Population Pharmacokinetics and Exposure-Response Analyses for Glofitamab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL): Confirmation of Efficacy and CRS Mitigation in Patients with Step-up Dosing

Introduction: Glofitamab (RG6026; RO7082859; CD20-TCB) is a novel '2:1' format T-cell-engaging bispecific antibody that has two CD20 and one CD3 binding domains, enabling increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing in B-cell malignancies. Clinical data from NP30179 demonstrated that fixed dosing of glofitamab (0.6-25mg) induced high and durable complete responses with a manageable safety profile in heavily pre-treated R/R NHL patients (pts; Dickinson, et al. EHA 2020). Obinutuzumab pretreatment (Gpt) 7 days prior to first administration of glofitamab was shown to be effective in mitigating the risk of cytokine release syndrome (CRS), allowing for rapid escalation of glofitamab to clinically active doses (Dickinson, et al. EHA 2020). We previously investigated population pharmacokinetics (popPK) and exposure-response (ER) relationships for glofitamab in NP30179; NCT03075696 (Djebli N, et al. Blood 2019), where modelling indicated step-up dosing would further mitigate CRS while maximizing efficacy. The present analysis is an update of previous models, including confirmatory data from the first step-up dosing (SUD) pts. Methods: Pts with indolent (i) or aggressive (a) R/R NHL received glofitamab fixed dosing (0.005-25mg every 2 or 3 weeks) or SUD (n=31, 2.5/10/16 and 2.5/10/30mg) following single Gpt 1000mg on Cycle (C) 1 Day (D) −7 to mitigate CRS. Serial and sparse glofitamab, and sparse G PK data were used to develop a popPK model in NONMEM® software (v7.4). The cut-off date of April 17, 2020 enabled inclusion of 16 (2.5/10/16mg) and 15 (2.5/10/30mg) SUD pts. Physiologically relevant covariates were investigated for their potential influence on glofitamab PK variability. Using the established G popPK model (Gibiansky, et al. CPT Pharmacometrics Syst Pharmacol 2014), G concentration-time profiles were constructed to estimate glofitamab receptor occupancy (RO%) in the presence of G competing for CD20 receptors over time. The relationship between glofitamab AvgRO% over the first 24 hours and CRS, with a focus on Grade (Gr) ≥2 CRS (defined by ASTCT criteria [Lee, et al. 2019]) was investigated in iNHL and aNHL pts combined. ER relationships between glofitamab time-averaged RO% (AvgRO%) up to C3D1, which is when the first response assessment was taken, and complete response rate (CRR) were characterized in aNHL pts who reached C3D1. Results : PopPK were analyzed in 230 iNHL and aNHL pts with ≥1 PK sample (fixed and SUD). ER relationships were analyzed in 95 aNHL pts with PK/efficacy data at C3D1, and in 204 iNHL and aNHL pts with PK/safety data. Glofitamab PK were best described using a two-compartment PK model with linear clearance and were comparable in pts with iNHL and aNHL. The effect of bodyweight on volumes and clearances was retained. Positive ER relationships were observed between AvgRO% over the first 24 hours and Gr ≥2 CRS in both iNHL and aNHL pts (p=0.002; Figure 1A), and between AvgRO% up to C3D1 and efficacy in aNHL pts (p=0.008; Figure 1B). Based on previous ER analyses (Djebli, et al. Blood 2019) of data from pts receiving fixed dosing, a SUD regimen (2.5/10/30mg Q3W) was selected to optimize the benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whilst allowing escalation to a higher dose associated with better clinical response. Updated ER analysis from fixed (n=199) and SUD (n=31) pts predicts an AvgRO% in the first 24 hours of 0.16% (0.10-0.29%), corresponding to a predicted Gr ≥2 CRS rate of 23.3% (20.8-26.8%) in iNHL and aNHL pts, and an AvgRO% to C3D1 of 0.75% (0.49-1.98%) corresponding to an anticipated CRR at Cycle 3 of 46.1% (42.7-53.8%) in aNHL pts. In comparison, clinical data from aNHL and iNHL pts receiving 2.5/10/16 and 2.5/10/30mg SUD (Hutchings, et al. ASH 2020) demonstrated a Gr ≥2 CRS rate of 21.6 % following the 2.5mg glofitamab dose (n=37), and a complete metabolic response rate of 40.6% (n=32). Conclusions: Glofitamab PopPK and ER relationships for efficacy/safety were updated, including data from SUD pts. These models and emerging SUD clinical data confirm that in NHL pts, the SUD regimen allowed glofitamab escalation up to 30mg to maximize efficacy while minimizing the risk of increased CRS at the first administration. These models are being developed further to support optimal biological-dose selection of glofitamab, both as monotherapy and in combination with other agents. Disclosures Djebli: F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Morcos:F. Hoffmann-La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Jaminion:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Guerini:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Kratochwil:F. Hoffmann-La Roche: Current Employment. Justies:F. Hoffmann-La Roche: Current Employment. Schick:F. Hoffmann-La Roche: Current Employment. Kwan:Genentech, Inc./ F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Humphrey:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Lundberg:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Carlile:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. OffLabel Disclosure: Glofitamab (RG6026; CD20-TCB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

