BackgroundCC-220 is a cereblon E3 ligase modulatory compound currently in development for the treatment of Systemic Lupus Erythematosus as well as other autoimmune conditions and multiple myeloma. As a high affinity ligand for cereblon, CC-220 administration results in significant reductions in ikaros (IKZF1) and aiolos (IKZF3), transcription factors which are genetically linked to SLE risk, and are overexpressed in the peripheral blood of SLE patients compared to healthy controls.ObjectivesTo describe the pharmacokinetics (PK), pharmacodynamics (PD), and the PK-PD relationship of CC-220 in subjects with SLE.MethodsCC-220-SLE-001 is a randomized, double-blinded, placebo-controlled, phase 2a dose escalation study to investigate the safety, PK, PD, and efficacy of CC-220 in patients with SLE. Forty-two (42) adult SLE subjects fulfilling SLE ACR criteria, having a history of SLE for ≥6 months and a baseline Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥4 were randomized to placebo or 1 of 4 escalating doses of CC-220 (0.3 mg QOD, 0.3 mg QD, 0.6/0.3 mg alternating QD, or 0.6 mg QD).ResultsCC-220 concentration-time profiles demonstrated dose proportionality between cohorts, with moderate accumulation in the non-alternating dose cohort. CC-220 significantly reduced total CD20+ B cells by as much as 96%, immature B cells by as much as 91.2%, switched memory B cells by as much as 81.4%, BAFFR+ B cells by as much as 67.5%, and plasmacytoid dendritic cells (pDCs) by as much as 86.5% (Day 85 median percent change from baseline). Whereas reductions in B cells were observed, CD4+ as well as CD8+ T cells increased, and the rise in T cells paralleled the observed increase in plasma cells in those subjects who received the highest dose (0.6 mg). An exposure-response analysis demonstrated decreasing B cells, pDCs and neutrophils with increased exposure to CC-220.ConclusionsIt was determined that 0.3 mg QD to 0.6/0.3 mg alternating QD reduced concentrations of B cells and pDC's while avoiding neutropenia. These findings, in combination with the PK, safety, and exploratory efficacy data, support continued development of CC-220 in SLE.Disclosure of InterestA. Gaudy Shareholder of: Celgene, Employee of: Celgene, Y. Ye Shareholder of: Celgene, Employee of: Celgene, S. Korish Shareholder of: Celgene, Employee of: Celgene, D. Hough Shareholder of: Celgene, Employee of: Celgene, M. Weiswasser Shareholder of: Celgene, Employee of: Celgene, S. Choi Shareholder of: Celgene, Employee of: Celgene, R. Furie Consultant for: Celgene, V. Werth Grant/research support from: Celgene, Consultant for: Celgene, P. Schafer Shareholder of: Celgene, Employee of: Celgene
BackgroundCereblon (CRBN) is a component of the E3 ubiquitin ligase complex, including cullin 4A, DNA damage binding protein 1, and regulator of cullin 1. CC-220 binds to cereblon, affecting the ubiquitin E3 ligase activity and mediating antiproliferative and immunomodulatory effects on lymphocytes. CC-220 is an orally available immunomodulator under development for autoimmune diseases.ObjectivesAssess the effects of CC-220 on immune responses to tetanus toxoid (T-cell-dependent antigen) and pneumococcal polysaccharide (T-cell-independent antigen), peripheral T and B lymphocytes, ex vivo cytokine productions, and in vitro rheumatoid factor antibody production from healthy subject samples.MethodsEffects of CC-220 on immune responses were assessed as part of a multiple-ascending dose study in healthy subjects. Protective levels of antitetanus titer were required for enrollment. Six subjects received CC-220 1 mg QD and 3 subjects received placebo QD for 28 days. On Day 14, subjects received vaccines of 23-valent pneumococcal polysaccharide (PPV23) and tetanus toxoid. Antibody responses, peripheral B- and T-cell counts, and ex vivo cytokines were measured. In addition, the effect of CC-220 on autoantibody production in vitro was assessed using activated and differentiated human peripheral blood mononuclear cells from donors with rheumatoid arthritis.ResultsCC-220 reduced immune responses to PPV23, with 60% of CC-220-treated