Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2738-2743 ◽  
Author(s):  
Mark S. Cragg ◽  
Martin J. Glennie
Keyword(s):  
Monoclonal Antibody ◽  
Natural Killer ◽  
Membrane Rafts ◽  
Antibody Specificity ◽  
Therapeutic Activity ◽  
Considerable Uncertainty ◽  
Complement Dependent Cytotoxicity ◽  
Xenograft Models ◽  
Anti Cd20

Abstract Despite the success of anti-CD20 monoclonal antibody (mAb) in the treatment of lymphoma, there remains considerable uncertainty about their mechanism(s) of action. Here, we show that certain of these reagents (rituximab and 1F5), which redistribute CD20 into membrane rafts, are bound efficiently by C1q, deposit C3b, and result in complement-dependent cytotoxicity (CDC). This activity is important in vivo, because complement depletion using cobra venom factor (CVF) markedly reduced the efficacy of rituximab and 1F5 in 2 lymphoma xenograft models. However, complement depletion had no effect on the potent therapeutic activity of B1, a mAb that does not redistribute CD20 into membrane rafts, bind C1q, or cause efficient CDC. Equivalent immunotherapy also occurred in the presence or absence of natural killer (NK) cells. Perhaps most surprising was the observation that F(ab′)2 fragments of B1 but not 1F5 were able to provide substantial immunotherapy, indicating that non-Fc-dependent mechanisms are involved with B1. In accordance with this, B1 was shown to induce much higher levels of apoptosis than rituximab and 1F5. Thus, although complement is important for the action of rituximab and 1F5, this is not so for B1, which more likely functions through its ability to signal apoptosis. (Blood. 2004;103:2738-2743)

scholarly journals Characterization of a humanized IgG4 anti-HLA-DR monoclonal antibody that lacks effector cell functions but retains direct antilymphoma activity and increases the potency of rituximab

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2736-2744 ◽  
Author(s):  
Rhona Stein ◽  
Zhengxing Qu ◽  
Susan Chen ◽  
David Solis ◽  
Hans J. Hansen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Effector Cell ◽  
Cell Functions ◽  
Hla Dr ◽  
Complement Dependent Cytotoxicity ◽  
Survival Pathway ◽  
Anti Cd20

AbstractHLA-DR is under investigation as a target for monoclonal antibody (mAb) therapy of malignancies. Here we describe a humanized IgG4 form of the anti-HLA-DR mAb L243, hL243γ4P (IMMU-114), generated to provide an agent with selectivity toward neoplastic cells that can kill without complement-dependent cytotoxicity (CDC) or antibody-dependent cellular-cytotoxicity (ADCC), so as to reduce reliance on intact immunologic systems in the patient and effector mechanism-related toxicity. In vitro studies show that replacing the Fc region of hL243γ1, a humanized IgG1 anti-HLA-DR mAb, with the IgG4 isotype abrogates the effector cell functions of the antibody (ADCC and CDC) while retaining its antigen-binding properties, antiproliferative capacity (in vitro and in vivo), and the ability to induce apoptosis concurrent with activation of the AKT survival pathway. Growth inhibition was evaluated compared with and in combination with the anti-CD20 mAb rituximab, with the combination being more effective than rituximab alone in inhibiting proliferation. Thus, hL243γ4P is indistinguishable from hL243γ1 and the parental murine mAb in assays dependent on antigen recognition. The abrogation of ADCC and CDC, which are believed to play a major role in side effects of mAb therapy, may make this antibody an attractive clinical agent. In addition, combination of hL243γ4P with rituximab offers the prospect for improved patient outcome.

scholarly journals Targeting Antibody Checkpoint Fcgriib Using Monoclonal Antibody BI-1206 to Overcome Therapeutic Resistance in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Alexa A Jordan ◽  
Joseph McIntosh ◽  
Yang Liu ◽  
Angela Leeming ◽  
William Lee ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Publicly Traded ◽  
In Vivo Efficacy ◽  
Mantle Cell ◽  
Xenograft Models

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.

Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 329-334 ◽  
Author(s):  
Jonathan W. Friedberg
Keyword(s):  
Follicular Lymphoma ◽  
Single Agent ◽  
Antibody Therapy ◽  
Resistance Mechanisms ◽  
Complement Dependent Cytotoxicity ◽  
Dependent Cell ◽  
Impact On Treatment ◽  
Anti Cd20 ◽  
In Vivo Cytotoxicity

Abstract Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy. Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects. The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance. There are multiple potential approaches to overcoming rituximab resistance, including rational biologic combination immunotherapy, engineered antibodies, and radioimmunoconjugates. Improved ability to overcome resistance will require further elucidation of critical signaling pathways involved in rituximab induced cytotoxicity and a comprehensive understanding of interactions between its multiple mechanisms of action.

Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

1998 ◽  
Vol 16 (6) ◽  
pp. 2169-2180 ◽  
Author(s):  
A L Yu ◽  
M M Uttenreuther-Fischer ◽  
C S Huang ◽  
C C Tsui ◽  
S D Gillies ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Target Cells ◽  
Complement Dependent Cytotoxicity ◽  
Clinical Responses

PURPOSE To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma. PATIENTS AND METHODS Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted. RESULTS The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied. CONCLUSION In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

scholarly journals Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD

Blood ◽  
2015 ◽  
Vol 125 (3) ◽  
pp. 570-580 ◽  
Author(s):  
Anne-Kathrin Hechinger ◽  
Benjamin A. H. Smith ◽  
Ryan Flynn ◽  
Kathrin Hanke ◽  
Cameron McDonald-Hyman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Chronic Gvhd ◽  
Therapeutic Activity ◽  
Cytokine Inhibition ◽  
Key Points ◽  
The Common

Key Points Monoclonal antibody blockade of the common γ chain attenuates acute and chronic GVHD. Common γ-chain cytokines increase granzyme B levels in CD8 T cells, which are reduced upon CD132 blockade in vivo.

scholarly journals Prenyltransferases Regulate CD20 Protein Levels and Influence Anti-CD20 Monoclonal Antibody-mediated Activation of Complement-dependent Cytotoxicity

2012 ◽  
Vol 287 (38) ◽  
pp. 31983-31993 ◽  
Author(s):  
Magdalena Winiarska ◽  
Dominika Nowis ◽  
Jacek Bil ◽  
Eliza Glodkowska-Mrowka ◽  
Angelika Muchowicz ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Protein Levels ◽  
Complement Dependent Cytotoxicity ◽  
Anti Cd20

The Humanized Anti-CD40 Monoclonal Antibody, SGN-40, Potentiates Chemotherapy Regimens in NHL Xenograft Models Via Pro-Apoptotic Signaling.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2342-2342 ◽  
Author(s):  
Timothy S. Lewis ◽  
Renee S. McCormick ◽  
Kim Kissler ◽  
Ivan J. Stone ◽  
Mechthild Jonas ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Family Member ◽  
Cytotoxic Agents ◽  
P53 Family ◽  
Signaling Mechanism ◽  
Xenograft Models

Abstract SGN-40 is a humanized antibody targeting CD40, a TNF receptor family member expressed on normal B cells, non-Hodgkin’s lymphoma (NHL), multiple myeloma, and a variety of carcinomas. Previous studies have shown that SGN-40 triggers proapoptotic signal transduction, mediates effector function (ADCC), and has in vivo antitumor activity in CD40+ lymphoma xenograft models. We now report in vivo efficacy data for SGN-40 in combination with the anti-CD20 monoclonal antibody, rituximab, and approved chemotherapy regimens for the treatment of NHL. The growth of subcutaneous Ramos tumors in SCID mice was delayed following SGN-40 or rituximab treatment. However, the combination of SGN-40 + rituximab (S-R) significantly improved efficacy over either antibody alone. SGN-40 was then tested with ICE (ifosfamide, carboplatin, etoposide) chemotherapy with or without rituximab (S-R-ICE and S-ICE). These studies demonstrated that both S-R-ICE and S-ICE treated mice had lower tumor burden than R-ICE or SGN-40 treated animals. Additionally, the effect of SGN-40 in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy with or without rituximab (S-R-CHOP and S-CHOP) was examined. S-R-CHOP and S-CHOP therapies showed a significant delay in tumor growth compared with R-CHOP or SGN-40 alone. Furthermore, the efficacy observed in S-R-ICE and S-R-CHOP treatments exceeded the S-R combination, suggesting that SGN-40 chemosensitizes lymphoma cells by a signaling mechanism in addition to augmenting ADCC when combined with rituximab. To better understand the chemosensitization effect of SGN-40 in xenograft models, signal transduction events triggered by SGN-40 were examined in vitro. SGN-40 treatment caused the sustained degradation of the BCL-6 protooncogene in several lymphoma cell lines, following prolonged MAP Kinase pathway activation. BCL-6 is implicated in lymphomagenesis of germinal center derived lymphomas, and is proteasomally degraded after phosphorylation by ERK1/2 MAPK. Immunohistochemical analyses of Ramos tumors harvested from mice following treatment with SGN-40 or S-CHOP revealed elevated numbers of apoptotic cells versus untreated tumors. A distinct downregulation of BCL-6 staining in Ramos tumor cells was also observed in SGN-40 and S-CHOP treated animals, correlating with increased cell death. Finally, in some NHL lines SGN-40 upregulated the p53 family member TAp63alpha, a chemo-sensitizing transcription factor capable of inducing apoptosis when overexpressed. When combined with cytotoxic agents, SGN-40 caused a greater induction of TAp63alpha compared with chemotherapy alone, a potential mechanism underlying the improved antitumor activity seen in combination studies. Collectively, these data suggest that SGN-40 signaling occurs at the tumor site, likely contributing directly to tumor cell killing and chemosensitization. These preclinical studies support our earlier work suggesting that addition of SGN-40 to standard therapeutic regimens may improve the outcome for patients with NHL.

