- and FcγRIII-dependent pathways, whereas B cells were not eliminated in FcR common γ chain–deficient mice. Monocytes were the dominant effector cells for B cell depletion, with no demonstrable role for T or natural killer cells. Although most anti-CD20 antibodies activated complement in vitro, B cell depletion was completely effective in mice with genetic deficiencies in C3, C4, or C1q complement components. That the innate monocyte network depletes B cells through FcγR-dependent pathways during anti-CD20 immunotherapy has important clinical implications for anti-CD20 and other antibody-based therapies.

scholarly journals IMMU-07. IMMUNE EFFECTOR CELL ASSOCIATED NEUROTOXICITY (ICANS) AMONG PEDIATRIC AND AYA PATIENTS: MD ANDERSON CANCER CENTER EXPERIENCE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii361-iii361
Author(s):  
Brandon Brown ◽  
Paolo Tambaro ◽  
Kris Mahadeo ◽  
Sajad Khazal ◽  
Priti Tewari ◽  
...  
Keyword(s):  
B Cell ◽  
Effector Cell ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Altered Mental Status ◽  
Cancer Center ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Impaired Ability ◽  
Car T

Abstract INTRODUCTION Immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) are potentially life-threatening complications associated with immune effector cell (IEC) therapies. We characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution. METHODS We reviewed clinical characteristics and severity (based on ASTCT Consensus Criteria) in pediatric and AYA patients with IEC products from 2018–2019 at MDACC. RESULTS Nine patients, median age 15.5 (range: 3–25) years received chimeric antigen receptor (CART) IEC therapy. Four (44%) developed ICANS within median of 8 (range: 3–27) days of CAR T cell infusion and median 6 (range: 2–7) days after CRS. Primary diagnoses were pre-B cell acute lymphoblastic leukemia (8) and mediastinal large B-cell lymphoma (1). Median CRS and ICANS severity grade was 2 (range 1–4). Symptoms included altered mental status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was performed in 3 and 1 had background slowing correlating with aphasia. CSF was obtained in two revealing lymphocytosis. All received prophylactic anti-epileptic medication and tocilizumab for concomitant CRS. Three received steroids. CONCLUSION ICANS may present in almost half of pediatric patients within one week of receiving CART products associated with CRS. CAR-T trafficking into the CSF may explain pleocytosis in the CSF. Prospective studies may clarify. Impaired ability to write a standard sentence and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients.

scholarly journals B Cell Depletion With an Anti-CD20 Antibody Enhances Alloreactive Memory T Cell Responses After Transplantation

2015 ◽  
Vol 16 (2) ◽  
pp. 672-678 ◽  
Author(s):  
J. Marino ◽  
J. T. Paster ◽  
A. Trowell ◽  
L. Maxwell ◽  
K. H. Briggs ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Memory T Cell ◽  
Cell Responses ◽  
Cd20 Antibody ◽  
Anti Cd20

Low doses of humanized anti-CD20 antibody, IMMU-106 (hA20), in refractory or recurrent NHL: Phase I/II results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8032-8032 ◽  
Author(s):  
F. Morschhauser ◽  
J. P. Leonard ◽  
L. Fayad ◽  
B. Coiffier ◽  
M. Petillon ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Serum Levels ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Open Label ◽  
Clear Cut ◽  
Cd20 Antibody ◽  
Anti Cd20

