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Pablo Umana - One of the best experts on this subject based on the ideXlab platform.

  • Combination therapy with the type II anti-CD20 Antibody obinutuzumab.
    Expert opinion on investigational drugs, 2017
    Co-Authors: Christian Klein, Marina Bacac, Pablo Umana, Günter Fingerle-rowson
    Abstract:

    ABSTRACTIntroduction: Obinutuzumab is a novel humanized type II glycoengineered anti-CD20 Antibody approved for first-line treatment of chronic lymphocytic leukemia (CLL) in combination with chlorambucil and for treatment of rituximab-refractory follicular lymphoma (FL).Areas covered: We describe current preclinical and clinical evidence supporting the combination of obinutuzumab with not only chemotherapy but also novel targeted therapies for B-cell hematologic malignancies, and its application in chemoimmunotherapy. We also provide an overview of the current clinical trial landscape investigating novel combination therapies based on obinutuzumab.Expert opinion: Within the next 10 years the treatment of B-cell malignancies with obinutuzumab is expected to increasingly move towards chemotherapy-free regimens. Novel combinations of obinutuzumab will be explored with targeted therapies, Antibody–drug conjugates, and/or other immunotherapeutic agents, with the aim to achieve clinically meaningful improvement...

  • GA101: A humanized third generation type II CD20 Antibody with superior cell death induction and glycoengineered Fc region for enhanced ADCC
    Cancer Research, 2007
    Co-Authors: Pablo Umana, Ekkehard Moessner, Peter Bruenker, Gabriele Unsin, Ursula Puentener, Roger Grau, Carla Schmidt, Christian Gerdes, Adam Nopora, Monika Patre
    Abstract:

    4186 Treatment of non-Hodgkin lymphoma (NHL) with rituximab, an Antibody targeting the B cell antigen CD20, in combination with chemotherapy has been established as standard clinical practice during recent years. Here we describe GA101, a novel humanized type II CD20 Antibody of the IgG1 isotype with superior cell death induction and a glycoengineered Fc region for enhanced ADCC. GA101 was humanized by grafting CDR sequences from the murine monoclonal Antibody B-ly1 on framework regions with fully human IgG1-kappa germline sequences. During humanization different elbow hinge sequences in the variable region were studied for their capability to induce cell death. Furthermore, the Fc region-carbohydrates were glycoengineered using GlycoMAb technology resulting in bisected, afucosylated Fc region-carbohydrates and enhanced affinity for the hFcgammaRIII receptor. The humanized Antibody GA101 binds CD20 as type II Antibody with nanomolar affinity. Its glycoengineered Fc region binds with 50-fold higher affinity to human FcgammaRIII receptors compared to non-glycoengineered antibodies. Increased FcgammaRIII binding results in a 50 to 100-fold increase in ADCC against CD20-expressing NHL cell lines. Modification of elbow hinge sequences within the Antibody variable framework regions results in enhanced caspase-independent cell death induction in normal and malignant B cells upon binding to CD20. In B-cell depletion assays with whole blood from healthy donors and B-cell leukemic patients, an assay combining ADCC-, CDC- and cell death-mediated mechanisms of action, GA101 is significantly more potent and efficacious than other CD20 antibodies, including rituximab and Fc-variants of rituximab that have increased ADCC. Finally, the in vitro superiority of GA101 also translates into superior efficacy in a number of subcutaneous and orthotopic in vivo xenograft models with NHL cell lines of different histological origin. In particular, GA101 induces i) complete tumor remission and long-term survival in subcutaneous models with the aggressive mantle cell lymphoma cell line Z138 and the diffuse large B cell lymphoma cell line SU-DHL4 and ii) increases overall survival in an orthotopic disseminated model of Z138 in direct comparison to rituximab. In summary, GA101 represents the first type II CD20 Antibody successfully engineered for increased ADCC with significantly enhanced efficacy in a variety of in vitro and in vivo preclinical models. Based on these data, GA101 is a promising third generation CD20 Antibody candidate for the treatment of B-cell malignancies.

