CC-122 Degrades the Lymphoid Transcription Factor Aiolos (IKZF3) By Modulating Cereblon and Shows Clinical Activity in a Phase Ib Study of Subjects with Relapsed or Refractory Non-Hodgkin’s Lymphoma and Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3500-3500 ◽  
Author(s):  
Vincent Ribrag ◽  
Silvia Damien ◽  
Mecide Gharibo ◽  
Mercede Gironella ◽  
Armando Santoro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Single Dose ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Cell Lymphoma ◽  
Employment Equity ◽  
Equity Ownership

Abstract Background: CC-122 is a novel non-phthalimide analog of the IMiDs® immunomodulatory drugs (lenalidomide and pomalidomide) and a first in class PPMTM (Pleiotropic Pathway Modifier) compound with multiple biological activities including potent anti-proliferative activity against B-lineage cells (10-fold greater than lenalidomide), anti-angiogenic activity (100-fold greater than lenalidomide) and immunomodulatory effects (10-fold greater than lenalidomide). The molecular target of CC-122 is cereblon (CRBN), a substrate receptor of the Cullin ring E3 ubiquitin ligase complex (CRL4CRBN). CC-122 promotes ubiquitination of lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) in a CRBN-dependent manner, leading to their subsequent degradation. Following establishment of 3mg once daily (QD) as the maximum tolerated dose (Blood 122:2905 2013), patients with advanced aggressive non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable patients. CC-122 was dosed at 3 mg QD in 28-day cycles until disease progression. Results: As of May 1, 2014, 93 total patients were enrolled in the expansion phase of the study. The NHL cohort included 21 patients with diffuse large B-cell lymphoma (DLBCL) and 1 patient with mantle cell lymphoma, and twenty-four patients were enrolled in the MM cohort. Results in solid tumor cohorts will be reported separately. All patients were ECOG performance status 0-2, the median number of prior systemic therapies was 4 (NHL) and 6 (MM). The most common (> 20%) adverse events (AEs) (grades 1-4) included neutropenia (69.6%), anemia (52%), asthenia (50%), pyrexia (35%), diarrhea (30%), cough (30%), thrombocytopenia (28%), and constipation (22%). Grade 3/4 AEs occurring in more than one patient were neutropenia (52%), anemia (26%), febrile neutropenia (13%), and thrombocytopenia (7%). CC-122 dose reduction was required in 36.4% of patients with NHL and 63% of patients with MM, the majority of which was due to neutropenia and occurred during cycle 1 or 2. CC-122 systemic exposure in NHL and MM patients was generally comparable after administration of single and multiple doses. Peak concentrations were observed between 30 minutes and 2 hours (median Tmax concentration = 1.5 h). Four treated patients with DLBCL had objective responses; one patient with complete response (CR) and 3 with partial responses (PR). Responses were observed in patients with germinal center B cell (GCB), non-GCB and Myc/Bcl2 over-expressing DLBCL. Four treated patients with MM had PR, and two of these responders were progression free beyond 10 cycles. A single dose of CC-122 3mg resulted in decreased Aiolos protein expression at 1.5 and 5 hours compared with baseline in peripheral B cells (median 38% and 53%) and T cells (median 31% and 54%) in the combined NHL (n = 16) and MM (n = 19) cohorts. Decrease in expression of Aiolos protein from baseline was also observed in lymph node biopsies of patients with DLBCL. Furthermore, CC-122 treatment decreased CD19+ B cells (median = 57% of baseline), expanded CD4-/CD8+/CD45RA-/CD45RO+ cytotoxic memory T cells (median = 320% of baseline), and expanded CD4+/CD8-/CD45RA-/CD45RO+ helper memory T cells (median = 154% of baseline) in peripheral blood samples from patients with MM (n = 9) and NHL (n = 3-12) subjects. Additionally, ex vivo activation of T cells after a single dose of CC-122 compared with baseline, as measured by IL-2 production, increased by a median of 776% (NHL n = 3 and MM n = 7). Conclusions: CC-122 shows promising initial clinical and pharmacodynamic activity in heavily pretreated relapse/refractory NHL and MM patients. Biomarker analysis indicates that the 3 mg QD dose of CC-122 results in rapid CRBN target engagement and Aiolos degradation in the peripheral blood lymphocytes of patients with NHL and MM patients and in NHL tumor tissue. Exploration of an intermittent dosing to mitigate neutropenia-related dose reductions and interruptions is ongoing and clinical studies exploring drug combinations with CC-122 are underway. Disclosures Ribrag: Celgene Corp: Consultancy. Rasco:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Wei:Celgene Corp: Employment, Equity Ownership. James:Celgene Corp: Employment. Hagner:Celgene Corp: Employment, Equity Ownership. Gandhi:Celgene Corp: Employment, Equity Ownership. Chopra:Celgene Corp: Employment, Equity Ownership. DiMartino:Celgene Corp: Employment, Equity Ownership. Pourdehnad:Celgene Corp: Employment, Equity Ownership. Stoppa:Celgene Jansen: Honoraria.

scholarly journals A Novel CD20xCD3 Bispecific Fully Human Antibody Induces Potent Anti-Tumor Effects Against B Cell Lymphoma in Mice

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4501-4501 ◽  
Author(s):  
Bindu Varghese ◽  
Jayanthi Menon ◽  
Luis Rodriguez ◽  
Lauric Haber ◽  
Kara Olson ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Tumor Cells ◽  
Bispecific Antibody ◽  
Tumor Regression ◽  
Employment Equity ◽  
Cynomolgus Monkeys ◽  
Nsg Mice ◽  
Equity Ownership