8032 Background: An open-label, multicenter study has shown that the humanized anti-CD20 antibody, IMMU-106 (hA20), which has framework regions of epratuzumab, has a good safety and efficacy profile in NHL pts when administered once-weekly × 4 at different doses. The trial is now focused on confirming the efficacy of lower doses (80–120 mg/m2/wk × 4). Methods: A total of 68 pts (35 male, 33 female; age 34–84) received hA20 at 750 (N=3), 375 (N=27), 200 (N=11), 120 (N=21), or 80 mg/m2 (N=6). They had follicular (FL, N=47) or other (N=21) B-cell NHL, were predominantly stage III/IV (N=47) at study entry, and had received 1–8 prior treatments (median, 2), including 1 (N=40) or more (N=21) rituximab regimens (without progression within 6 months). Results: Sixty- six pts completed all 4 infusions; 1 pt progressed during treatment and withdrew, while another pt with hives and chills after prior rituximab discontinued treatment after a similar episode at 1st infusion. hA20 was generally well tolerated, with shorter infusion times (typically 2 h initially and 1 h subsequently) at lower doses. Drug-related adverse events were transient, Grade 1–2, most occurring only at 1st infusion, and there was no evidence of HAHA in 54 pts now evaluated. Mean antibody serum levels increased with dose and infusions; serum clearance at 375 mg/m2 appears similar to rituximab. Currently, 48 pts with at least 12 wks follow-up were evaluated by Cheson criteria: 32 FL pts had 15 (47%) OR's with 7 (22%) CR/CRu's, even after 2–4 prior rituximab-regimens, and 17 non-FL pts had 6 (38%) OR's, with 1 CRu in a marginal zone NHL pt. At a median follow-up of 11 mo., 9/21 pts with ORs are continuing responses, including 4 long-lived responses (15–20 mo). The evaluated pts include 17 pts at 120 mg/m2 who had 5 (29%) ORs with 3 (17%) CR/CRu's. Responses at 80 mg/m2 remain to be evaluated, but B-cell depletion occurs after the 1st infusion even at this low dose. Conclusions: hA20 appears well-tolerated, with no evidence of significant adverse events other than minor infusion reactions, even at short infusion times. B-cell depletion and responses have occurred at all doses evaluated, with no clear-cut evidence of a dose-response. As such, the study is continuing to confirm the efficacy of lower doses. No significant financial relationships to disclose.

scholarly journals P0374TREATMENT EFFICACY OF BIOSIMILAR RITUXIMAB (TRUXIMA) COMPARED TO THE ORIGINATOR (MABTHERA) IN PATIENTS WITH ANCA ASSOCIATED VASCULITIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
PEK GHE TAN ◽  
Jennifer O'Brien ◽  
Rachna Bedi ◽  
Megan Griffith ◽  
Marie Condon ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
B Cell ◽  
Induction Therapy ◽  
Subgroup Analysis ◽  
Treatment Efficacy ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Anca Associated Vasculitis ◽  
Infusion Reactions

Abstract Background and Aims Truxima is a biosimilar version of rituximab. It was licensed & launched in the United Kingdom in April 2017. A biosimilar medicine is made to be highly similar in quality, safety and efficacy to existing licensed “reference” biological medicine and the cost is often significantly lower. A recent systematic review showed comparable long-term efficacy and safety of biosimilar rituximab to the originator drug in treatment of rheumatoid arthritis and non-hodgkin’s lymphoma. Fewer data are available in regards to the efficacy of biosimilar rituximab in treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). A retrospective study was thus conducted in our centre to examine the efficacy of Truxima when compared to the reference rituximab (MabThera) in the treatment of patients with AAV. Method All patients with new or relapsing AAV who received first ever rituximab therapy between 1/1/2016 and 31/12/2018 were identified via hospital dispensing database. Patients were stratified into Truxima or MabThera treatment group depending on the version of rituximab administered. Primary outcomes that were assessed include: time to B cell depletion (defined as absolute B cell count (ABC) ≤10) and repletion (i.e ABC >10 and >20); time to antimyeloperoxidase(MPO)/antiproteinase 3(PR3)-ANCA negativity; Secondary outcomes assessed include: overall survival, time to major relapse (defined as relapse requiring further course of rituximab for remission induction); adverse events including episodes of neutropenia, hypogammaglobulinemia and major infusion reactions. Subgroup analysis in patients who received concomitant cyclophosphamide and rituximab or other induction therapy was performed to examine if it impacts on the treatment efficacy. Results 59 and 60 patients received Truxima and MabThera respectively for treatment of new or relapsing AAV. The baseline characteristic (age, gender, entry estimated Glomerular Filtration Rate, proportion of patients received concomitant cyclophosphamide, ANCA serology and organ involvement) of both group were comparable. All patients achieved clinical remission following induction treatment. Using Kaplan Meier analysis and log rank test, no difference was identified in time to B cell depletion or repletion (Figure 1&2), MPO/PR3-ANCA negativity (Figure 3), overall survival or major relapses requiring further rituximab as induction therapy. Treatment efficacy of Truxima and MabThera did not differ in subgroup analysis. However we observed that patients who received concurrent cyclophosphamide during induction therapy achieved MPO/PR3-ANCA negativity more rapidly compared to those who did not irrespective of the version of rituximab received. No difference in adverse events such as major infusion reactions was seen in either group upon first rituximab exposure. Two patients in each group developed reactions following repeated dosing of rituximab. Conclusion Biosimilar rituximab Truxima appears to have comparable treatment efficacy compared to the reference drug in our cohort of patients with AAV.

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