Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1185-1192 ◽  
Author(s):  
Julie A. McEarchern ◽  
Ezogelin Oflazoglu ◽  
Leigh Francisco ◽  
Charlotte F. McDonagh ◽  
Kristine A. Gordon ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Hematologic Malignancies ◽  
Effector Cells ◽  
Effector Functions ◽  
Normal Tissues ◽  
Non Hodgkin Lymphoma ◽  
Human Igg1 ◽  
Constant Domains

Abstract Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is highly restricted but is aberrantly expressed in hematologic malignancies including non-Hodgkin lymphoma (NHL), Hodgkin disease, and multiple myeloma. In addition, solid tumors such as renal cell carcinoma, nasopharyngeal carcinoma, thymic carcinoma, meduloblastoma, and glioblastoma express high levels of this antigen. To functionally target CD70-expressing cancers, a murine anti-CD70 monoclonal antibody was engineered to contain human IgG1 constant domains. The engineered antibody retained the binding specificity of the murine parent monoclonal antibody and was shown to induce Fc-mediated effector functions including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis in vitro. Further, administration of this antibody significantly prolonged survival of severe combined immunodeficient (SCID) mice bearing CD70+ disseminated human NHL xenografts. Survival of these mice was dependent upon the activity of resident effector cells including neutrophils, macrophages, and natural killer (NK) cells. These data suggest that an anti-CD70 antibody, when engineered to contain human IgG1 constant domains, possesses effector cell–mediated antitumor activity and has potential utility for anticancer therapy.

scholarly journals Expression of the oncofetal ED-B–containing fibronectin isoform in hematologic tumors enables ED-B–targeted 131I-L19SIP radioimmunotherapy in Hodgkin lymphoma patients

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2265-2274 ◽  
Author(s):  
Stefanie Sauer ◽  
Paola A. Erba ◽  
Mario Petrini ◽  
Andreas Menrad ◽  
Leonardo Giovannoni ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Hodgkin Lymphoma ◽  
Hematologic Malignancies ◽  
Current Treatment ◽  
Cancer Therapies ◽  
Bone Marrow Biopsies ◽  
Normal Tissues ◽  
Non Hodgkin Lymphoma ◽  
Promising Target

Abstract Current treatment of hematologic malignancies involves rather unspecific chemotherapy, frequently resulting in severe adverse events. Thus, modern clinical research focuses on compounds able to discriminate malignant from normal tissues. Being expressed in newly formed blood vessels of solid cancers but not in normal mature tissues, the extradomain B of fibronectin (ED-B FN) is a promising target for selective cancer therapies. Using immunohistology with a new epitope retrieval technique for paraffin-embedded tissues, ED-B FN expression was found in biopsies from more than 200 Hodgkin and non-Hodgkin lymphoma patients of nearly all entities, and in patients with myeloproliferative diseases. ED-B FN expression was nearly absent in normal lymph nodes (n = 10) and bone marrow biopsies (n = 9). The extent of vascular ED-B FN expression in lymphoma tissues was positively correlated with grade of malignancy. ED-B FN expression was enhanced in lymph nodes with severe lymphadenopathy and in some hyperplastic tonsils. The in vivo accessibility of ED-B FN was confirmed in 3 lymphoma patients, in whom the lymphoma lesions were visualized on scintigraphy with 131I-labeled L19 small immunoprotein (131I-L19SIP). In 2 relapsed Hodgkin lymphoma patients131I-L19SIP radioimmunotherapy induced a sustained partial response, qualifying ED-B FN as a promising target for antibody-based lymphoma therapies.

scholarly journals Combination of Loncastuximab Tesirine and Polatuzumab Vedotin Shows Increased Anti-Tumor Activity in Pre-Clinical Models of Non-Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2273-2273
Author(s):  
Nikoleta Sachini ◽  
Asma Jabeen ◽  
Patrick H van Berkel ◽  
Francesca Zammarchi
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Hodgkin Lymphoma ◽  
Annexin V ◽  
Publicly Traded ◽  
Non Hodgkin Lymphoma ◽  
Clinical Models ◽  
Anti Tumor Activity