Abstract Bispecific antibodies that redirect effector T cells to kill tumor cells have shown considerable promise in both pre-clinical and clinical studies. However, these bispecific formats can have short half-lives necessitating constant infusion of the molecules into patients. We report here on a novel full-length human IgG CD20xCD3 bispecific antibody (REGN1979) that targets CD20 expressed on normal and malignant B cells and CD3 expressed on T cells in humans and cynomolgus monkeys. Our results demonstrate CD20-target cell-dependent activation and cytokine release by T cells, and efficient redirected T cell lysis of target tumor cells. Raji B cell lymphomas grown as tumors in NOD SCID IL2R gamma deficient (NSG) mice and co-implanted with human peripheral blood mononuclear (PBMC) cells were completely inhibited when treated at the time of implantation with a low dose (0.004 mg/kg; 2x/week) of REGN1979. As expected, T cells were required for this tumor inhibition, since treatment in the absence of human T cells was not effective. REGN1979 bispecific antibody also demonstrated potent activity against other tumor cells expressing CD20, as it significantly delayed CD20-transduced B16F10.9 tumor growth in immune-competent mice. Most importantly, REGN1979 induced dramatic tumor regression in large advanced (500-900 mm3) Raji tumors, associated with long-lasting tumor control. The tumor-infiltrating lymphocytes (TILs) in B cell lymphomas in these untreated NSG mice were found to express the inhibitory receptors Tim-3 and PD-1 and were the predominant fraction of T cells in the tumors and in the circulation. T cells in mice treated with REGN1979 showed decreased Tim-3 and PD-1 expression in the circulation accompanied by complete tumor regression. In further studies, REGN1979 (dosed at 0.4 mg/kg; 2x/week) was superior to rituximab therapy (dosed at 8 mg/kg; 5x/week) and comparable to the CD19xCD3 BiTE (dosed at 0.5 mg/kg; 5x/week) in suppressing established Raji tumors (200-400mm3). Pre-clinical studies in cynomolgus monkeys to assess activity of the bispecific antibody for depleting B cells in circulation and various lymphoid organs showed that a single injection of REGN1979 (0.1 mg/kg) was more potent at depleting CD20+ B cells in the mesenteric lymph nodes than a high dose of rituximab (30 mg/kg). In separate studies, REGN1979 was also found to have a long half-life (>14 days) in the circulation of monkeys following depletion of B cells. These studies show potent activity of a new class of fully human bispecific antibodies for treating tumors, and support clinical testing of REGN1979 in patients with CD20+ cancers. Figure 1 Figure 1. Disclosures Varghese: Regeneron Pharmaceuticals: Employment, Equity Ownership. Menon:Regeneron Pharmaceuticals: Employment, Equity Ownership. Rodriguez:Regeneron Pharmaceuticals: Employment, Equity Ownership. Haber:Regeneron Pharmaceuticals: Employment, Equity Ownership. Olson:Regeneron Pharmaceuticals: Employment, Equity Ownership. Duramad:Regeneron Pharmaceuticals: Employment, Equity Ownership. Oyejide:Regeneron Pharmaceuticals: Employment, Equity Ownership. Smith:Regeneron Pharmaceuticals: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals: Employment, Equity Ownership. Kirshner:Regeneron Pharmaceuticals: Employment, Equity Ownership.

Constitutive Chemokine Receptor Expression in B-Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3590-3590
Author(s):  
Michelle S. Bryson ◽  
Ruth F. Jarrett ◽  
Lesley Sheild ◽  
Gerard J. Graham
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Hodgkin’S Lymphoma ◽  
Memory T Cells ◽  
Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Mantle Cell

Abstract Chemokines are small peptides (∼8-14KDa) that play an essential role in both the innate and adaptive immune system. Chemokines are primarily involved in leukocyte trafficking, but are also involved in a number of cellular mechanisms. They elicit their effect through G-protein coupled receptors, the chemokine receptors (CKR). Functionally chemokines and their receptors are classified as inflammatory or constitutive. Constitutive CKRs and their ligands have a role in numerous diseases including malignancy, chronic inflammation and HIV infection. This study aimed to examine constitutive CKR expression in sub-types of B-cell NHL, of which there are limited studies so far. Lymph node preparations from patients with NHL were examined by flow cytometry using antibodies to CD20, CCR4, CCR6, CCR7, CCR9, CCR10, CXCR4 and CXCR5. The percentage of CD20 positive cells expressing the CKR under investigation was then calculated. The following cases were examined; follicular lymphoma (FL), n=11, Diffuse large B-cell lymphoma (DLBCL), n=11, mantle cell lymphoma (MCL) n=17, Burkitt’s lymphoma (BL), n=9 and MALT lymphoma, n=10. A number of differences between NHL sub-types were detected. FL cases generally had a lower expression of all the CKRs. CXCR5 and CXCR4 expression was high in all sub-types (>84% of B-cells) with no significant differences found, this would be expected as these CKRs are widely expressed in all B-cells. CCR10 expression was low or absent, with no significant differences detected. CCR6 and CCR9 show highest expression in MALT lymphomas, consistent with previous studies, but in comparison with other sub-types the differences was not significant. The most significant results were found with CCR7 and CCR4. CCR7 is expressed on naive T-cells, memory T-cells, B-cells and dendritic cells and is involved in the homing of lymphocytes to lymph nodes. CCR7 is currently the second most commonly reported CKR to be upregulated in malignancy, after CXCR4 and is related. We found very high levels of CCR7 in Mantle cell lymphoma (>90% of B-cells) as compared to other sub-types (p=0.005). CCR4 is expressed on Th2 and Treg lymphocytes, memory T cells and in a small subset of mature B-cells. CCR4 expression in T-cells has been correlated with an adverse prognosis in T-cell NHL and Hodgkin’s lymphoma, yet no systematic studies looking at CCR4 expression in B-cell neoplasms has been reported. These results showed a significant increase in CCR4 expression (>50% of B-cells) in DLBCL, MCL, MALT and BL as compared to FL (p<0.0001). We showed that there are differences in constitutive CKR expression in the different B-cell NHL types, with CCR4 expression being the most interesting finding. How CCR4 expression relates to prognosis in these lymphomas is as yet unknown but is under investigation. Targeting of the chemokine system using anti-CCR4 is already being used in clinical trials for T-cell neoplasms, and may be of potential benefit in selected B-cell neoplasms. Furthermore, the development of anti-CCR7 strategies may prove to be of benefit in the traditionally poor prognosis MCL patients.