  • Novel 3rd Generation Humanized Type II CD20 Antibody with Glycoengineered Fc and Modified Elbow Hinge for Enhanced ADCC and Superior Apoptosis Induction.
    Blood, 2006
    Co-Authors: Pablo Umana, Ekkehard Moessner, Peter Bruenker, Gabriele Unsin, Ursula Puentener, Roger Grau, Carla Schmidt, Christian Gerdes, Tobias Suter, Adam Nopora
    Abstract:

    Background: Treatment of B-cell non-Hodgkin lymphoma (NHL) with antibodies targeting CD20 in conjunction with combination chemotherapy is standard clinical practice. Two different types of CD20 MAb differing significantly in their mode of CD20 binding and biological activities have been identified (Cragg and Glennie. Blood103: 2738–2743, 2004): type I antibodies, as rituximab, are potent in complement mediated cytotoxicity, whereas type II antibodies, as tositumomab, effectively initiate target cell death via caspase-independent apoptosis with concomitant phosphatidylserine exposure. GA101 is a humanized and optimized, third generation, type II CD20 IgG1 Antibody that exhibits enhanced ADCC and superior caspase-independent apotosis induction in comparison with currently available CD20 MAbs. Material and Methods: GA101 was humanized by grafting CDR sequences from the murine monoclonal Antibody B-ly1 on framework regions with fully human IgG1-kappa germline sequences. During humanization different elbow hinge sequences in the variable region were studied for their capability to induce apoptosis. Furthermore, the Fc region-carbohydrates were glycoengineered using GlycoMAb™ technology leading to bisected, afucosylated Fc region-carbohydrates. Results: The humanized GA101 Antibody bound CD20 as type II Antibody with nanomolar affinity. Its glycoengineered Fc region bound with 50-fold higher affinity to human FcgammaRIII receptors compared to a standard, non-glycoengineered Antibody. Increased FcgammaRIII binding led to a 10–100-fold increase in ADCC against CD20-expressing NHL cell lines. Modification of elbow hinge sequences within the Antibody variable framework regions resulted in a strong apoptosis-inducing activity of GA101 upon CD20 binding on target cells. Direct comparison to other CD20 antibodies GA101 showed enhanced apoptosis induction in both a panel of NHL cell lines and ex vivo in samples from patients with a variety of B-cell malignancies. Furthermore, in B-cell depletion assays with whole blood from healthy donors and B-cell leukemic patients, an assay combining ADCC-, CDC- and apoptosis-mediated mechanisms of action, GA101 was significantly more potent and efficacious than other CD20 antibodies, including rituximab and Fc-variants of rituximab that have increased ADCC. Finally, the in vitro superiority of GA101 also translated into superior efficacy in vivo. In NHL xenograft models of different histological origin, including aggressive DLBCL and MCL, treatment with GA101 results in complete tumor remission and long-term survival (cure) compared to tumor stasis, at best, for rituximab. Conclusion: Compared to existing CD20 antibodies GA101 represents a novel, third generation Antibody with significantly enhanced efficacy in a variety of in vitro and in vivo preclinical models. GA101 constitutes the first type II CD20 Antibody successfully engineered for increased ADCC. Based on these data, GA101 is a promising therapeutic Antibody candidate for the treatment of B-cell malignancies.

Andreas J. Steck - One of the best experts on this subject based on the ideXlab platform.

Sabine Lang - One of the best experts on this subject based on the ideXlab platform.

  • preclinical activity of the type ii CD20 Antibody ga101 obinutuzumab compared with rituximab and ofatumumab in vitro and in xenograft models
    Molecular Cancer Therapeutics, 2013
    Co-Authors: Sylvia Herter, Inja Waldhauer, Frank Herting, Erwin Van Puijenbroek, Olaf Mundigl, Tina Weinzierl, Tanja Fauti, Gunter Muth, Doris Zieglerlandesberger, Sabine Lang
    Abstract:

    We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal Antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), Antibody-dependent cell-mediated cytotoxicity (ADCC), Antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by Antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 Antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation.

  • Superior Efficacy of the Novel Type II, Glycoengineered CD20 Antibody GA101vs. the Type I CD20 Antibodies Rituximab and Ofatumumab
    Blood, 2010
    Co-Authors: Sylvia Herter, Inja Waldhauer, Tina Otz, Frank Herting, Sabine Lang, Valeria G. Nicolini, Michaela Römmele, Thomas Friess, Erwin Van Puijenbroek, Marina Bacac
    Abstract:

    Abstract 3925 GA101 is Type II, glycoengineered CD20 monoclonal Antibody currently in PhII/III clinical trials. We have previously shown that GA101 mediates superior in vitro and in vivo activity compared to the Type I CD20 Antibody rituximab. By epitope mapping and crystallography we have shown that GA101 recognizes CD20 in a unique way that is different from Type I CD20 antibodies and have proposed that this may be the basis for the Type II character of GA101. Here we compare for the first time GA101 with rituximab, the standard of care in various clinical settings in NHL and B-CLL in combination with chemotherapy, as well as with the Type I CD20 Antibody ofatumumab, which was recently approved for treatment of B-CLL patients refractory to fludarabine and alemtuzumab. The following assays were used to compare the three anti-CD20 antibodies: i) Binding to NHL cell lines Z138 (MCL, ca. 60.000 CD20 binding sites per cell) and SU-DHL4 (DLBCL, ca. 1 Mio CD20 binding sites per cell) assessed by FACS, ii) Cell death induction, detected by AxV/PI staining and FACS, on a panel of NHL cell lines, iii) Antibody dependent cellular cytotoxicity mediated by PBMNCs as effector and Z138, SU-DHL4 as target cells (ADCC, LDH release assay); iv) Complement dependent cytotoxicity with Z138, SU-DHL4 as target cells (CDC, LDH release assay) and v) B-cell depletion (assessed by FACS) in whole blood from healthy donors. Dose-dependent anti-tumoral activity was assessed in a s.c. SU-DHL4 NHL xenograft model in Scid beige mice. Survival experiments in a disseminated Z138 MCL model are ongoing and an update on the results will be included as part of the poster presentation. Ofatumumab (“Arzerra”) was purchased from a local pharmacy, GA101 and rituximab were obtained from Hoffmann La Roche AG, Basel. First, binding studies confirmed that GA101 shows half-maximal binding to NHL cells relative to rituximab and ofatumumab, a known property of Type II CD20 antibodies. EC50 values of binding were comparable indicating that GA101, rituximab and ofatumumab have apparent binding affinities in the low nanomolar range on NHL cells independent of the level of CD20 expression. Second, the three CD20 antibodies were compared for their induction of direct cell death as measured by AxV/PI staining. Overall, GA101 mediated superior direct cell death induction compared to rituximab and ofatumumab utilizing a panel of NHL cell lines of different origins. Immune effector-related mechanisms of action were subsequently compared by ADCC and CDC assays. GA101, a glycoengineered Antibody with enhanced affinity for FcgRIIIa, was found to exhibit up to 100-fold higher ADCC potency than rituximab and ofatumumab on Z138 and SU-DHL4 cells. CDC, as expected for a Type II CD20 Antibody was ca. 10 to 1,000 less potent compared to the Type I antibodies rituximab and ofatumumab. In order to integrate the different mechanisms of action (direct cell death, ADCC, CDC), autologous ex vivo B-cell depletion assays with whole blood from healthy donors containing natural immune effector cells, human complement and physiological concentrations of human immunoglobulins were performed. These studies showed that GA101 was more potent in terms of EC50 values and more efficacious in terms of absolute B-cell depletion when compared to rituximab and ofatumumab. Finally, the dose-dependent effects of the three CD20 antibodies was studied on the growth of s.c. SU-DHL4 DLBCL xenografts in SCID beige mice. GA101 induced a dose-dependent anti-tumoral effect including complete tumor remission and was superior to the Type I antibodies rituximab and ofatumumab at saturating Antibody doses. In summary, the preclinical data presented herein demonstrate that the Type II, glycoengineered CD20 Antibody GA101 is differentiated from the Type I CD20 antibodies rituximab and ofatumumab by its superior overall activity supporting its further clinical investigation. Of note, in contrast to previous publications, in this series of assays no superior preclinical activity of ofatumumab was observed when compared to rituximab. Disclosures: Herter:Roche: Employment, Patents & Royalties. Waldhauer:Roche: Employment. Otz:Roche: Employment. Herting:Roche: Employment, Patents & Royalties. Lang:Roche: Employment. Nicolini:Roche: Employment. Rommele:Roche: Employment. Friess:Roche: Employment, Patents & Royalties. Van Puijenbroek:Roche: Employment. Bacac:Roche: Employment. Weidner:Roche: Employment, Equity Ownership. Gerdes:Roche: Employment, Equity Ownership, Patents & Royalties. Umana:Roche: Employment, Equity Ownership, Patents & Royalties. Klein:Roche: Employment, Equity Ownership, Patents & Royalties.