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ADG152, a Novel CD20xCD3 T Cell Engager Prodrug with Enhanced Therapeutic Index, Demonstrates Strong Anti-Tumor Activity with Improved Safety

Blood ◽

10.1182/blood-2021-147573 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1204-1204

Author(s):

Bin Cai ◽

Aaron N Nguyen ◽

Songmao Zheng ◽

Jianfeng Shi ◽

Guizhong Liu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Board Of Directors ◽

Tumor Cells ◽

Cytokine Release ◽

Publicly Traded ◽

Advisory Committees ◽

The Past

Abstract Recent clinical data illustrate the effectiveness of CD20xCD3 T cell engagers (TCEs) that redirect the patient's endogenous T cells to eliminate CD20-positive tumor cells. While several of these products have demonstrated promising clinical activities in B-cell malignancies, their potential therapeutic utility is limited by cytokine release syndrome (CRS), even after strategies such as step-up dosing are implemented. ADG152 is a novel CD20xCD3 TCE prodrug engineered using Adagene's SAFEbody technology to minimize or eliminate CRS and on-target/off-tumor toxicities. The anti-CD20 arm of ADG152 has been engineered for enhanced binding to CD20 compared to other clinical stage or approved antibodies, while its anti-CD3 arm has modulated affinity for CD3 and is also masked by a conditionally activable peptide. In normal tissues and in circulation, the masking moiety on the anti-CD3 arm can function to block the binding of ADG152 to T cells; however, in an activable condition such as the tumor microenvironment where protease activity has been reported to be elevated, the masked antibody can be activated, enabling the activated ADG152 to simultaneously engage T cells and neighboring CD20-expressing tumor cells. In vitro studies showed that ADG152 has enhanced binding to human B cells and CD20-positive Raji tumor cells compared with the benchmark CD20xCD3 TCE plamotamab. On the other hand, ADG152 has significantly reduced binding to the human CD3 δ/ε protein dimer and no binding to human CD3+, CD4+, and CD8+ T cells isolated from PBMCs of normal human donors. Consistent with these results, ADG152 shows significantly decreased ability (more than 100-fold) compared with the benchmark and the unmasked parental molecule to activate CD8+ T cells and to induce T cell-mediated killing in the presence of tumor cells in vitro. ADG152 demonstrated strong anti-tumor effects in vivo. In a human PBMC-engrafted Raji xenograft mouse tumor model, dosing with ADG152 resulted in almost complete tumor growth inhibition at 1.5 mg/kg. In exploratory toxicology studies in cynomolgus monkeys, ADG152 resulted in significantly less cytokine release in monkey blood compared with benchmark, giving ~100-fold safety margin for ADG152 for cytokine induction (Figure). In addition, ADG152 was as effective as the benchmark at inducing B cell depletion from peripheral blood of cynomolgus monkeys. In summary, the preclinical characterization of ADG152 demonstrates that our SAFEbody platform can be used to engineer safe and potent bispecific T cell engagers with increased therapeutic index by allowing for strong anti-tumor activities in mice at doses with minimal cytokine release in monkeys, thereby supporting its advancement to clinical development either as a single agent or in combination with other therapies for the treatment of CD20-expressing B cell malignancies. Figure 1 Figure 1. Disclosures Cai: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Nguyen: Sparcbio, LLC: Ended employment in the past 24 months; Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Zheng: Janssen Pharmaceuticals: Ended employment in the past 24 months; Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Shi: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Liu: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Li: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Du: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Frankel: Cytovia Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company; Adagene Inc.: Consultancy, Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; IMV: Consultancy; Precision Biosciences: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Immunai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Minerva Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Consultancy; RAPT Therapeutics: Consultancy; Syros: Consultancy. Luo: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Xu: Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Adagene Inc.: Current Employment, Current equity holder in publicly-traded company.

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Novel CAR T Modules (Tmod) to Target HLA-Class I Loss in Lymphoma

Blood ◽

10.1182/blood-2020-134041 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Agnes E. Hamburger ◽

Breanna DiAndreth ◽

Mark E. Daris ◽

Melanie L. Munguia ◽

Kiran Deshmukh ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Publicly Traded ◽