scholarly journals Low Dose of Human scFv-Derived BCMA-Targeted CAR-T Cells Achieved Fast Response and High Complete Remission in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 960-960 ◽  
Author(s):  
Songfu Jiang ◽  
Jie Jin ◽  
Siguo Hao ◽  
Min Yang ◽  
Linjun Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Single Dose ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Dose Infusion ◽  
Human Scfv ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: B Cell Mature Antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy emerges as promising treatment for patients with relapse/refractory multiple myeloma (RRMM). Previous studies indicate patients who receive high-dose CAR-T cells may achieve better remission but have worse adverse events, like cytokine release syndrome (CRS). To solve this dilemma, we have developed novel autologous CAR-T therapeutics CT053 that are genetically modified T cells comprising an extracellular anti-BCMA human scFv and an intracellular 4-1BB costimulatory motif connected to a CD3-zeta T cell activation domain. Methods: A multi-center investigator-initiated clinical study is designed to evaluate CT053 in patients with RRMM who have failed in the prior treatment with ≥2 regimens, including a proteasome inhibitor, an immunomodulatory agent, and anti-CD38 monoclonal antibody. All patients have ≥50% BCMA expression on malignant cells. Patients are subjected to the lymphodepletion with 20-25 mg/m2 fludarabine and 300-500 mg/m2 cyclophosphamide daily for 2-4 days prior to receiving single-dose infusion of CT053 CAR-T cells. In case of progressive disease, patient may be dosed again on basis of investigators' evaluation of the disease status, BCMA expression and CAR-T persistence. Most enrolled patients received a single dose of 1.5 x 108 cells, except for 1 patient who received 0.5 x 108 cells and 1 patient who was infused with 1.8 x 108 cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs) and CAR T related AEs. Additional outcome measures include clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, overall and progression-free survival, pharmacokinetics and pharmacodynamic of CT053. Results: The study was performed in compliance with the declaration of Helsinki. As of the data cut-off date (July 10th, 2018), 16 patients (median 55 [39 to 67] years old) with a median of 3.9 (0.4 to 16.7) years since MM diagnosis, were infused with CT053. Patients had a median of 4 prior different regimens (range 2 to 10), and 56% (9/16) patients received prior autologous or allogeneic stem cell transplant. Among 16 patients, no neurotoxicity and no dose-limiting toxicities (DLT) were observed. The most common grade≥3 CAR-T related AEs were 3 thrombocytopenia (19%), 3 leukopenia (19%), 2 anemia (13%), 2 neutropenia (13%), 2 fever (13%) (Figure 1A). CRS was reported in 3 patients, including 1 Grade 3, 1 Grade 2 and 1 Grade 1, who had rapid recovery after Tocilizumab administration. 13/16 patients were eligible for initial evaluation of early clinical response with a median observation period of 8 (4 to 36) weeks. Overall response rate (ORR) in 13/13 patients was 100% post treatment. 12/13 patients (92%) quickly achieved partial response (4 PR), very good PR (6 VGPR), and complete response (2 CR) within 4 weeks post single-dose infusion (Figure 1B). 5/12 patients (42%) who were dosed at ≥1.5 x 108 CT053 CAR-T cells obtained CR at a median of 8 weeks post treatment. Durable responses from 4 weeks towards the data cut-off date were found in 12/13 patients (92%). One relapse from VGPR by the Week 12 was reported in a patient who had aggressive RRMM at enrollment and received the reduced dose of lymphodepletion regimen at 19 mg/m2 fludarabine and 192 mg/m2 cyclophosphamide for 2 days prior to CT053 infusion. Because positive BCMA expression on malignant cells was verified at relapse, the patient was re-dosed with CT053 at the Week 16 and subjected to the further evaluation. All patients had detectable CAR-T expansion from Day 3 post CT053 infusion. Expansion peaks were found on Day 7 (5/13), Day 14 (6/13) and Day 21 (2/13). 11/13 patients had notable persistence of CT053 CAR-T cells up to 4-6 months. The only relapsed patient had the lowest CAR-T expansion peak among 13 patients, indicating the potential correlation between CAR-T expansion and response outcome. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT053 CAR-T cells. Major AEs were transient, manageable, and reversible. 100% ORR in 13/13 evaluable patients were reported post single-dose infusion of 0.5~1.8 x 108 cells. 5/12 patients who were dosed at ≥1.5 x 108 CAR-T cells rapidly achieved durable CR at median of 8 weeks, suggesting CT053 could be developed as competitive therapeutics to treat patients with RRMM. Disclosures Ruan: CARsgen Therapeutics: Employment. Xiao:CARsgen Therapeutics: Employment, Equity Ownership. Wang:CARsgen Therapeutics: Employment, Equity Ownership. Li:CARsgen Therapeutics: Employment, Equity Ownership.

scholarly journals Immunotherapy with Long-Lived Anti-CD20 × Anti-CD3 Bispecific Antibodies Stimulates Potent T Cell-Mediated Killing of Human B Cell Lines and of Circulating and Lymphoid B Cells in Monkeys: A Potential Therapy for B Cell Lymphomas and Leukemias

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3111-3111 ◽  
Author(s):  
Seung Y. Chu ◽  
Sung-Hyung Lee ◽  
Rumana Rashid ◽  
Hsing Chen ◽  
Emily W. Chan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Half Life ◽  
Bispecific Antibodies ◽  
Employment Equity ◽  
Cynomolgus Monkeys ◽  
Equity Ownership ◽  
Anti Cd20

