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Anti-CD22 and Anti-CD79B Antibody Drug Conjugates Are Active in Different Molecular Diffuse Large B-Cell Lymphoma Subtypes

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Anti-CD22 and Anti-CD79B Antibody Drug Conjugates Are Active in Different Molecular Diffuse Large B-Cell Lymphoma Subtypes Leukemia (2015) 29, 1578–1586 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu ORIGINAL ARTICLE Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes M Pfeifer1, B Zheng2, T Erdmann3,4, H Koeppen2, R McCord2, M Grau5, A Staiger6, A Chai2, T Sandmann2, H Madle3,4, B Dörken1, Y-W Chu2, AI Chen7, D Lebovic8, GA Salles9, MS Czuczman10, MC Palanca-Wessels11,12, OW Press11, R Advani13, F Morschhauser14, BD Cheson15, P Lenz5,GOtt6, AG Polson2, KE Mundt2 and G Lenz3,4 Antibody drug conjugates (ADCs), in which cytotoxic drugs are linked to antibodies targeting antigens on tumor cells, represent promising novel agents for the treatment of malignant lymphomas. Pinatuzumab vedotin is an anti-CD22 ADC and polatuzumab vedotin an anti-CD79B ADC that are both linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In the present study, we analyzed the activity of these agents in different molecular subtypes of diffuse large B-cell lymphoma (DLBCL) both in vitro and in early clinical trials. Both anti-CD22-MMAE and anti-CD79B-MMAE were highly active and induced cell death in the vast majority of activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL cell lines. Similarly, both agents induced cytotoxicity in models with and without mutations in the signaling molecule CD79B. In line with these observations, relapsed and refractory DLBCL patients of both subtypes responded to these agents. Importantly, a strong correlation between CD22 and CD79B expression in vitro and in vivo was not detectable, indicating that patients should not be excluded from anti-CD22-MMAE or anti- CD79B-MMAE treatment because of low target expression. In summary, these studies suggest that pinatuzumab vedotin and polatuzumab vedotin are active agents for the treatment of patients with different subtypes of DLBCL. Leukemia (2015) 29, 1578–1586; doi:10.1038/leu.2015.48 INTRODUCTION monoclonal antibody (mAB) rituximab into the therapy of DLBCL – Diffuse large B-cell lymphoma (DLBCL) represents a hetero- has significantly improved prognosis.10 12 Nevertheless, a sub- geneous diagnostic category.1 This heterogeneity can partially stantial number of patients relapse after first-line therapy. These be explained by the existence of different molecular subtypes relapsed or refractory DLBCL patients are characterized by dismal identified by gene expression profiling.2–5 Applying the cell of outcome.13 origin classification, at least two major molecular subtypes can be A novel therapeutic approach is the use of antibody drug distinguished. The germinal center B-cell-like (GCB) DLBCLs are conjugates (ADCs) in which cytotoxic drugs are attached to derived from germinal center B cells, whereas activated B-cell-like antibodies that are directed against antigens expressed on tumor (ABC) DLBCLs originate from activated B cells.2,3 GCB and ABC cells.14 Recently, this strategy has been shown to be very effective DLBCLs depend on different oncogenic pathways that are in the treatment of malignant lymphoma patients. The anti-CD30 frequently activated by somatic mutations.1 Importantly, the ADC brentuximab vedotin achieved high response rates in existence of molecular subtypes as well as specific mutations patients with relapsed or refractory CD30-positive Hodgkin’s – appear predictive of response to pathway inhibitors such as lymphoma and anaplastic large-cell lymphoma (ALCL).15 17 ibrutinib, and immunomodulatory agents such as lenalidomide or CD22 and CD79B are physiologically expressed in the vast proteasome inhibitors.6–8 Thus, the assignment of DLBCL patients majority of B cells and therefore represent promising targets for into molecular subtypes is becoming increasingly important to ADCs. Preclinical data for an anti-CD79B and an anti-CD22 antibody ensure that patients are selected for the most efficacious conjugated to the microtubule-disrupting agent monomethyl treatment regimens. Finally, ABC and GCB DLBCLs also show auristatin E (MMAE) indicated the efficacy in B-cell lymphomas significant differences in outcome when treated with including Burkitt lymphoma, mantle cell lymphoma, follicular immunochemotherapy.9 The introduction of the anti-CD20 lymphoma and DLBCL.18–20 However, these studies did not 1Department of Hematology, Oncology and Tumor Immunology, Charité—Universitätsmedizin Berlin, Germany; 2Genentech Inc., 1 DNA Way, South San Francisco, CA, USA; 3Division of Translational Oncology, Department of Medicine A, University Hospital Münster, Münster, Germany; 