Private Company ◽

Car T Cells ◽

The Past ◽

Car T Cell ◽

Car T

Background: Chimeric Antigen Receptor (CAR) T-cell therapy is a proven, powerful clinical modality. However, it is still limited by the fundamental obstacle of cancer therapy: discriminating cancer from normal cells. Current FDA-approved CAR T-cell therapies eliminate normal B cells, leaving patients with B cell aplasia, hypogammaglobulinemia, and susceptible to infection. HLA-Class I loss of heterozygosity (LOH) occurs at an average frequency of ~13% among cancers and specifically ~13% in DLBCL (Broad Institute TCGA database). These losses are irreversible and distinguish the cancer from normal cells. To exploit LOH at the HLA locus, we target the remaining allelic product in tumors with LOH. We evaluated a novel AND NOT Boolean logic gate CAR T module (Tmod) T-cell system to target HLA-A*02 (A2) LOH in lymphoma using both in vitro and in vivo models. Methods: To model tumor cells that have lost A2 via LOH, we used CD19+ Raji lymphoma tumor cells. To model the corresponding "normal" cells, we established CD19+ Raji cells stably expressing A2 (CD19+/A2+ Raji). We then engineered human primary T cells to express a modular signal-integration circuit designed to be activated only by CD19+ lymphoma that do not express A2 (CD19+/A2- Raji). Each primary Tmod CAR T cell expresses both a CD19 activator (A) module using a CD19-targeting 3rd generation CAR, and a separate A2-targeting blocker (B) module using a novel A2-targeting inhibitory receptor. Human primary Tmod CAR T cells were engineered to co-express the A/B modules. First, T cells were stimulated via CD3/CD28 activation, followed by A/B module lentivirus transduction, and enriched for the B module. In vitro Tmod CAR T cells were evaluated for selective killing of CD19+/A2- Raji compared with CD19+/A2+ Raji. For in vivo proof of concept, both CD19+/A2- Raji and CD19+/A2+ Raji cell lines were injected and established into flanks of immunocompromised NGS mice and challenged with adoptive transfer of engineered human primary Tmod CAR T cells. Results: Engineered primary Tmod CAR T cells selectively killed CD19+/A2- Raji and spared CD19+/A2+ Raji (Figure 1). Tmod CAR T cells reversibly cycled from a state of non-killing, "block", to cytotoxicity and back, depending on the CD19+/A2- Raji vs. CD19+/A2+ Raji cells to which they were exposed. Importantly, primary Tmod CAR T cells selectively eliminated only the CD19+/A2- Raji cells in mixed cultures. In vivo, Tmod CAR T cells selectively eradicated CD19+/A2- Raji. More importantly, Tmod CAR T cells did not eradicate CD19+/A2+ Raji in vivo. Conclusions: CD19-targeting Tmod CAR T cells demonstrated robust and selective killing, distinguishing Raji lymphoma lines, one with A2 (CD19+/A2+) and one without (CD19+/A2-), both in vitro and in vivo. A critical requirement for Tmod CAR T-cell therapy is to determine reversibility and lack of anergy in the kill-"block"-kill and "block"-kill-"block" scenarios. This result demonstrates that Tmod CAR T cells do not terminally differentiate into one state (blockade or activation), but rather can switch back and forth as they integrate signals from "normal" and tumor cells. Furthermore, because Tmod CAR T cells can selectively target malignant B cells, it may increase the clinical therapeutic window for CAR T. Tmod CAR T cells may provide a powerful system to address hematologic malignancies and solid tumors with HLA-Class I LOH. Disclosures Hamburger: A2 Biotherapeutics: Current Employment, Current equity holder in private company. DiAndreth:A2 Biotherapeutics: Current Employment. Daris:A2 Biotherapeutics: Current Employment, Current equity holder in private company. Munguia:A2 Biotherapeutics: Current Employment, Current equity holder in private company. Deshmukh:A2 Biotherapeutics: Current Employment. Mock:A2 Biotherapeutics: Current Employment, Current equity holder in private company. Asuelime:A2 Biotherapeutics: Current Employment, Current equity holder in private company. Lim:A2 Biotherapeutics: Current Employment, Current equity holder in private company. Kreke:A2 Biotherapeutics: Current Employment, Current equity holder in private company; Gilead: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Tokatlian:A2 Biotherapeutics: Current Employment, Current equity holder in private company. Maloney:A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Bioline Rx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties, Research Funding. Go:A2 Biotherapeutics: Current Employment, Current equity holder in private company; Amgen: Current equity holder in publicly-traded company; Allogene: Divested equity in a private or publicly-traded company in the past 24 months; Gilead: Current equity holder in publicly-traded company; Illumina: Divested equity in a private or publicly-traded company in the past 24 months. Kamb:A2 Biotherapeutics: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

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Early Clinical Results of a Novel Anti-CD20 Chimeric Antigen Receptor (CAR)-T Cell Therapy for B-Cell NHL Patients Who Are Relapsed/Resistant Following CD19 CAR-T Therapy

Blood ◽

10.1182/blood-2020-138538 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Shiguang Ye ◽

Jiaqi Huang ◽

Shigui Zhu ◽

Xin Yao ◽

Lili Zhou ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Chimeric Antigen Receptor ◽