Abstract CD20 is highly expressed on normal and malignant B cells, and is a well-established target of antibody therapeutics for B cell leukemias and lymphomas. However, a limitation of approved anti-CD20 antibodies such as rituximab, ofatumumab, and obinutuzumab is that they are unable to stimulate T cell-mediated killing of CD20+ B cells. To exploit the potent activity intrinsic to T cell immunotherapy while maintaining the favorable dosing regimen of a therapeutic antibody, we have designed novel humanized bispecific antibodies that bind to both CD20+ B cells and CD3+ T cells. Such antibodies act via a mechanism known as "redirected T cell-cytotoxicity" (RTCC), because they stimulate targeted T cell-mediated killing regardless of T cell receptor antigen specificity. Unlike other bispecific formats, these antibodies possess a full Fc domain and spontaneously form stable heterodimers that are readily manufactured. Their Fc domain was also engineered to abolish binding to Fcγ receptors (to reduce the potential for nonselective T cell activation), yet preserve binding to human FcRn (to maintain long serum half-life). We first generated a series of affinity-optimized anti-CD20 × anti-CD3 bispecific antibodies and screened these using RTCC assays in which bispecifics stimulated killing of the CD20+ Ramos B cell line by purified human T cells. From this cell-based screen, we selected two candidates for further study in animal models. The bispecific antibodies XmAb13676 and XmAb13677 have identical T cell-engaging domains with 8 nM affinity for human CD3. XmAb13676 stimulated T cell killing of Ramos cells with an EC50 of ~53 ng/ml (~420 pM), while XmAb13677 (with higher affinity for CD20) had an EC50 of ~2 ng/ml (~16 pM). To assess in vivo half-life, we next dosed mice with 2 mg/kg of XmAb13676 or XmAb13677. In marked contrast to non-Fc domain-containing bispecific antibody formats, XmAb13676 and XmAb13677 had an extended serum half-life in mice of 6.7 and 6.6 days, respectively. Because these bispecifics were optimized for binding to human CD20 and CD3 targets and do not crossreact with mouse antigens, we evaluated efficacy in cynomolgus monkeys. We treated 3 monkeys per group with a single dose of XmAb13676 or XmAb13677 at 0.03, 0.3, or 3 mg/kg. Within 4 hr after dosing, T cells were strongly activated and stimulated depletion of over 97% of circulating CD40+ B cells, with the two 3 mg/kg groups showing greatest depletion. B cells continued to decrease for 24 to 48 hr after dosing, with the high-dose groups remaining at baseline levels for the duration of the study (29 days). CD4+ and CD8+ T cells in the circulation were activated immediately after treatment with XmAb13676 and XmAb13677, and this state was sustained for over 48 hr, as measured by greatly increased levels of the activation markers CD25 and CD69. Bispecific antibodies also induced rapid margination of CD4+ and CD8+ T cells from the circulation, with blood T cell populations returning to baseline from 2 to 7 days after dosing. Notably, CD40+ cells in lymph nodes and in bone marrow were depleted by over 90% at all doses, and at the higher dose levels, these B cell populations had not recovered by 29 days after treatment. Our results demonstrate that bispecific antibodies can recruit and activate T cells to efficiently kill CD20+ B cells not only in the circulation but also in the more resistant reservoir of lymphoid organs. These preclinical data in cynomolgus monkeys provide a rationale for clinical assessment of anti-CD20 × anti-CD3 bispecific antibodies in patients with CD20+ B cell leukemias and lymphomas. Disclosures Chu: Xencor: Employment, Equity Ownership. Lee:Xencor, Inc.: Employment, Equity Ownership. Rashid:Xencor, Inc.: Employment, Equity Ownership. Chen:Xencor, Inc.: Employment, Equity Ownership. Chan:Xencor, Inc.: Employment, Equity Ownership. Phung:Xencor, Inc.: Employment, Equity Ownership. Pong:Xencor, Inc.: Employment, Equity Ownership. Endo:Xencor, Inc.: Employment, Equity Ownership. Miranda:Xencor, Inc.: Employment, Equity Ownership. Bonzon:Xencor, Inc.: Employment, Equity Ownership. Leung:Xencor, Inc.: Employment, Equity Ownership. Muchhal:Xencor, Inc.: Employment, Equity Ownership. Moore:Xencor, Inc.: Employment, Equity Ownership. Bernett:Xencor, Inc.: Employment, Equity Ownership. Szymkowski:Xencor, Inc.: Employment, Equity Ownership. Desjarlais:Xencor, Inc.: Employment, Equity Ownership.

Targeted Depletion of B-Cell Subsets by Anti-CD22 and Anti-CD79bAntibody Drug Conjugates: Illumination of the Mechanism of Action through Pharmacodynamic Biomarkers

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3923-3923
Author(s):  
Franklin Fuh ◽  
Caroline Looney ◽  
Dongwei Li ◽  
Kirsten Achilles Poon ◽  
Randall Dere ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Mechanism Of Action ◽  
Peripheral Blood ◽  
Employment Equity ◽  
Ki 67 ◽  
Cynomolgus Monkeys ◽  
Drug Conjugates ◽  
Equity Ownership