Abstract Loncastuximab tesirine-lpyl (formerly ADCT-402) is an antibody-drug conjugate (ADC) comprising a humanised anti-CD19 monoclonal antibody conjugated to the pyrrolobenzodiazepine (PBD) dimer-based payload tesirine. Once bound to CD19 on the cell membrane, loncastuximab tesirine is rapidly internalised and the released PBD dimer warhead causes interstrand DNA crosslinks which ultimately trigger cell death. Pre-clinically, loncastuximab tesirine has shown potent and specific anti-tumor activity in lymphoma models both as single agent and in combination with other approved drugs, like venetoclax, idelalisib and bendamustine (Zammarchi, Corbett et al. 2018, Tarantelli, Spriano et al. 2019). Loncastuximab tesirine has been recently approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and it is currently being tested in multiple clinical trials, either as monotherapy or in combination with other anti-lymphoma drugs. Polatuzumab vedotin is an ADC composed of a humanized anti-CD79b monoclonal antibody conjugated to monomethyl auristatin E (vcMMAE) and it is approved by the FDA for treatment of r/r DLBCL when used in combination with bendamustine and rituximab. Here, we investigated the in vitro and in vivo anti-tumor activity of loncastuximab tesirine combined with polatuzumab vedotin in pre-clinical models of non-Hodgkin lymphoma (NHL). In vitro, the combination of loncastuximab tesirine and polatuzumab vedotin was tested in three human-derived, CD19 and CD79b-positive NHL cell lines (WSU-DLCL2, TMD8 and Ramos) and it resulted in synergistic (TMD8 and Ramos) and additive (WSU-DLCL2) activity, as assessed by the Chou-Talalay method. Quantification of cell viability (propidium iodide [PI]-negative and Annexin V-negative) and early/late apoptosis (Annexin V-positive and PI-negative/ Annexin V-positive and-PI positive) on TMD8 and Ramos cells treated with loncastuximab tesirine, polatuzumab vedotin or the combination of the two agents showed a significant reduction of viable cells accompanied by an increase in apoptotic cells in the combination setting compared to the single agents. In vivo, loncastuximab tesirine was tested either alone (0.25 or 0.5 mg/kg, single dose) or in combination with polatuzumab vedotin (1 mg/kg, single dose) in the WSU-DLCL2 xenograft model. At the highest dose of loncastuximab tesirine, combination with polatuzumab vedotin resulted in improved anti-tumor activity and superior response rate compared to the 2 agents in monotherapy. All treatment regimens were well tolerated by the mice, as assessed by body weight measurements and frequent observation for signs of treatment-related side effects. In conclusion, the combination of loncastuximab tesirine and polatuzumab vedotin resulted in improved anti-tumor activity both in vitro and in vivo in lymphoma preclinical models and it was well tolerated. Altogether, these novel pre-clinical data warrant translation of the combination of loncastuximab tesirine and polatuzumab vedotin into the clinic for the treatment of NHL. Disclosures Sachini: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jabeen: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. van Berkel: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Zammarchi: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

scholarly journals Bypassing Phase Variation of Lipooligosaccharide (LOS): Using Heptose 1 Glycan Mutants To Establish Widespread Efficacy of Gonococcal Anti-LOS Monoclonal Antibody 2C7

2019 ◽  
Vol 88 (2) ◽  
Author(s):  
Srinjoy Chakraborti ◽  
Sunita Gulati ◽  
Bo Zheng ◽  
Frank J. Beurskens ◽  
Janine Schuurman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Polymorphonuclear Leukocytes ◽  
Phase Variation ◽  
Human Infection ◽  
Phase Variable ◽  
Content Type ◽  
Human Igg1 ◽  
And Function