Overall Response Rate ◽

Response Rate ◽

Tumor Regression ◽

Publicly Traded ◽

Overall Response ◽

Car T Cells ◽

Car T

Background: Relapse due to loss of the CD19 targeted epitope presents a therapeutic challenge of CD19 CAR-T therapy. These patients universally have poor outcomes. CD20 is a proven therapeutic target for B-Cell Non-Hodgkin Lymphomas (B-NHL), supported by previously approved and widely used monoclonal antibody therapy. C-CAR066 is a novel 2nd generation chimeric antigen receptor T (CAR-T) therapy. Preclinical studies suggest that C-CAR066 has superior anti-tumor activity compared to CAR-Ts derived from scFVs of Leu16, Rituximab, and Obinutuzumab, Methods: NCT04036019 is a single arm, single-center, non-randomized phase I clinical trial conducted at Shanghai Tongji Hospital to evaluate the safety and efficacy of C-CAR066 in subjects with r/r B cell lymphoma who were previously treated with anti-CD19 CAR-T therapy. The primary objective of the study is to evaluate incidence and severity of treatment emergent adverse events. The secondary objectives include determining overall response rate (ORR), PFS, and OS. C-CAR066 is manufactured in a serum free, semi-automated, and digitally closed system. C-CAR066 is administered to patients as a single intravenous dose after a standard 3-day cyclophosphamide/fludarabine conditioning regimen. Results: As of Aug 3, 2020, 7 patients (all DLBCL) were enrolled and infused with C-CAR066 with a dose range of 2.0 x 106 to 5.0 x 106 CAR-T cells. The manufacturing success rate was 100%. All patients had relapsed after anti-CD19 CAR-T treatment, only one of the patients had achieved CR following anti-CD-19 CAR-T therapy. C-CAR066 treatment was well tolerated with reversible grade 1~2 CRS in six patients, grade 3 CRS in another patient, and no neurotoxicity events. 6/7 patients showed clinical improvement (best overall response rate, BOR = 85.7%). The best overall responses include 3 CR and 3PR. All patients responded to C-CAR066 treatment and showed different degrees of tumor regression (45-100%). Furthermore, the expansion and proliferation of C-CAR066 CAR-T cells in the peripheral blood positively correlated with the extent of tumor regression. Conclusion: C-CAR066 has a favorable safety profile and shows promising early efficacy in patients with r/r NHL following CD19 CAR-T therapy. It confirms that C-CAR066 has a different mechanism of action compared to anti-CD-19 CAR-T therapy. These data provide strong scientific rationale to the strategy of targeting both CD20 and CD19 tumor antigens and to ask whether this leads to superior clinical benefit to targeting either CD19 or CD20 alone in NHL. Disclosures Huang: Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Zhu:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Yao:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Zhu:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Zheng:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Chen:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Lan:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Chen:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Wei:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Shu:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Ye:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Zhang:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Wang:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Hong:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Ren:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Zhang:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Humphries:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.Yao:Cellular Biomedicine Group Inc:Current Employment, Current equity holder in publicly-traded company.

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Aging-Associated Epigenetic Reprogramming Alters the Germinal Center Reaction and Targets Pathways Related to Lymphomagenesis

Blood ◽

10.1182/blood-2021-152684 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 676-676

Author(s):