Abstract Abstract 3923 CD22 and CD79b are cell surface receptors whose expression is limited to B-cells. Both CD22 and CD79b are expressed on NHL and CLL patient B-cells, as well as on relapsed NHL B-cells (Dornan et al., 2009; Polson et al., 2010). In order to develop a target specific therapy for the treatment of CLL and NHL, we generated anti-CD22 and anti-CD79b antibody drug conjugates (ADCs) linked to an auristatin, a potent anti-mitotic drug that disrupts cellular mitosis through inhibition of tubulin polymerization. Preliminary efficacy data have shown that these ADCs have significant activity in preclinical xenograft models of NHL, while minimal activity was observed with the unconjugated antibody (AG Polson et al, 2010). To evaluate the cellular effects and characterize the mechanism of action (MOA) of these ADCs, we have examined the pharmacokinetics and the pharmacodynamic effects in non-human primates. Substantial B cell depletion was observed after administration of either anti-CD22-ADC or anti-CD79b-ADC to cynomolgus monkeys. By comparison, the extent and duration of B cell depletion was less substantial in animals dosed with unconjugated anti-CD22 or anti-CD79b antibodies. We evaluated several potential mechanisms for the depletion, including antibody opsonization, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and internalization of drug conjugates which leads to subsequent intracellular release of cytotoxic drug and cell death. Our data from in vitro anti-CD22 studies showed minimal to no ADCC or CDC activity, suggesting that these mechanisms play little to no role in vivo. Consistent with the expected MOA of ADCs, we observed depletion of proliferating splenic follicular germinal center B cells in cynomolgus monkeys following dosing with anti-CD22 ADC. Furthermore, in studies with either anti-CD22-ADC or anti-CD79b-ADC, preferential depletion of proliferating Ki67+ B lymphocytes (compared to Ki67- B lymphocytes) was observed in peripheral blood of ADC-dosed animals, and not in animals dosed with the unconjugated antibody or with vehicle control. This preferential depletion was observed on Days 8 and 15, but was not seen on Day 21 or at subsequent time points, which correlated with the expected serum clearance of the ADC. In contrast, we observed that administration of either ADC resulted in a dose-dependent decrease in circulating non-proliferating B cells one day after dosing. Taken together, these observations agree with the proposed mechanism of action of initial depletion of both proliferating and non-proliferating B cells via antibody-mediated opsonization at early time points after dosing (1-2 days) with subsequent preferential depletion of proliferating B lymphocytes mediated by the auristatin component of the anti-CD22 and anti-CD79b ADCs. These data support CD22 and CD79b ADCs as promising candidate therapeutics for the treatment of NHL and CLL, as both anti-CD22 and anti-CD79b drug conjugates are capable of targeting Ki-67+ (proliferating) B cells in lymphoid tissues and peripheral blood. In CLL, Ki-67+ cells in bone marrow have been hypothesized to represent pathogenic ‘stem’ cells, and our preliminary data indicate increased percentages of Ki-67+ B cells in the peripheral blood of CLL patients compared to normal healthy adults. As both anti-CD22 and anti-CD79b ADCs specifically deplete proliferating B cells, the development of these ADCs represents an effective way to target proliferating pathogenic B cells in NHL and CLL, and offers a more favorable risk-benefit profile than traditional chemotherapeutic agents. Disclosures: Fuh: Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Looney:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Li:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Poon:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Dere:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Ramakrishnan:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Polson:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Prabhu:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership. Williams:Genentech/Hoffmann-La Roche Inc.: Employment, Equity Ownership.

scholarly journals Sequence Level Analysis of Hodgkin Lymphoma Clonotypes Detected in Peripheral Blood Using a Next-Generation Sequencing Approach

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1610-1610
Author(s):  
Yasuhiro Oki ◽  
Sattva S. Neelapu ◽  
Michelle Fanale ◽  
Larry W. Kwak ◽  
Luis Fayad ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Expression Level ◽  
Employment Equity ◽  
Tumor Biopsy ◽  
Cellular Compartment ◽  
Equity Ownership ◽  
Level Analysis

Abstract Background: Classical Hodgkin lymphoma (CHL) has been established as B-cell malignancy characterized by a clonal expansion of pathognomonic Reed Sternberg cells (Marafioti et al. Blood 2000). A previous report suggests that clonotypic B-cells may be present in the blood of patients with CHL; however, the relationship between these circulating clonotypic B-cells and CHL is unclear. We utilized the LymphoSIGHT™ method, a next-generation sequencing approach, to detect lymphoma-specific clonotypes in peripheral blood in patients with CHL at diagnosis or disease recurrence as well as in follow-up blood samples. This method has the sensitivity to detect one lymphoma cell per million leukocytes in peripheral blood, and has been applied to minimal residual disease (MRD) detection in multiple B-cell malignancies. We evaluated the extent of somatic hypermutation in the lymphoma clonotypes, and performed sequence and expression level analyses of the lymphoma clonotype repertoire. Methods: Frozen primary tumor biopsy samples were first analyzed for clonality at the immunoglobulin heavy chain (IGH) and kappa chain (IGK) loci using the LymphoSIGHT method. Rearranged immunoglobulin gene segments (IGH-VDJ, IGH-DJ and IGK) in the genomic DNA and/or RNA were amplified with locus-specific primer sets, sequenced, and analyzed using standardized algorithms for clonotype determination. Clonotypes with a frequency >5% in the B-cell repertoire of the tumor biopsy were considered to represent tumor clonotypes. IGH-VDJ clonotypes with a frequency >2% in DNA were deemed to be cancer-specific if the clonotype was not present in the RNA. Such clonotypes were then quantitated in serum and peripheral blood mononuclear cells (PBMC), and DNA sequence and/or RNA expression level analysis was performed. Results: A total of 17 CHL patients were analyzed. A high-frequency clonal rearrangement was identified for at least one receptor (IGH-VDJ, IGH-DJ and IGK) in 12 of 17 cases (71%). Lymphoma-specific clonotypes were detected in blood samples from 8 of 11 patients (73%). Notably, a lymphoma-specific clonotype was detected in the serum compartment in 8 of 9 cases (89%) tested (Figure 1A), while it was detected in PBMC only in 3 of 9 cases (33%) tested (Figure 1B). Follow-up samples obtained from three patients in remission were negative for the tumor-specific clonotype in both the serum and cellular compartments. We conducted sequence and expression level analysis of each IGH-VDJ clonal rearrangement. We calculated the number of somatic mutations in each lymphoma-specific clonotype compared to the germline sequence in the interrogated region. In the ten patients with IGH-VDJ clonal rearrangements, we observed a median of 14 somatic mutations (range 0 to 27). This confirms that HRS cells correspond in their developmental stage to germinal or post-germinal center B-cells. While IGH-VDJ clonotypes were observed frequently in DNA obtained at diagnosis, IGH-VDJ clonotypes were not detected in the RNA from the same sample. We evaluated the relationship between the presence of lymphoma-specific clonotypes in the cellular compartment at diagnosis and eventual progression. All three untreated patients that were positive at baseline in the cellular compartment experienced relapse or progression (at 3, 11 and 17 months). In contrast, zero of 5 patients without detectable lymphoma-specific clonotypes in their cellular compartment at baseline experienced relapse (follow up duration 23-45 months, log-rank test p=0.004). Conclusions: This is the first clinical assay that can be used to detect and monitor MRD in CHL. Lymphoma-specific sequences can be identified in serum in 80% of cases. Our preliminary analysis suggests that the presence of lymphoma-specific clonotypes in PBMCs may indicate high risk for recurrence. This study demonstrates proof-of-principle and underscores the promise of a new methodology to measure disease burden and provide prognostic information from a blood test in patients with CHL. Figure 1. Lymphoma clonotype levels in A) cell-free plasma and B) PBMC samples are shown for the different patients. Figure 1. Lymphoma clonotype levels in A) cell-free plasma and B) PBMC samples are shown for the different patients. Figure 2 Figure 2. Disclosures Klinger: Sequenta, Inc.: Employment, Equity Ownership. Carlton:Sequenta, Inc.: Employment, Equity Ownership. Kong:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Cell Enrichment for FISH: A Novel Diagnostic Tool in Challenging Cases of Low Bone Marrow Involvement By Mature B-Cell Neoplasms