ABSTRACT The sialylatable lacto-N-neotetraose (LNnT; Gal-GlcNAc-Gal-Glc) moiety from heptose I (HepI) of the lipooligosaccharide (LOS) of Neisseria gonorrhoeae undergoes positive selection during human infection. Lactose (Gal-Glc) from HepII, although phase variable, is commonly expressed in humans; loss of HepII lactose compromises gonococcal fitness in mice. Anti-LOS monoclonal antibody (MAb) 2C7, a promising antigonococcal immunotherapeutic that elicits complement-dependent bactericidal activity and attenuates gonococcal colonization in mice, recognizes an epitope comprised of lactoses expressed simultaneously from HepI and HepII. Glycan extensions beyond lactose on HepI modulate binding and function of MAb 2C7 in vitro. Here, four gonococcal LOS mutants, each with lactose from HepII but fixed (unable to phase-vary) LOS HepI glycans extended beyond the lactose substitution of HepI (lactose alone, Gal-lactose, LNnT, or GalNAc-LNnT), were used to define how HepI glycan extensions affect (i) mouse vaginal colonization and (ii) efficacy in vitro and in vivo of a human IgG1 chimeric derivative of MAb 2C7 (2C7-Ximab) with a complement-enhancing E-to-G Fc mutation at position 430 (2C7-Ximab-E430G). About 10-fold lower 2C7-Ximab-E430G concentrations achieved similar complement-dependent killing of three gonococcal mutants with glycan extensions beyond lactose-substituted HepI (lactose alone, LNnT, or GalNAc-LNnT) as 2C7-Ximab (unmodified Fc). The fourth mutant (Gal-lactose) resisted direct complement-dependent killing but was killed approximately 70% by 2C7-Ximab-E430G in the presence of polymorphonuclear leukocytes and complement. Only mutants with (sialylatable) LNnT from HepI colonized mice for >3 days, reiterating the importance of LNnT sialylation for infection. 2C7-Ximab-E430G significantly attenuated colonization caused by the virulent mutants.

Re-Educating Myeloma Associated Macrophages with Lenalidomide

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2034-2034 ◽  
Author(s):  
Heiko Bruns ◽  
Hanna Gehlen ◽  
Jens Nolting ◽  
Shirin Pasemann ◽  
Peter Brossart ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Stromal Cell ◽  
Plasma Cells ◽  
In Vivo Studies ◽  
Effector Cells ◽  
Effector Functions ◽  
Anti Inflammatory

Abstract Introduction: The bone marrow niche plays a critical role in determining the fate of malignant plasma cells in multiple myeloma (MM). Macrophages are an abundant component of the stromal cell compartment and are believed to support proliferation, survival, and drug resistance of MM cells. Conversely, macrophages can directly kill tumor cells and participate in antitumor immune responses as effector cells. Moreover, macrophages are key immune effector cells for the therapeutic effect of monoclonal antibodies. Lenalidomide, an immunomodulatory drug (IMiD®) is used for the treatment of MM, also in the combination with therapeutic antibodies. Lenalidomide is thought to target the stromal support, but its precise influence on the phenotype or the effector functions of macrophages is still unclear. Methods: To investigate the effect of lenalidomide on the interaction between macrophages and malignant plasma cells in vitro, we coincubated lenalidomide pretreated macrophages with several MM cell lines, and analysed the viability, proliferation and phenotype. For in vivo studies we utilized 5TMM mice, a suitable animal model for MM. Animals were treated with lenalidomide (50 mg/kg 5days/week) for 3 weeks, and the effector functions and phenotype of isolated bone marrow macrophages were analyzed. In addition, macrophages in the bone marrow of MM patients treated with lenalidomide were characterized by immunohistochemistry and flow cytometry. Results: We showed, that infiltrating macrophages in the bone marrow of MM patients display an anti-inflammatory M2-like phenotype characterized by the expression of surface marker CD163, CD206, PD-L1 and cytokine/chemokine secretion (e.g. IL10, CXCL10, APRIL, BAFF and RANKL). Incubation of macrophages with lenalidomide in vitro, substantially changed their transcriptional program (e.g. downregulation of IRF4 and upregulation of IRF5) and their phenotype (e.g. downregulation of the surfaces marker CD163, CD206, and upregulation of CD16, CD64, CD40 and CD86). Furthermore, we show that lenalidomide treatment decreases the expression of RANKL, BAFF and APRIL, while tumoricidal effector molecules (e.g. TRAIL, cathelicidine, Granzyme B) were increased. When lenalidomide treated macrophages were cocultured with MM cells significant cytotoxicity was detected, for all MM cell lines tested. In contrast, untreated macrophages promote tumor growth and viability of MM cells. Conclusion: Lenalidomide in vitro influences macrophages by reverting an anti-inflammatory M2 like profile to a more immunogenic phenotype. In addition it impacts on the support function by decreasing the secretion of important growth factors for B-cells. Similar results were observed in first in vivo studies. Taken together our results imply that lenalidomide interrupts an important stromal cell function thereby influencing survival of MM cells. Disclosures No relevant conflicts of interest to declare.

Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4370-4372 ◽  
Author(s):  
Ezogelin Oflazoglu ◽  
Ivan J. Stone ◽  
Kristine A. Gordon ◽  
Iqbal S. Grewal ◽  
Nico van Rooijen ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Effector Cell ◽  
Treatment Strategies ◽  
Large Cell ◽  
Hematologic Malignancies ◽  
Effector Cells ◽  
Cell Functions ◽  
Cell Ablation

Increased expression of CD30 is associated with a variety of hematologic malignancies, including Hodgkin disease (HD) and anaplastic large cell lymphoma (ALCL). The anti-CD30 monoclonal antibody SGN-30 induces direct antitumor activity by promoting growth arrest and DNA fragmentation of CD30+ tumor cells. In this study, we investigated the contributions of Fc-mediated effector cell functions to SGN-30 activity. We determined that antibody-dependent cellular phagocytosis, mediated by macrophages, to contribute significantly to antitumor activity in vitro. To delineate the identity of the host effector cells involved in mediating antitumor activity in vivo, we studied the effects of effector cell ablation in a disseminated model of HD (L540cy). Depletion of macrophages markedly reduced efficacy of SGN-30, demonstrating that macrophages contribute significantly to SGN-30 efficacy in this model. These findings may have implications for patient stratification or combination treatment strategies in clinical trials conducted with SGN-30 in HD and ALCL.

TSP-A74, a Novel Therapeutic Monoclonal Antibody Against TfR1 for Treatment of Hematologic Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5214-5214
Author(s):  
Lilin Zhang ◽  
Fumiko Nomura ◽  
Youichi Aikawa ◽  
Yukio Sudo ◽  
Kazuhiro Morishita ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Cell Lymphoma ◽  
Xenograft Model ◽  
Hematologic Malignancies ◽  
Tumor Growth Inhibition ◽  
Xenograft Models ◽  
Complete Tumor

Abstract Transferrin receptor 1(TfR1) is a type II transmembrane glycoprotein regulating the intracellular uptake of iron and is involved in cell growth, proliferation and survival. TfR1 is highly expressed on malignant cells, including those of hematologic malignancies. Therefore, TfR1 may be an attractive target for therapeutic monoclonal antibodies. We generated a panel of fully-human, anti-TfR1 monoclonal antibodies and evaluated the anti-tumor effects of these antibodies both in vitro and in vivo. The results led to the selection of TSP-A74, an antibody with potent in vitro and in vivo anti-tumor activity, for further evaluation in several hematologic malignancy models. First, the efficacy of TSP-A74 was evaluated in acute myeloid leukemia (AML) models. Two AML cell lines, Kasumi-1 and HL-60, were subcutaneously inoculated in severe combined immunodeficiency (SCID) mice. After the tumors were grown to a size of 150 mm3, TSP-A74 was administrated intravenously (IV) once weekly for 4 weeks at doses of 0.4, 2 and 10 mg/kg and 1, 3 and 10 mg/kg for the Kasumi and HL60 xenograft models, respectively. TSP-A74 demonstrated complete tumor regression in these two xenograft models at 10 mg/kg and complete tumor growth suppression in the Kasumi model at 2 mg/kg. Even at the low dose of 1 mg/kg, TSP-A74 demonstrated tumor growth inhibition (TGI) of 60% in the HL60 model. Next, the anti-tumor efficacy of TSP-A74 was assessed in an acute lymphoblastic leukemia (ALL) model. The ALL cell line, CCRF-CEM, was engrafted into SCID mice intravenously. After 3 days, TSP-A74 was administrated IV at a dose of 10 mg/kg once weekly for 4 weeks. The control mice (n=10) rapidly developed leukemia and none survived at 42 days after leukemia cell engraftment. However, 7 of 10 (70%) mice treated with TSP-A74 survived to 179 days after engraftment when the study was terminated. Finally, the efficacy of TSP-A74 was evaluated in non-Hodgkin's lymphoma subcutaneous xenograft models. TSP-A74 produced complete regression of established tumors in the SU-DHL-2 (diffuse large B-cell lymphoma) xenograft model at a dose of 3 mg/kg and tumor growth inhibition of 100 % in the HH (cutaneous T cell lymphoma) xenograft model at a dose of 10 mg/kg. These results indicate that the human anti-TfR1 monoclonal antibody, TSP-A74, could be a new therapeutic candidate for hematologic malignancies. Disclosures Zhang: Perseus Proteomics Inc.: Employment. Nomura:Perseus Proteomics Inc.: Employment. Aikawa:Perseus Proteomics Inc.: Employment. Sudo:Perseus Proteomics Inc.: Employment. Morishita:Perseus Proteomics Inc.: Research Funding.