Rossella Marullo ◽

Maria Victoria Revuelta ◽

Wendy Béguelin ◽

Juan Lara-Garcia ◽

Leandro Cerchietti

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Rna Sequencing ◽

Germinal Center ◽

Gene Promoters ◽

Publicly Traded ◽

Immune Synapse ◽

Germinal Center Reaction ◽

The Past

Abstract Aging is associated with suboptimal germinal center (GC) responses and inferior outcomes of GC-derived lymphomas such as diffuse large B-cell lymphoma (DLBCL). At the molecular level, aging is characterized by epigenetic alterations of DNA CpG methylation and chromatin architecture that ultimately affect cellular functions. The B-cell/T-cell immune synapse during the transitional stages of the GC is governed by a series of epigenetic switches. Frequent mutations in DLBCL directly impact epigenetic regulators and signaling pathways in the immune synapse. Here, we investigated the impact of aging-associated epigenetic alterations in the functionality of the GC response in parallel with biological characteristics of DLBCL in the elderly. We conducted an integrative characterization of epigenomic, transcriptomic and phenotypic changes of B and T cells during the GC reaction in younger (3-4 months) vs. older (21-23 months) mice by immunophenotyping (flow cytometry), DNA methylation sequencing of sorted sub-populations, single cell (SC) RNA-sequencing (coding and BCR/TCR) and SC-multiomics (integration of RNA-sequencing and ATAC-sequencing). We also performed DNA methylation sequencing, RNA-sequencing and NGS in a cohort of 266 DLBCL including 51 pts >75 y.o. In agreement with reported phenotypes in elderly humans (Collier D. et al., Nature, 2021), the GC reaction in older mice was characterized by a significative reduction in IgG3+ (p=0.0001) and increased in IgM+ (p=0.009) B cells (FAS+ CD38-); whereas the non-GC B cell compartment (FAS- CD38+) displayed an increase in age-associated B cells (ABCs, p=0.0001) and reduction in follicular B-cells (p=0.004). Furthermore, older mice displayed an expansion of a FAS+CD38+ population of B cells (p=0.0001). Regarding T cells, we observed a global reduction in CD4+ (p=0.01) but not in CD8+ cells; however, older mice showed an expansion of PD1+/CD4+ and PD1+/CD8+ T cells (p=0.0004 and p=0.0003, respectively). Furthermore, older mice displayed increased TFH (p=0.0001), Tregs (p=0001) and ICOS+ Treg (p=0001) populations. SC-RNA-seq of B and T cells validated these alterations and identified transcriptionally-defined sub-populations including expansion of clonal GZMK CD8+ TOX+ T cells (TAA cells) and activation of "cytokine production" in T cells (FDR=3.01e-27), both phenotypes associated with "inflammaging" (Mogilenko et al., Immunity, 2020). Epigenetic changes in older B-cells showed aberrant hypermethylation of gene promoters and hypomethylation of intergenic regions including enhancers, resulting in changes of chromatin architecture and gene expression. In GC B-cells but not naïve B-cells (NBC), genes whose promoter was aberrantly hypermethylated in older mice were enriched for targets of SUZ12 (FDR= 5.1e -12), EZH2 (FDR= 5.1e -12) and JARID2 (FDR= 6.8e -10), key components of the PRC2 complex. Older mice B-cells also displayed decreased chromatin accessibility in genes functionally enriched for "semaphorin-plexin signaling pathway" (FDR=5.3e -03) which regulates TFH/B-cell immune synapse as well as decreased expression of linker histone H1 isoforms B-E in GCB cells (q=0.0006; q=0.0003; q=0.008, q=4.64E-10, respectively). Notably, the age-associated reprogramming observed in the germinal center reaction globally targets pro-tumorigenic pathways that are comparably altered in elderly DLBCL. We observed that older pts (>75 y.o.) vs. younger pts (55-65 y.o.) had increased hypermethylation of gene promoters and hypomethylation of intergenic regions with deregulation of epigenetic modifiers (including PCR2 members) and immune synapse genes (including BCR signaling). There were no differences in the prevalence of specific mutations between these two populations. However, DLBCL in elderly are more frequently of the ABC subtype (~60%, p<0.05) and presented with an inflammatory tumor microenvironment (41% vs 27% in younger DLBCL, p<0.001, corrected by COO) that is characterized by increased infiltration of macrophages (p=0.001), Tregs (p=0.001) and CD8+ PD1 highcells (p=0.001), phenocopying changes observed in the germinal center of older mice. Thus, age-associated epigenetic reprogramming results in perturbation of pathways regulating the B-cell/T-cell immune synapse during the normal germinal center reaction and may underlie some of the biological characteristics observed in elderly DLBCL patients. Disclosures Lara-Garcia: Johnson and Johnson: Current holder of individual stocks in a privately-held company; Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Moderna: Divested equity in a private or publicly-traded company in the past 24 months; Pfizer: Divested equity in a private or publicly-traded company in the past 24 months; Regeneron: Divested equity in a private or publicly-traded company in the past 24 months; Merck: Divested equity in a private or publicly-traded company in the past 24 months; Fortress Biotech: Divested equity in a private or publicly-traded company in the past 24 months. Cerchietti: Celgene: Research Funding; Bristol Myers Squibb: Research Funding.

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Early Response Observed in Pediatric Patients with Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma Treated with Sequential Chimeric Antigen Receptor T Cells

Blood ◽

10.1182/blood-2019-125753 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1945-1945 ◽

Cited By ~ 3

Author(s):