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2992-2992
Author(s):  
Farzad Nooraie ◽  
J. Dianne Keen-Kim ◽  
Derek Denton Lyle ◽  
Shannon Dingivan ◽  
Austin Mauch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Detection Rate ◽  
Cell Detection ◽  
Employment Equity ◽  
Cell Enrichment ◽  
Equity Ownership ◽  
Blood Specimens

Abstract Cytogenetic studies are useful tools which can provide diagnostic, prognostic and management information for mature B-cell neoplasms. Mature B-cells do not grow well in cytogenetic cultures. Therefore, detection, characterization and differentiation of scant mature B-cell neoplasms or minimal residual disease can be difficult in bone marrow or peripheral blood specimens. FISH provides more sensitive information than G-band chromosome analysis. However, in cases with low-level involvement of the marrow, abnormal FISH results may be missed or not reported when abnormalities do not exceed experimentally determined cut-off values. To increase the sensitivity of abnormal mature B-cell detection, we developed an enrichment method utilizing pan B-cell antibodies. This method separates mature B-cells from the remaining bone marrow and/or peripheral blood cells. We selected 59 bone marrow and peripheral blood specimens from patients referred for mature B-cell neoplasms (except for myeloma) for use in the validation. These specimens had 1% to 10% monoclonal mature B-cells detected by flow cytometry and were enriched using cell-separating technologies. Each specimen was divided into four equal portions, with three of four portions undergoing enrichment using different pan B-cell antibodies. The fourth portion was reserved for standard non-enriched testing and was used for comparison to results obtained in the enriched portions. A variety of corresponding FISH analyses were performed in each of the four portions, based upon the disease state. FISH results were obtained by two independent scoring technologists. Enrichment with B-cell antibodies improved detection of FISH abnormalities that may not have otherwise been observed in the patient specimens. 42% (25/59) of samples had abnormalities detected within the enriched portion that were not detected in the standard non-enriched portion. Of these, 64% (16/25) had a FISH abnormality that was a critical finding for the final diagnosis, prognosis and/or management of the patient. Enrichment also increased the sensitivity of FISH abnormality detection. 29% (17/59) of samples had abnormalities that were detected in both the enriched and non-enriched portions. However, detection was on average 15-fold more sensitive. The average detection rate of FISH abnormalities in the non-enriched portion was 3%, which is at or near the experimentally determined cut-off value for most FISH probes. In contrast, the average detection rate of FISH abnormalities in the enriched portion was 56%. In 5% (3/59) of cases, detection of FISH aberrations in enriched specimens helped to distinguish two separate neoplastic processes in the bone marrow. These results demonstrate the increased opportunity for detecting FISH aberrations in enriched versus non-enriched specimens. Mature B-cell enrichment and subsequent FISH testing in cases of scant mature B-cell neoplastic involvement of the bone marrow and/or peripheral blood is a novel and powerful cytogenetic technique. This technique enriches bone marrow and/or peripheral blood specimens for targeted abnormal cells and increases the number of those cells analyzed by FISH testing, thus allowing for a higher detection rate of genetic abnormalities. Disclosures Nooraie: Genoptix Inc., A Novartis Company: Employment, Equity Ownership. Keen-Kim:Genoptix Inc., A Novartis Company: Employment, Equity Ownership. Lyle:Genoptix Inc., A Novartis Company: Employment, Equity Ownership. Dingivan:Genoptix Inc., A Novartis Company: Employment, Equity Ownership. Mauch:Genoptix Inc., A Novartis Company: Employment, Equity Ownership. Lynes:Genoptix Inc., A Novartis Company: Employment. Castillo:Genoptix Inc., A Novartis Company: Employment. Kolker:Genoptix Inc., A Novartis Company: Employment. Cancino:Genoptix Inc., A Novartis Company: Employment, Equity Ownership.

Targeting Cereblon with the High Affinity Immunomodulatory Compound CC-220: A Novel Therapeutic Agent for B Cell Dyscrasias

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1055-1055 ◽  
Author(s):  
Peter H Schafer ◽  
Emily Rychak ◽  
Derek Mendy ◽  
Anastasia Parton ◽  
Lori Capone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
T Cells ◽  
B Cell ◽  
Binding Studies ◽  
Employment Equity ◽  
Amino Terminal ◽  
High Affinity ◽  
Equity Ownership ◽  
Affinity Beads