Anti-CD20-Interferon-α Fusion Protein Demonstrates Potent Direct Growth Inhibition, Antibody-Dependent Cellular Cytotoxicity, and Enhanced Complement-Dependent Cytotoxicity Against Human B Cell Lymphomas In Vitro, and Activity Against Multiple Human NHL Xenografts In Vivo

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2724-2724
Author(s):  
Reiko E Yamada ◽  
Kristopher K Steward ◽  
Gataree Ngarmchamnanrith ◽  
Sanjay Khare ◽  
Raj Sachdev ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Growth Inhibition ◽  
B Cell ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Complement Dependent Cytotoxicity ◽  
Direct Growth ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Human B Cell

Abstract Abstract 2724 The type 1 interferons (IFNα and IFNβ) are potent regulators of malignant cell growth. IFNα has anti-proliferative and pro-apoptotic effects against many cancers, including non-Hodgkin lymphomas (NHL), and immunostimulatory effects including activation of natural killer cells, dendritic cells, and T cell anti-tumor immunity. Until now however, the clinical use of these agents has been limited by the inability to achieve effective concentrations of IFN at sites of tumor without causing systemic toxicity. We recently reported the ability of an anti-CD20 antibody-IFNα fusion protein to induce apoptosis and promote in vivo eradication of CD20-expressing mouse and human B cell lymphomas (C. Xuan et al, Blood 115:2864, 2010). We now report on the preclinical anti-lymphoma activity of a recombinant anti-CD20-human IFNα (IgG1 anti-CD20-hIFNα) fusion protein derived from rituximab variable region sequences. Anti-CD20-hIFNα was evaluated against a large panel of human B cell NHL lines representing aggressive histologies including Burkitt (Daudi, Raji, Ramos), diffuse large B cell (SUDHL-4, OCI-Ly2, OCI-Ly3, OCI-Ly19, HBL-1, RC-K8), and mantle cell (Granta-519) lymphomas. Proliferation was measured by [3H]-thymidine incorporation in quadruplicate 48 hour cultures, apoptosis measured by Annexin-V and propidium iodide (PI) staining, complement-dependent cytotoxicity (CDC) measured by PI flow cytometry, and antibody-dependent cellular cytotoxicity (ADCC) measured by LDH release using peripheral blood mononuclear cell effectors. NHL xenografts Daudi, Raji, and Namalwa were grown in SCID mice. Equimolar doses of rituximab and fusion protein were compared in each assay. Against IFN-sensitive CD20-negative U266 tumor cells, anti-CD20-hIFNα fusion protein had 10–15% IFNα bioactivity when compared to conventional recombinant IFNα (rIFNα). However, when targeting CD20-positive Daudi cells the inhibitory growth activity is significantly enhanced over rIFNα. Anti-CD20-hIFNα fusion protein induced stronger direct growth inhibition than rituximab (23.3–93.1% vs. 0.0–39.8%); particularly against Burkitt (44.7–93.1% vs. 0.0–10.4%) and germinal center-type diffuse large B cell (59.0–88.8% vs. 10.5–39.8%) NHLs. Tumor growth inhibition by anti-CD20-hIFNα was associated with substantial apoptosis in some cell lines. The ADCC activity of fusion protein against Daudi, Ramos, and Raji cells was identical to that of rituximab. Against established human NHL xenografts (Daudi, Raji, and Namalwa), fusion protein achieved improved survival compared to rituximab. Surprisingly, anti-CD20-hIFNα exhibited superior CDC compared to rituximab against Daudi (62.0% vs. 28.3%), Ramos (81.0% vs. 57.3%), and Raji (78.0% vs. 54.6%) cells. We hypothesized that the increased CDC activity of the fusion protein might result from enhanced target cell avidity due to the IFNα moeity binding to IFNα receptors (IFNAR) on the tumor cell surface. However, this was not the case, as flow cytometric studies demonstrated no improvement of fusion protein binding over rituximab, and comparable Kd values. Also, antibody blockade of IFNAR-IFNα interactions, or pre-incubation with excess free IFNα did not prevent the increased CDC activity of anti-CD20-hIFNα fusion protein against Ramos cells. Moreover, the enhanced CDC depended upon linkage of IFNα to the anti-CD20 antibody, as CDC using rituximab plus equimolar free IFNα was equivalent to rituximab alone, suggesting superior complement fixation by anti-CD20-hIFNα. In conclusion, we have demonstrated that anti-CD20-hIFNα has substantially stronger direct anti-proliferative and CDC activities than rituximab against human lymphomas, while retaining potent ADCC activity. The greater effects of IFNα targeted to NHL via fusion protein suggest a broader therapeutic index than rIFNα. Anti-CD20-hIFNα fusion protein is also superior to rituximab in vivo against multiple human NHL xenografts. These results support the further development of anti-CD20-hIFNα fusion protein for the treatment of B cell malignancies. Disclosures: Khare: ImmunGene, Inc.: Employment. Sachdev:ImmunGene, Inc.: Employment. Grewal:ImmunGene, Inc.: Employment.