4Cluster of Excellence EXC 1003, Cells in Motion Münster, Germany; 5Department of Physics, Philipps-University, Marburg, Germany; 6Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch- Institute of Clinical Pharmacology, Stuttgart, Germany; 7Department of Hematology-Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; 8Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA; 9Hematology Department, Hospices Civils de Lyon - Université de Lyon, Pierre-Bénite, France; 10Department of Medicine and Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA; 11Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 12Seattle Genetics Inc, Bothell, WA, USA; 13Stanford University Medical Center, Stanford University, Stanford, CA, USA; 14Department of Hematology, Centre Hospitalier Régional Universitaire de Lille, Lille, France and 15Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington DC, USA. Correspondence: Dr KE Mundt, Genentech Inc., DNA Way 1, South San Francisco 94080, CA, USA or Professor G Lenz, Division of Translational Oncology, Department of Medicine A, University Hospital Münster, Albert-Schweitzer-Campus 1, Münster 48149, Germany. E-mail: [email protected] or [email protected] Received 25 August 2014; revised 8 January 2015; accepted 13 February 2015; accepted article preview online 24 February 2015; advance online publication, 8 May 2015 Anti-CD22 and anti-CD79B ADCs in DLBCL subtypes M Pfeifer et al 1579 investigate whether ABC or GCB DLBCL or lymphomas character- The anti-CD22-mAB SP104 (Ventana) was used according to the ized by specific mutations respond differentially to these agents. manufacturer’s instructions. The anti-CD79B-mAB AT-107-2 (0.25 μg/ml; Of particular interest in this respect are mutations affecting CD79B AbD Serotec, Oxford, UK) was incubated for 60 min at 37 oC. Human tonsils that have been reported to have an impact on B-cell receptor (BCR) were used as positive controls. The staining results are reported as H-score 21 as previously described that includes both numbers of positive tumor cells internalizationinmouseBcells. To this end, we analyzed the 28,29 efficacy of anti-CD22-MMAE and anti-CD79B-MMAE in a large panel as well as the staining intensities. The H-score was calculated for staining of tumor cells using the following formula: of cell lines derived from DLBCL patients of both molecular H-Score = (% at 0) × 0+(% at 1+) × 1+(% at 2+) × 2+(% at 3+) × 3. Thus, subtypes including cell lines characterized by CD79B mutations. To this score produces a continuous variable that ranges from 0 to 300.28,29 validate our in vitro findings, we investigated responses observed in A modified H-score was used in the cell lines that displayed a rather DLBCL patients treated in two recent phase-I studies. uniform intensity of protein expression in a given case: % cells positive × predominant expression intensity (0–3). MATERIALS AND METHODS Determination of molecular DLBCL subtypes Antibody drug conjugates Classification into molecular DLBCL subtypes was performed analogously The following ADCs were used in the present study. As previously to Wright et al.3 The detailed algorithm is described in Supplementary described, pinatuzumab vedotin is an anti-CD22-MMAE ADC (DCDT2980S), Materials and Methods and the data are summarized in Supplementary whereas polatuzumab vedotin (DCDS4501A) represents an anti-CD79B- Figure 1. MMAE ADC.18,22 Pinatuzumab vedotin and polatuzumab vedotin are the drug candidates used in two phase-I clinical trials in relapsed and refractory lymphoma patients.23,24 Determination of IC50 concentrations and correlation analyses The IC50 concentrations were calculated as described in detail in the Supplementary Materials and Methods. Cell lines Human DLBCL, ALCL and multiple myeloma (MM) cell lines were cultured as previously described in RPMI (Life Technologies, Carlsbad, CA, USA) with Mutation analysis of CD79B in primary DLBCL patient samples 10% fetal calf serum (Sigma-Aldrich, St Louis, MO, USA), except for OCI-Ly1, Detailed protocols are available in the Supplementary Materials and OCI-Ly2, OCI-Ly3, OCI-Ly4, OCI-Ly7, OCI-Ly10, OCI-Ly19 and TMD8 that Methods. The primer sequences are summarized in Supplementary Table 1. were cultured in Isocove’s modified Dulbecco medium (Life Technologies) 25,26 supplemented with 10% fetal calf serum. Western blotting Western blot analysis was performed as previously described.30,31 Viability assay, sub-G1 and cell cycle analysis Detailed protocols are available in the Supplementary Materials and Methods. RESULTS CD22 and CD79B expression in DLBCL Determination of CD22 and CD79B surface expression To assess the expression pattern of the targets of anti-CD22-MMAE using flow cytometry and anti-CD79B-MMAE, we measured
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