Christian Klein - One of the best experts on this subject based on the ideXlab platform.

  • Combination therapy with the type II anti-CD20 Antibody obinutuzumab.
    Expert opinion on investigational drugs, 2017
    Co-Authors: Christian Klein, Marina Bacac, Pablo Umana, Günter Fingerle-rowson
    Abstract:

    ABSTRACTIntroduction: Obinutuzumab is a novel humanized type II glycoengineered anti-CD20 Antibody approved for first-line treatment of chronic lymphocytic leukemia (CLL) in combination with chlorambucil and for treatment of rituximab-refractory follicular lymphoma (FL).Areas covered: We describe current preclinical and clinical evidence supporting the combination of obinutuzumab with not only chemotherapy but also novel targeted therapies for B-cell hematologic malignancies, and its application in chemoimmunotherapy. We also provide an overview of the current clinical trial landscape investigating novel combination therapies based on obinutuzumab.Expert opinion: Within the next 10 years the treatment of B-cell malignancies with obinutuzumab is expected to increasingly move towards chemotherapy-free regimens. Novel combinations of obinutuzumab will be explored with targeted therapies, Antibody–drug conjugates, and/or other immunotherapeutic agents, with the aim to achieve clinically meaningful improvement...

  • Obinutuzumab (GA101) for the Treatment of Chronic Lymphocytic Leukemia and Other B-cell Non-Hodgkin's Lymphomas: A Glycoengineered Type II CD20 Antibody
    Oncology research and treatment, 2015
    Co-Authors: Valentin Goede, Christian Klein, Stephan Stilgenbauer
    Abstract:

    Obinutuzumab (GA101) is a humanized, monoclonal type II CD20 Antibody modified by glycoengineering. The glycoengineered Fc portion enhances the binding affinity to the FcγRIII receptor on immune

  • Glycoengineered CD20 Antibody Obinutuzumab Activates Neutrophils and Mediates Phagocytosis Through CD16B More Efficiently Than Rituximab
    Blood, 2013
    Co-Authors: Josee Golay, Fabio Da Roit, Luca Bologna, Jeanette H W Leusen, Alessandro Rambaldi, Christian Klein, Claudia Ferrara Koller, Martino Introna
    Abstract:

    Background Obinutuzumab (GA101) is a third generation, glycoengineered defucosylated anti-CD20 Antibody which shows higher binding affinity for CD16A than fully glycosylated rituximab (RTX). This higher binding leads to stronger NK mediated Antibody dependent cellular cytotoxicity activity (ADCC) by obinutuzumab compared to that induced by RTX. The GPI-anchored CD16B molecule is highly homologous to CD16A and is the major FcγR on polymorphonuclear neutrophils (PMN). We have therefore investigated the binding of obinutuzumab to CD16B and its functional activity on human PMN compared to parent rituximab (RTX) or to defucosylated rituximab (G2 Antibody). Methods Binding to CD16B of glycoengineered or fully glycosylated anti-CD20 antibodies was measured by surface plasmon resonance (Biacore). For PMN activation and phagocytosis, we have used either purified PMN or analyzed PMN function in unmanipulated whole blood assays from normal donors or CLL patients. PMN activation was measured as CD11b upregulation and CD62L downmodulation by flow cytometry. Phagocytosis by PMN of chronic lymphocytic leukemia (CLL) cells was measured by triple fluorescence (PKH26, CD15-FITC and CD19-APC) and flow cytometry. Results Obinutuzumab or glycoengineered defucosylated rituximab (called G2) bound CD16B with about 7 fold higher affinity, compared to non-glycoengineered wild type parental antibodies. This was true either using surface plasmon resonance or measuring Antibody binding to live PMN. Furthermore obinutuzumab activated PMN, either purified or in whole blood, more efficiently than RTX. Activation resulted in a 50% increase in CD11b expression and 70% down-modulation of CD62L on PMN and in release of TNFα, IL-6 and IL-8. Activation was not accompanied by generation of reactive oxygen species or ADCC, but led to phagocytosis of anti-CD20 Antibody opsonized CLL targets by purified PMN. Indeed up to 50% phagocytic PMN could be observed in presence of obinutuzumab or G2 antibodies after 6-24 hours incubation of purified PMN with CLL targets. Significant phagocytosis (15%) was also observed in whole blood, but only in presence of glycoengineered antibodies, and was followed by up to 50% PMN death. Finally we show, using blocking F(ab) and F(ab’)2 fragments specific for CD16B and CD32A, that both these receptors are involved in PMN activation, phagocytosis and cell death induced by glycoengineered anti-CD20 antibodies. The possible effect of NA1 and NA2 polymorphisms of CD16B on obinutuzumab binding and phagocytosis is under further investigation. Conclusions We conclude that phagocytosis by PMN is an additional mechanism of action of obinutuzumab, mediated through its higher binding affinity for CD16B compared to RTX. Phagocytosis takes place in whole blood and is followed by PMN death. This effect may in part explain the neutropenia observed after treatment of B-CLL patients with GA101. Disclosures: Golay: Roche Glycart AG: Research Funding. Ferrara Koller:Roche Glycart AG: Employment. Rambaldi:Roche Italia: Consultancy, Honoraria. Klein:Roche Glycart AG: Employment. Introna:Roche Glycart AG: Research Funding.