Combination of the glycoengineered Type II CD20 antibody obinutuzumab (GA101) and The novel Bcl-2 selective Inhibitor GDC-0199 Results in superior In Vitro and In Vivo Anti-tumor activity in models Of B-Cell Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4412-4412 ◽  
Author(s):  
Deepak Sampath ◽  
Sylvia Herter ◽  
Frank Herting ◽  
Ellen Ingalla ◽  
Michelle Nannini ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Agent ◽  
Employment Equity ◽  
Direct Cell ◽  
Xenograft Models ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Agent Treatment

Introduction Obinutuzumab (GA101) is a novel glycoengineered type II, anti-CD20 monoclonal antibody induces a high level of direct cell death. As a result of glycoengineering, GA101 has increased affinity for FcgRIIIa on effector cells resulting in enhanced direct cell death and ADCC induction. GA101 is currently in pivotal clinical trials in CLL, indolent NHL and DLCBL. ABT-199 (GDC-0199) is a novel, orally bioavailable, selective Bcl-2 inhibitor that induces robust apoptosis in preclinical models of hematological malignancies and is currently in clinical trials for CLL, NHL and MM. Based on their complementary mechanisms of action involving increased apoptosis (GDC-0199) or direct cell death (GA101) the combination of anti-CD20 therapy with a Bcl-2 inhibitor has the potential for greater efficacy in treating B lymphoid malignancies. Experimental Methods The combination of GA101 or rituximab with GDC-0199 was studied in vitro utilizing assays that measure direct cell death induction/apoptosis (AxV/Pi positivity) on WSU-DLCL2, SU-DHL4 DLBCL and Z138 MCL cells by FACS and the impact of Bcl-2 inhibition on ADCC induction. In vivo efficacy of the combination of GA101 or rituximab and GDC-0199 was evaluated in SU-DHL4 and Z138 xenograft models. Results GA101 and rituximab enhanced cell death induction when combined with GDC-0199 in SU-DHL4, WSU-DLCL2 and Z138 cell lines. When combined at optimal doses an additive effect of the two drugs was observed. GDC-0199 did not negatively impact the capability of GA101 or rituximab to induce NK-cell mediated ADCC. Combination of GDC-0199 and GA101 induced a greater than additive anti-tumor effects in the SU-DHL4 and Z138 xenograft models resulting in tumor regressions and delay in tumor regrowth when compared to monotherapy. Moreover, continued single-agent treatment with GDC-0199 after combination with GA101 resulted in sustained in vivo efficacy in the SU-DHL4 model. Conclusions Our data demonstrate that the combination of GA101 with GDC-0199 results in enhanced cell death and robust anti-tumor efficacy in xenograft models representing NHL sub-types that is comparable to the combination of rituximab with GDC-0199. In addition, single-agent treatment with GDC-0199 following combination with GA101 sustains efficacy in vivo suggesting a potential benefit in continued maintenance therapy with GDC-0199. Collectively the preclinical data presented here supports clinical investigation of GA101 and GDC-0199 combination therapy, which is currently in a phase Ib clinical trial (clinical trial.gov identifier NCT01685892). Disclosures: Sampath: Genentech: Employment, Equity Ownership. Herter:Roche: Employment. Herting:Roche: Employment. Ingalla:Genentech: Employment. Nannini:Genentech: Employment. Bacac:Roche: Employment. Fairbrother:Genentech: Employment, Equity Ownership. Klein:Roche Glycart AG: Employment.

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