Abstract Abstract 1055 Background: Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex including CUL4A, DDB1, and ROC-1, and was found to be the molecular binding target of thalidomide (Thalomid®), lenalidomide (Revlimid®), and pomalidomide. CC-220 is a novel immunomodulatory compound developed with increased potency and is currently in development for the treatment of immune conditions. The effect of CC-220 on CRBN binding, ubiquitination, and cell proliferation was profiled. Methods: Binding studies to CRBN were conducted using thalidomide analog-conjugated beads in a competitive assay. Endogenous CRBN from human U266 multiple myeloma (MM) cells was measured by incubating cell extracts with varying concentrations of either CC-220 or pomalidomide as a positive control. Affinity beads coupled to a thalidomide acid analog were incubated with the U266 extracts and, after extensive washing of the beads, the bound proteins were eluted. CRBN binding to the thalidomide-coupled affinity beads was determined by quantitative CRBN immunoblot determination. CRBN ubiquitination was measured in HEK293T cells, which were transfected with an amino-terminal His-biotin-tagged CRBN construct, then preincubated with compounds for one hour followed by treatment with the MG132 proteasome inhibitor (to arrest degradation of ubiquitinated proteins). Cells were lysed and processed to measure CRBN ubiquitination by SDS-PAGE and immunoblot analysis using an anti-ubiquitin antibody. Cell proliferation studies were conducted in lenalidomide-sensitive and -refractory multiple myeloma cells. Lenalidomide-resistant or -sensitive H929 MM cell lines were treated with CC-220 for 5 days, and then cell proliferation and viability were assessed by 7-aminoactinomycin D (7-AAD) staining. T-cell costimulation was measured in purified primary human T cells stimulated using immobilized anti-CD3 antibody in cell culture for 2 days, and cytokine secretion was measured by ELISA. Immunoglobulin M and G (IgG and IgM) production was measured from normal donor peripheral blood mononuclear cells by culturing in the presence of the B cell differentiation factors recombinant human IL-2 (20 U/mL), IL-10 (50 ng/mL), IL-15 (10 ng/mL), His-tagged CD40 Ligand (50 ng/mL), polyHistidine mouse IgG1 antibody (5 μg/mL), and ODN 2006-Human TLR9 ligand (10 μg/mL) for 4 days, followed by IL-2, IL-10, IL-15, and IL-6 (50 ng/mL) for an additional 3 days. IgM and IgG were measured by ELISA. Results: In the competitive CRBN binding studies, preincubation with pomalidomide at a concentration of 3 μM resulted in approximately 50% less CRBN bound to the affinity beads, while CC-220 at a concentration of 0.1 μM resulted in similar CRBN binding. CRBN ubiquitination studies in the transfected HEK293T cells resulted in the following potencies: CC-220 IC50 = 0.19 μM; lenalidomide IC50 = 12.9 μM; and pomalidomide IC50 = 21.6 μM. The IC50 value for inhibition of proliferation by CC-220 shifted from 0.01 μM in the parental H929 cell line and 0.04 μM in the DMSO-treated subclone to 0.51–1.58 μM in the lenalidomide-resistant subclones. A 50% decrease in cell cycle (S-phase) was evident after 24 hours of treatment of H929 cells with CC-220. At 48 hours, CC-220 decreased expression of survivin and retinoblastoma protein (pRB) and increased expression of the cyclin-dependent kinase inhibitor p27. CC-220 costimulated IL-2 production by T cells with an EC50 of approximately 0.29 nM, compared with 10 nM for pomalidomide. CC-220 inhibited IgM and IgG production with an IC50 of 0.35 and 2.1 nM, respectively, compared to 17 nM and 63 nM for pomalidomide. Conclusions: The results indicate that CC-220 binds to CRBN with approximately 30-fold higher affinity than pomalidomide, and inhibits CRBN ubiquitination with approximately 110-fold greater potency than pomalidomide in this system. CC-220 is approximately 34-fold more potent than pomalidomide for costimulating IL-2 production by T cells, and is 30- to 48-fold more potent than pomalidomide for inhibiting immunoglobulin production. In summary, CC-220 is a novel high affinity CRBN ligand with cellular potencies 1 or 2 orders of magnitude greater than that of pomalidomide, and is currently in development for the treatment of immune conditions, including those involving B cell dyscrasias. Disclosures: Schafer: Celgene: Employment, Equity Ownership. Rychak:Celgene: Employment, Equity Ownership. Mendy:Celgene Corp.: Employment, Equity Ownership. Parton:Celgene Corp: Employment, Equity Ownership. Capone:Celgene Corp: Employment, Equity Ownership. Lopez-Girona:Celgene Corp: Employment, Equity Ownership. Daniel:Celgene Corporation: Employment. Chopra:Celgene Corp: Employment, Equity Ownership.

scholarly journals Immunological Consequences of Lenalidomide with and without Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3070-3070
Author(s):  
Jake A. Kloeber ◽  
Teresa K. Kimlinger ◽  
Jessica L. Haug ◽  
Kimberly J. Henderson ◽  
S.Vincent Rajkumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Research Funding ◽  
Nk Cell ◽  
Single Agent ◽  
Cell Populations ◽  
Newly Diagnosed