  • glycoengineered CD20 Antibody obinutuzumab activates neutrophils and mediates phagocytosis through cd16b more efficiently than rituximab
    Blood, 2013
    Co-Authors: Josee Golay, Fabio Da Roit, Luca Bologna, Claudia Ferrara, Jeanette H W Leusen, Alessandro Rambaldi, Christian Klein, Martino Introna
    Abstract:

    Obinutuzumab (GA101) is a glycoengineered type 2 CD20 Antibody with enhanced CD16A-binding and natural killer–mediated cytotoxicity. CD16B is highly homologous to CD16A and a major FcγR on human polymorphonuclear neutrophils (PMNs). We show here that glycoengineered obinutuzumab or rituximab

  • Anti-CD20 Antibody GA101 Shows Higher Cytotoxicity but Is Competitively Displaced by Rituximab in Mantle Cell Lymphoma.
    Blood, 2009
    Co-Authors: Daniel A. Heinrich, Yvonne Zimmermann, Grit Hutter, Wolfgang Hiddemann, Christian Klein, Kristina Decheva, Marc Weinkauf, Tobias Weiglein, Martin Dreyling
    Abstract:

    Abstract 2704 Poster Board II-680 Background: Mantle cell lymphoma (MCL) is characterized by a poor long-term prognosis with a median survival of 3–5 years. Type I anti-CD20 Antibody rituximab has demonstrated a clear anti-proliferative effect in MCL and achieves increased response rates in combination with chemotherapy. GA101, a third-generation IgG1 anti-CD20 Antibody displays improved ADCC and superior direct cell death induction by virtue of glycoengineering compared to rituximab and its targeting a type II epitope on CD20, respectively. Methods: Using a panel of MCL cell lines (Rec-1, HBL-2, Jeko-1, Granta-519, JVM-2 and Z-138) we determined the effect of GA101 alone as well as in combination with rituximab on cell viability and proliferation. Karpas-422 (Diffuse Large B-Cell Lymphoma) was used as a control cell line. MCL and Karpas-422 cells were treated with GA101 or rituximab at concentrations of 1 – 20μg/ml and rituximab. Cell viability was analyzed by trypan-blue exclusion tests at 0h, 24h, 48h and 72h. The panel of MCL cell lines and Karpas-422 were then treated with GA101 and rituximab each at 1 and 10 μg/ml to determine potential synergism of Antibody combinations. Accordingly, a fractional product calculation was performed: synergism > 0,1; antagonism Results: After mono-exposure with GA101 (1 μg/ml), Granta-519 and Rec-1 showed the highest sensitivity (65–75% cell reduction in Granta-519 and 35–40% in Rec-1). Intermediate results were gained for Z-138, HBL-2, Jeko-1 and JVM-2 and Karpas-422 (15–20%). rituximab mono-exposure at 12,5 μg/ml showed a 25% reduction of cell count in Granta-519, 20% in HBL-2 and Conclusions: Although GA101 is competitively displaced by rituximab, GA101 demonstrates higher efficacy in MCL cell lines than rituximab, even at a more than 10-fold lower concentration. Currently RNA-array- and Western blot analysis are being performed to identify the critical pathways responsible for the superior cytotoxicity of GA101. Disclosures: Klein: Discovery Oncology, Roche Diagnostics GmbH: Employment. Weinkauf: Lilly Deutschland GmbH: Research Funding. Hutter: Lilly Deutschland GmbH: Research Funding. Zimmermann: Lilly Deutschland GmbH: Research Funding. Dreyling: Roche: Honoraria, Research Funding.