Wenqun Zhang ◽

Bo Hu ◽

Ling Jing ◽

Jing Yang ◽

Shan Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Pediatric Patients ◽

Response Rate ◽

Car T Cell ◽

Non Hodgkin Lymphoma ◽

Car T ◽

To Receive

Background:Outcomes for pediatric patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) are poor despite use of high-intensity chemotherapy. CAR-T has shown efficacy in treating refractory/relapsed leukemia in pediatric patients and non-Hodgkin lymphoma in adult patients. Objectives:To assess the safety and efficacy of sequential CAR-T in the treatment of refractory/ relapsed B-NHL in pediatric patients. Design/Methods:In our ongoing clinical trial (ChiCTR1800014457), we enrolled and treated 17 pediatric patients with refractory/relapsed B-NHL. Following leukapheresis, T cells were activated with CD3 and CD28 antibodies for 24h, then transduced with lentivirus encoding anti-CD19-CD3zeta-4-1BB CAR and cultured for 5-6 days in serum-free media containing IL2, IL7, IL15, IL21. Meanwhile, all patients briefly received lympho-depleting chemotherapies consisting of fludarabine (30 mg/m2/day) and cyclophosphamide (250 mg/m2/day) on days −5, −4 and −3 according to tumor burden and patient state. On day 0, all patients received a single-dose infusion of CAR-T cells. CAR-T cell dose ranged from 0.5 to 3 million/kg. CAR-T cell numbers and cytokines were measured weekly. Tumor responses were evaluated at day 30 and day 60 post infusion and every two months thereafter. Adverse events were graded according to CTCAEv4 except cytokine release syndrome (CRS) was graded according to Lee et al. Results:Treated patients had relapsed/refractory Burkitt lymphoma (BL) (13/17), diffuse large B cell lymphoma (DLBCL) (2/17), B-lymphoblastic lymphoma (B-LBL) (2/17), and ranged from 4.5-18.0 years old. By St Jude's staging, 9 cases (46.7%) were in stage III, 8 cases (53.3%) were in stage IV. There were 3 cases with CNS involvement (17.6%) and 7 cases with bone marrow involvement (41.2%). They all failed at prior treatment including an average of 8.9 (6-15) courses of chemotherapy. They were then treated with sequential CAR-T cell therapy. A total of 26 courses of CAR-T cell infusion were administered. The overall complete response rate (CRR) was 41.7% (7/17) when first course of CAR-T therapy was conducted, which were all CD19 targeted. Among the 10 patients who did not achieve CR, 2 patients achieved PR with ongoing response, 1 patient died of severe CRS and progression at day 6 and another patient refused to continue the following therapy when tumor progressed at day 99, and he died 1 week later, the other 6 continued to receive second course of CAR-T therapy targeting CD20 or CD22, and 3 of them achieved CR. Thus the overall CRR increased to 58.8% (10/17). The 3 patients, who still did not achieve CR, continued to receive third course of CAR-T therapy targeting CD20 or CD22. Two of them finally achieved CR and the other failed to get CR and is now retreated with chemotherapy and oral Olaparib and Venclexta. Thus, with a median follow-up of 6.2 months (1-18 months), the overall response rate of sequential CAR-T therapy was 94.1% (16/17) and the overall CRR was 70.6% (12/17). Toxicity information through day 30 revealed the occurrence of mild CRS in 8 subjects (47.1%, grade I n=8, grade II n=0), severe CRS in 9 subjects (52.9%, grade III n=8, grade IV n=1). Neurotoxicity was observed in 7 cases (41.2%, seizure in 3 cases, tremor in 4 cases, headache in 1 cases). One case who died rapidly at day 6 of therapy suffered severe CRS (high fever, Capillary leak syndrome, severe pleural effusion, respiratory failure, shock, cardiopulmonary arrest) and neurotoxicity besides disease progression. Other patients with severe CRS and neurotoxicity recovered fully after glucocorticoid use and symptomatic treatment including anti-epilepsy, fluid, dehydrating agent. No case used tocilizumab. Response assessments were performed at day 15, 30, 45, 60. Updated enrollment, toxicity and response assessments will be presented. Conclusion: CD19/CD20/CD22-CAR-T therapy showed promising efficacy for pediatric patients with r/r B-NHL and the toxicities are tolerable with proper symptomatic and supportive treatment. Sequential CAR-T therapy can improve the efficacy compared with a single course of CAR-T infusion. Disclosures No relevant conflicts of interest to declare.

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In Vivo Pre-Clinical Evaluation of LOXO-305 Alone and in Combination with Venetoclax, Rituximab, R-CHOP or Obinutuzumab on Human Xenograft Lymphoma Tumor Models in Mice

Blood ◽

10.1182/blood-2020-140581 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Eliana B. Gomez ◽

Wenjuan Wu ◽

Jennifer R Stephens ◽

Mary S. Rosendahl ◽

Barbara J. Brandhuber

Keyword(s):