Introduction: Recent advancements in the treatment of multiple myeloma (MM) have centered on engaging the immune system to target multiple myeloma cells. Although these therapies are being combined with immunomodulatory imide drugs (IMiDs) and corticosteroids, the individual contributions of these drugs on the immune system of MM patients has not been examined in the upfront setting. In this study, we examined the peripheral blood immunophenotypes of newly diagnosed multiple myeloma (NDMM) patients receiving the IMiD lenalidomide with or without the corticosteroid dexamethasone. Methods: To characterize immunophenotypes, we utilized flow cytometry to profile white blood cell populations from 35 patients enrolled in a clinical trial testing the efficacy of lenalidomide with and without dexamethasone in NDMM (NCT00772915). In this trial, all patients were initiated on single-agent lenalidomide. Dexamethasone was initiated in patients that did not meet desirable responses or for disease progression. At each cycle, peripheral blood was stained with a 17-marker antibody panel against several immune lineages and functional surface markers. We grouped patients into two groups: 1) lenalidomide alone or 2) lenalidomide with dexamethasone according to their treatment regimen at each cycle timepoint. Results: First we confirmed anti-myeloma cell activity for both groups by measuring a steady decline in circulating plasma cells in both groups. Examining peripheral blood immunophenotypes showed an expected decrease in T cells and a smaller decrease in B cells in both groups of patients. Closer inspection of B cell populations revealed a switch towards a more immature B cell phenotype in both treatment groups. This was measured as a switch from CD19-CD20+ cells to CD19+CD20- B cells. Inspection of T cell subsets revealed that patients receiving single-agent lenalidomide had a sustained decrease in the levels of CD4+ T cells and increase in the levels of CD8+ T cells. This was seen in both naïve and regulatory T cells evidenced by a decrease in the CD4/CD8 ratio among CD28+ T cells as well as CD25+ T cells. Importantly, this alteration did not lead to sustained alterations in the overall level of CD25+ or CD28+ T cells, and the addition of dexamethasone reverses this trend. In addition to the effects seen on T and B cell numbers, we detected expansions of NK cell populations in patients receiving lenalidomide alone. This expansion is detected as an overall increase in CD56+ mononuclear cells with the majority of cells being CD56+CD3- cells. Conclusions: Our data show that lenalidomide and dexamethasone therapy have shared but distinct effects on peripheral blood immunophenotypes in NDMM. Both drugs alter B cells numbers and populations leading to an expansion of CD19+CD20- B cells. However, lenalidomide alone decreases the CD4/CD8 T cell ratio; and, lenalidomide more strongly expands NK cell populations. The addition of dexamethasone reverses this trend and leads to a restoration of the CD4/CD8 ratio. This suggests that lenalidomide without dexamethasone might be counterproductive in immunotherapies intended to recruit CD4+ T cells. Conversely, lenalidomide alone could increase the efficacy of immunotherapies dependent on NK cell recruitment such as antibody-dependent cellular cytotoxicity (ADCC). This information may benefit future investigations of immune responses in MM patients and improve the adoption of immunotherapies to MM patients. Figure Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

scholarly journals MGD011, Humanized CD19 x CD3 DART® Protein with Enhanced Pharmacokinetic Properties, Demonstrates Potent T-Cell Mediated Anti-Tumor Activity in Preclinical Models and Durable B-Cell Depletion in Cynomolgus Monkeys Following Once-a-Week Dosing

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1775-1775 ◽  
Author(s):  
Liqin Liu ◽  
Annie Lam ◽  
Ralph Alderson ◽  
Yinhua Yang ◽  
Hua Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Target Cells ◽  
Employment Equity ◽  
Cynomolgus Monkeys ◽  
Lymphoma Line ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract CD19, a lymphocyte-specific marker expressed from early B-lymphocyte development through mature memory B cells, is highly represented in B-cell malignancies, making it attractive for targeted interventions. MGD011 is a Dual-Affinity Re-Targeting (DART®) protein designed to redirect T-cells to eliminate CD19-expressing cells through co-engagement of CD19 and CD3 in a monovalent binding fashion. MGD011 was engineered with a modified Fc domain that is inactivated for binding to FcγRs but retains binding to the neonatal Fc receptor (FcRn) of the immunoglobulin salvage pathway, allowing for extended pharmacokinetic (PK) properties and convenient dosing at a once-a-week or longer interval. To enable preclinical toxicokinetics and dose optimization, MGD00011 was also designed to cross-react with non-human primates. MGD011 demonstrates bispecific binding to B and T cells isolated from human and cynomolgus monkey blood. MGD011 mediates potent in vitro redirected T-cell killing of B-cell lymphoma cell lines and effective autologous B-cell depletion of human or cynomolgus monkey peripheral blood mononuclear cells (PBMCs). MGD011-mediated killing of CD19 target cells was accompanied by target-dependent T-cell expansion and activation, cytokine release and upregulation of perforin and granzyme B, consistent with the redirected T-cell mediated killing mechanism of action endowed in its design. Two tumor models in NOD/SCID/IL2 receptor gamma chain-deficient (NSG) or NSG/beta2-microglobulin-deficient (NSG/Bm2-/-) mice were used to ascertain in vivo activity of MGD011. The growth of newly-implanted tumor xenografts of HBL-2 cells, a mantle cell lymphoma line, or Raji cells, a Burkitt’s lymphoma line, was efficiently inhibited by intravenous (IV) administration of MGD011 following the subcutaneous (SC) implantation of the target cells co-mixed with activated human T cells in Winn’s tumor models. Furthermore, in human PBMC-reconstituted mice bearing pre-established intradermal (ID) HBL-2 xenografts, MGD011 demonstrated potent anti-tumor activity with high complete response rates and no evidence of relapse over the study duration. To assess the safety and pharmacodynamic activity of MGD011, a dose-escalation study of MGD011 administered once weekly by 2-hour IV infusion was conducted in cynomolgus monkeys. MGD011 was well tolerated at doses up to 100 µg/kg, the highest dose tested, with no drug-related adverse findings and modest elevations in serum cytokines. MGD011-related pharmacological effects included marked decrease in circulating B cells at doses as low as 0.5 µg/kg, profound reduction of CD20+ cells in lymphoid organs and only modest recovery 4 weeks after the last dose. As expected, MGD011 displays prolonged PK properties, consistent with that of a human IgG1 in monkeys. In summary, the safety, activity and PK profiles of MGD011 support further investigation as a therapeutic candidate for treatment of B-cell malignancies. Disclosures Liu: Macrogenics Inc.: Employment, Equity Ownership. Lam:Macrogenics Inc.: Employment, Equity Ownership. Alderson:Macrogenics Inc: Employment, Equity Ownership. Yang:Macrogenics Inc: Employment, Equity Ownership. Li:Macrogenics Inc: Employment, Equity Ownership. Long:Macrogenics Inc: Employment, Equity Ownership. Gorlatov:Macrogenics Inc: Employment, Equity Ownership. Burke:Macrogenics Inc: Employment, Equity Ownership. Ciccarone:Macrogenics Inc: Employment, Equity Ownership. Nordstrom:Macrogenics Inc: Employment, Equity Ownership. Johnson:Macrogenics Inc: Employment, Equity Ownership. Moore:Macrogenics Inc: Employment, Equity Ownership. Bonvini:Macrogenics Inc: Employment, Equity Ownership.

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