David M. Goldenberg - One of the best experts on this subject based on the ideXlab platform.

  • Subcutaneous veltuzumab, a humanized anti-CD20 Antibody, in the treatment of refractory pemphigus vulgaris.
    JAMA dermatology, 2014
    Co-Authors: Christoph T. Ellebrecht, Eun J. Choi, David Allman, Donald E. Tsai, William A. Wegener, David M. Goldenberg, Aimee S. Payne
    Abstract:

    Importance B-cell depletion with the anti-CD20 Antibody rituximab is highly effective for pemphigus vulgaris (PV) treatment. However, most patients experience relapse, and intravenous rituximab infusions are expensive. Therefore, cost-effective anti-CD20 therapies are desirable. Observations A compassionate-use investigational new drug protocol was approved to administer veltuzumab, a second-generation humanized anti-CD20 Antibody, to a patient with refractory PV. Veltuzumab was administered as two 320-mg (188 mg/m 2 ) subcutaneous doses 2 weeks apart, resulting in complete remission of disease off therapy. The disease relapsed 2 years after treatment. A second cycle of subcutaneous veltuzumab, using the same dosage regimen, again induced complete remission off therapy, which remained at 9 months. No serious adverse events occurred during 35 months of follow-up. Serum veltuzumab levels were 22 and 29 μg/mL 2 weeks after the first dose of each cycle, and the drug remained detectable in the serum for longer than 3 months. Relapse and response to veltuzumab generally correlated with desmoglein 3 enzyme-linked immunosorbent assay index values. Shortly after a relapse that occurred after a long-term remission, the patient demonstrated an elevated naive (CD19 + CD27 − ) to memory (CD19 + CD27 + ) B-cell ratio of 19.5 and transitional (CD19 + CD24 + CD38 + ) B-cell frequency of 12.5%. Conclusions and Relevance Subcutaneous veltuzumab may be a safe, effective, and more economical alternative to intravenous rituximab for PV therapy. Clinical trials of subcutaneous veltuzumab for PV are warranted.

  • Subcutaneous injections of low-dose veltuzumab (humanized anti-CD20 Antibody) are safe and active in patients with indolent non-Hodgkin’s lymphoma
    Haematologica, 2010
    Co-Authors: George O. Negrea, William A. Wegener, Heather Horne, Nick Teoh, Rebecca Elstrom, Steven L. Allen, Kanti R. Rai, Rashid M. Abbasi, Charles M. Farber, David M. Goldenberg
    Abstract:

    Background Subcutaneous injections of anti-CD20 antibodies may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies. Design and Methods A pilot study was undertaken to evaluate the potential for subcutaneous dosing with 2nd generation anti-CD20 Antibody veltuzumab in patients with CD20+ indolent non-Hodgkin’s lymphoma. Patients with previously untreated or relapsed disease received 4 doses of 80, 160, or 320 mg veltuzumab injected subcutaneously every two weeks. Responses were assessed by computed tomography scans, with other evaluations including adverse events, safety laboratories, B-cell blood levels, serum veltuzumab levels, and human anti-veltuzumab Antibody (HAHA) titers. Results Seventeen patients (14 follicular lymphoma; 13 stage III or IV disease; 5 treatment-naive) completed treatment with only occasional, mild-moderate, transient injection reactions and no other safety issues. Subcutaneous veltuzumab demonstrated a slow release pattern over several days, achieving a mean Cmax of 19, 25 and 63 μg/mL at 80, 160, and 320 mg doses for a total of 4 administrations, respectively. Depletion of circulating B cells occurred after the first injection. The objective response rate (partial responses plus complete responses plus complete responses unconfirmed) was 47% (8/17) with a complete response/complete response unconfirmed rate of 24% (4/17); 4 of 8 objective responses continued for 60 weeks or more. All serum samples evaluated for human anti-veltuzumab Antibody were negative. Conclusions Subcutaneous injections of low-dose veltuzumab are convenient, well tolerated, and capable of achieving sustained serum levels, B-cell depletion, and durable objective responses in indolent non-Hodgkin’s lymphoma. ([Clinicaltrials.gov][1] identifier: [NCT00546793][2]) [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00546793&atom=%2Fhaematol%2F96%2F4%2F567.atom