B Cell ◽

Human Tumor ◽

Tumor Xenograft ◽

Human Tumor Xenograft ◽

Publicly Traded ◽

B Cell Malignancies ◽

The Past ◽

Wholly Owned Subsidiary ◽

Xenograft Models ◽

Btk Inhibitors

Introduction: Bruton's Tyrosine Kinase (BTK) is an essential component of normal and malignant B-cell receptor signaling. Covalent BTK inhibitors have transformed the treatment of B-cell malignancies. Despite the marked efficacy of covalent BTKi, treatment failure can occur through the development of resistance and discontinuation for adverse events. The activity of these covalent BTK inhibitors are markedly reduced or absent in the presence of BTK cysteine binding site (C481) mutations. Moreover, these agents share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that may sometimes lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover, ultimately manifesting as acquired resistance for some patients. To address these limitations, LOXO-305, a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal low nM potency was developed. Proof-of-concept Phase I results demonstrated LOXO-305's anti-tumor activity across patients with heavily pretreated B-cell malignancies (Mato et al. ASH 2019). We previously showed pre-clinical data demonstrating that LOXO-305 potently inhibited wild-type (WT) BTK and different variants of the BTK mutation C481 with nanomolar potency and caused regression in BTK-dependent lymphoma mouse xenograft models (Brandhuber et al. SOHO 2018, and Gomez et al. ASH 2019). Here we describe the activity of LOXO-305 alone or in combination with venetoclax (BCL-2 inhibitor), in TMD8 BTK WT and TMD8 BTK C481S human tumor xenograft models of diffuse large B lymphoma and a REC-1 human tumor xenograft model of mantle cell lymphoma in mice. We also report the activity of LOXO-305 alone and in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) or obinutuzumab (anti-CD20 antibody), in the TMD8 xenograft tumor model. Methods: In all studies, tested articles were administered alone and in combination, following different dosing regimens. Table 1 shows the tested compound(s), dosing frequency, cell line used, disease, BTK status (WT or C481S), and mouse strain used, for each study presented in this abstract. Human TMD8 BTK WT, TMD8 BTK C481S or REC-1 cells were injected subcutaneously in the right flank of mice. When tumors reached a mean volume between 150 mm3 and 400 mm3, mice were randomized based on their tumor volumes. Mice were next dosed for 17 to 23 days depending on the study design. The potencies of the compounds stand-alone or in combination on the inhibition of the tumor growth were assessed based on the tumor volume changes and weights after collection at the end of the study. Additionally, in the TMD8 studies, the plasma concentrations of tested articles were measured at multiple time points after the last dose. Results: All treatments were well tolerated without any significant body weight loss or clinical signs being observed on the mice. LOXO-305 potently inhibited the growth of BTK WT and BTK C481S driven xenograft tumors. In all combinations tested, significantly greater tumor growth inhibition was observed in groups where LOXO-305 was co-administered with clinically approved agents. Conclusion: These data suggest that the co-administration of LOXO-305 with venetoclax, R-CHOP or obinutuzumab could have an increased benefit for patients with B-cell malignancies compared to stand-alone treatments and warrants further investigation. Disclosures Gomez: Loxo Oncology, Inc, a wholly owned subsidiary of Eli Lilly and Company: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Wu:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Stephens:Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Rosendahl:Loxo Oncology, Inc, a wholly owned subsidiary of Eli Lilly and Company: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Brandhuber:Loxo Oncology, Inc, a wholly owned subsidiary of Eli Lilly and Company: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months.

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Echocardiographic Changes of Carfilzomib Therapy in Multiple Myeloma Patients

Blood ◽

10.1182/blood-2020-140090 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Waled Bahaj ◽

Anas Albawaliz ◽

Madeline E Begemann ◽

Anuj Shrestha ◽

Brett Sperry ◽

...

Keyword(s):

Statistical Significance ◽

Systolic Dysfunction ◽

Community Setting ◽

Categorical Variables ◽

Cardiac Complications ◽

Publicly Traded ◽

Private Company ◽

Chi Square ◽

Difficult Decision ◽

The Past

Introduction: Carfilzomib is a proteasome inhibitor that is known to be associated with cardiotoxicity. Current clinical data on Carfilzomib associated with cardiotoxicity is generated in clinical trials from which patients with severe cardiovascular comorbidities were excluded. In this study, we have reported real-word experience on outcome of cardiotoxicity in patients managed by physicians in a community setting. Methods: We performed a retrospective analysis evaluating for cardiac complications in MM patients who received Carfilzomib at our institution in the last 5 years. Pre- and post-therapy echocardiogram findings were compared. Chi-square tests were used to compare categorical variables with an α level set at 0.05 for statistical significance. Results: Among the 28 identified patients who had pre- and post- Carfilzomib therapy echocardiogram imaging, (18 patients, 64%) had at least one echocardiographic abnormality. The main changes were in heart functions (10/28), whereas systolic dysfunction is seen in 9 patients while only one patient had diastolic dysfunction, pulmonary artery pressure (6/28), and wall motion abnormalities (5/28). (11/28) patients had disease progression. We did not notice any correlation to variables such as; age, duration of therapy, dose differences, and number of lines of therapies. Furthermore, two patients were rechallenged with Carfilzomib after echocardiographic worsening; one of them tolerated the treatment well, while the other had further worsening that led to holding the therapy. Conclusion: Several echocardiographic changes could be related to Carfilzomib therapy. Our study was limited due to the sample size and the retrospective nature of the analysis. Larger studies are needed to detect and correlate more echocardiogram variables in this population. Rechallenging these patients with Carfilzomib, particularly during relapse stages, will remain a difficult decision especially if the therapy was effective. Disclosures Raza: Advisory board Incyte, Amgen, Celgene, Kite, Janseen, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Moderna: Current equity holder in publicly-traded company; Drrx: Divested equity in a private or publicly-traded company in the past 24 months; Gilead, Sierra, Abbot, Acasti, Amicus: Current equity holder in private company; Received Honorarium/speaker bureu from Janseen, Celgene, Takeda: Ended employment in the past 24 months, Honoraria, Speakers Bureau.