subjects (3/5) showing normal response (≥2-fold of baseline or >1 μg/mL increase from baseline in antibodies against >70% serotypes) compared with 100% of placebo subjects (2/2) showing normal responses. However, the reduction was mild, as all CC-220 subjects were able to mount normal immune responses to 12 out of 23 serotypes. Immune responses to tetanus toxoid were similar between CC-220-treated subjects and placebo subjects, with 60% of CC-220 subjects (3/5) and 50% of placebo subjects (1/2) demonstrating a 4-fold increase from baseline in antitetanus IgG titer. Following 14 days of CC-220 dosing, peripheral B-cell counts were decreased from baseline by 79%, and T-cell counts were decreased by 22%. In ex vivo assays, CC-220 increased IL-2 and interferon-γ production from anti-CD3-stimulated whole blood and inhibited IL-1α and IL-1β production from lipopolysaccharide-stimulated whole blood. In an in vitro assay using cells from donors with rheumatoid arthritis, CC-220 inhibited the production of rheumatoid factor.ConclusionsCC-220 1 mg QD modestly decreased the T-cell-independent antibody response to PPV23, but did not affect the recall response to tetanus toxoid, a T-cell-dependent antibody response. These responses are consistent with CC-220 inhibition of B-cell differentiation while enhancing T-cell cytokine production.Disclosure of InterestY. Ye Employee of: Celgene Corporation, P. Schafer Employee of: Celgene Corporation, M. Thomas Employee of: Celgene Corporation, D. Weiss Employee of: Celgene Corporation, A. Gaudy Employee of: Celgene Corporation, Z. Yang Employee of: Celgene Corporation, ...
survival (OS) and progression free survival (PFS) in MM patients. Furthermore, the preclinical activity of a new GPRC5DxCD3 bispecific antibody (JNJ-7564) in development for the treatment of MM was evaluated, as well as biomarkers for in vitro JNJ-7564 response. Methods: GPRC5D protein expression was assessed by flow cytometry on BM MNCs derived from healthy donors (HD) and MM patients. GPRC5D gene expression levels were analyzed in purified CD138 + MM cells derived from patients who participated in 5 large randomized clinical trials (HOVON65, MRC-IX, TT2, TT3 and APEX). MM cell lysis by JNJ-7564 (0.00064-4 µg/ml; 48 hour-incubation) was evaluated in MM cell lines and whole BM samples from newly diagnosed (ND) and relapsed/refractory (RR) MM patients. At baseline, the MNCs were characterized for the composition of T-cell subsets. T-cell activation and degranulation were measured by flow cytometry based on expression of CD25 and CD107a, respectively. Results: GPRC5D protein expression was significantly higher on MM cells compared to other BM cells, including HD plasma cells (fig 1A). GPRC5D protein expression was positively correlated with BCMA expression (r = 0.44; P = 0.02), but was independent of tumor load, and CD38 or PD-L1 expression on MM cells. Gene expression levels of GPRC5D were highly variable in MM, and independent of age and ISS stage, but were significantly higher in patients with t(4;14) or gain 1q. There was no association with OS or PFS in the 5 clinical trials (n = 1421). JNJ-7564 effectively killed GPRC5D + MM cell lines (MM1.S, UM9 (fig 1B) and RPMI8226) in a dose-dependent manner using HD peripheral blood MNCs as effector cells. Co-incubation with patient-derived BM stromal cells resulted in a modest impairment of killing capacity in MM1.S and RPMI8226 cells. In MM patient samples (n = 20), the mean lysis of MM cells with 4.0 µg/mL JNJ-7564 was 62% (range: −8-97%; fig 1C), while NK-cell and T-cell frequencies were not affected. JNJ-7564 was also effective in samples from extensively pretreated daratumumab (DARA)-refractory patients (DRMM; n = 6; median of 6 prior lines; mean lysis with 4.0 µg/mL: 70%; range: 44-97%). Maximal lysis of primary MM cells was not associated with the level of GPRC5D expression on MM cells, effector:target ratio, or frequency of regulatory T-cells. JNJ-7564-mediated MM cell lysis was associated with activation and degranulation of CD4+ and CD8+ T-cells (fig 1D).
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