scholarly journals Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Shiming Ye ◽  
Melvin I. Fox ◽  
Nicole A. Belmar ◽  
Mien Sho ◽  
Debra T. Chao ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Tumor Xenograft ◽  
Immune Effector ◽  
Effector Cells ◽  
Innate Immune Effector ◽  
Receptor Monoclonal Antibody

Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.

scholarly journals Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1062-1070 ◽  
Author(s):  
David M. Goldenberg ◽  
Edmund A. Rossi ◽  
Rhona Stein ◽  
Thomas M. Cardillo ◽  
Myron S. Czuczman ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Lines ◽  
Single Amino Acid ◽  
High Dose ◽  
Non Hodgkin Lymphoma ◽  
Single Amino Acid Change ◽  
Human Lymphoma ◽  
Anti Cd20

Abstract Veltuzumab is a humanized anti-CD20 monoclonal antibody with complementarity-determining regions (CDRs) identical to rituximab, except for one residue at the 101st position (Kabat numbering) in CDR3 of the variable heavy chain (VH), having aspartic acid (Asp) instead of asparagine (Asn), with framework regions of epratuzumab, a humanized anti-CD22 antibody. When compared with rituximab, veltuzumab has significantly reduced off-rates in 3 human lymphoma cell lines tested, aswell as increased complement-dependent cytotoxicity in 1 of 3 cell lines, but no other in vitro differences. Mutation studies confirmed that the differentiation of the off-rate between veltuzumab and rituximab is related to the single amino acid change in CDR3-VH. Studies of intraperitoneal and subcutaneous doses in mouse models of human lymphoma and in normal cynomolgus monkeys disclosed that low doses of veltuzumab control tumor growth or deplete circulating or sessile B cells. Low- and high-dose veltuzumab were significantly more effective in vivo than rituximab in 3 lymphoma models. These findings are consistent with activity in patients with non-Hodgkin lymphoma given low intravenous or subcutaneous doses of veltuzumab. Thus, changing Asn101 to Asp101 in CDR3-VH of rituximab is responsible for veltuzumab's lower off-rate and apparent improved potency in preclinical models that could translate into advantages in patients.

SGN-70, a Humanized Anti-CD70 Antibody, Targets CD70-Expressing Hematologic Tumors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2492-2492
Author(s):  
Julie A. McEarchern ◽  
Charlotte F. McDonagh ◽  
Leia M. Smith ◽  
Kerry Klussman ◽  
Ezogelin Oflazoglu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Hematologic Malignancies ◽  
Myeloma Cell ◽  
Long Bone ◽  
Protein Levels ◽  
Normal Tissues ◽  
Significant Expression

Abstract Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is restricted to activated lymphocytes but is aberrantly expressed in hematologic malignancies and solid tumors including non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease, multiple myeloma (MM), Waldenstrom’s macroglobulinemia, renal cell carcinoma, glioblastoma, and nasopharyngeal carcinoma. To target CD70-expressing hematologic malignancies, we have engineered a humanized IgG1 anti-CD70 antibody that mediates lysis of tumor targets via ADCC and CDC and facilitates antibody dependent cellular phagocytosis in vitro. In vivo, administration of SGN-70 prolonged survival of SCID mice bearing CD70+ disseminated human NHL or MM xenografts. Intravenous injection of the CD70+ MM cell line MM.1S resulted in disease as measured by onset of paralysis, presence of CD138+ MM cells in the bone marrow, and increasing levels of circulating human Ig lambda light chain. SGN-70 treatment of MM.1S-bearing mice significantly delayed onset of paralysis and reduced the monoclonal protein levels detected in serum approximately 4-fold compared to untreated or non-binding antibody control-treated mice. Whereas myeloma cells comprised 32±6.4 % of mononuclear cells in the long bone marrow of control mice, SGN-70 treatment reduced the myeloma cell fraction to 4.9±1.9% of mononuclear cells recovered. SGN-70 treatment also significantly extended the survival of mice bearing disseminated Raji tumors (NHL) compared to control mice. Survival benefit was absent when mice received an Fc-modified antibody deficient in effector functions, confirming that the activity of SGN-70 in these models was dependent upon Fc-FcγR interaction with host immune cells. Together, these data demonstrate that SGN-70 possesses effector cell-mediated antitumor activity and provides rationale for clinical study of SGN-70 in CD70+ hematologic malignancies.

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