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Teclistamab is an active T cell–redirecting bispecific antibody against B-cell maturation antigen for multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2020002393 ◽

2020 ◽

Vol 4 (18) ◽

pp. 4538-4549 ◽

Cited By ~ 2

Author(s):

Kodandaram Pillarisetti ◽

Gordon Powers ◽

Leopoldo Luistro ◽

Alexander Babich ◽

Eric Baldwin ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

B Cell ◽

Bispecific Antibody ◽

Cell Maturation ◽

B Cell Maturation ◽

Xenograft Models ◽

Rpmi 8226 ◽

B Cell Maturation Antigen

Abstract B-cell maturation antigen (BCMA), a member of the tumor necrosis factor family of receptors, is predominantly expressed on the surface of terminally differentiated B cells. BCMA is highly expressed on plasmablasts and plasma cells from multiple myeloma (MM) patient samples. We developed a BCMAxCD3 bispecific antibody (teclistamab [JNJ-64007957]) to recruit and activate T cells to kill BCMA-expressing MM cells. Teclistamab induced cytotoxicity of BCMA+ MM cell lines in vitro (H929 cells, 50% effective concentration [EC50] = 0.15 nM; MM.1R cells, EC50 = 0.06 nM; RPMI 8226 cells, EC50 = 0.45 nM) with concomitant T-cell activation (H929 cells, EC50 = 0.21 nM; MM.1R cells, EC50 = 0.1 nM; RPMI 8226 cells, EC50 = 0.28 nM) and cytokine release. This activity was further increased in the presence of a γ-secretase inhibitor (LY-411575). Teclistamab also depleted BCMA+ cells in bone marrow samples from MM patients in an ex vivo assay with an average EC50 value of 1.7 nM. Under more physiological conditions using healthy human whole blood, teclistamab mediated dose-dependent lysis of H929 cells and activation of T cells. Antitumor activity of teclistamab was also observed in 2 BCMA+ MM murine xenograft models inoculated with human T cells (tumor inhibition with H929 model and tumor regression with the RPMI 8226 model) compared with vehicle and antibody controls. The specific and potent activity of teclistamab against BCMA-expressing cells from MM cell lines, patient samples, and MM xenograft models warrant further evaluation of this bispecific antibody for the treatment of MM. Phase 1 clinical trials (monotherapy, #NCT03145181; combination therapy, #NCT04108195) are ongoing for patients with relapsed/refractory MM.

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Preclinical Results of an Allogeneic, Universal CD19/CD7-Targeting CAR-T Cell Therapy (GC502) for B Cell Malignancies

Blood ◽

10.1182/blood-2021-148500 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1722-1722

Author(s):

Jianning Ge ◽

Chunhui Yang ◽

Jing Sun ◽

Jiao Chen ◽

Shuyi Qiu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Publicly Traded ◽

Mouse Xenograft ◽

Car T Cell ◽

Car T ◽

Cell Acute Lymphoblastic Leukemia

Abstract Background Autologous CD19 CAR-T therapies show very promising clinical efficacy, but are limited in their applicability by several factors including cost, time to manufacture, and other factors involving patients own T-cell qualities. GC027, a CD7 targeting allogeneic, universal CAR-T (UCAR-T) currently in development for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) has demonstrated robust expansion and anti-leukemia efficacy with a manageable safety profile in an investigator-initiated trial in China. These data suggest that, a single CD7 targeting CAR-T therapy is able to generate a therapeutic window by suppressing host vs graft (HvG) rejection of UCAR-T cells by patients' own NK and T cells, and achieve efficacy in patients with T-ALL. Based on these findings we developed GC502, a CD19/CD7 dual-targeting, allogeneic CAR-T therapy for B-cell malignancies, in which the CD19 CAR moiety targets malignant cells while CD7 CAR moiety suppresses HvG in variety of preclinical models. Methods GC502 was manufactured using leukopaks from HLA-unmatched healthy donors. It contains a 4-1BB based 2 nd-generation dual targeting CAR comprising an anti-CD19 and an anti-CD7 single-chain variable fragments (scFvs). TRAC and CD7 loci were disrupted to avoid graft vs host disease and fratricide, respectively. To select the leading CAR candidate, CAR expression and functionalities of CAR constructs with different heavy-light (H-L) chain orientations of the dual CAR were analyzed via in vitro assays and mouse xenograft models, in comparing to single CD19 CAR and CD7 CAR products. To achieve optimal anti-tumor efficacy, a T-cell enhancer was included in the CAR construct. Result Gene editing and dual CAR orientation selection TRAC and CD7 double knockout efficiencies were constantly above 97% across multiple donor pan T cells. Although CD19/CD7 CAR expression levels in different H-L chain orientations were similar, in the final CAR-T product as measured by flow cytometry (FCM) analysis, significant difference was observed in their cytotoxicity and in vitro expansion under repeated antigen stimulations by CD19+ B-cell acute lymphoblastic leukemia (B-ALL) cell line Nalm6 and CD7+ T-cell line CCRF-CEM. CAR candidates mediated the strongest cytotoxicity and most durable response were selected for further optimizations. CAR construct optimizations For the leading candidates, we first assessed the dual CAR efficacy after incorporation of an enhancer. While the IL-2, TNFα and IFNγ secretion levels were comparable, enhancer addition significantly improved tumor killing and CAR-T cell expansion under repeated stimulations by either CD19+ or CD7+ target cells. Anti-leukemia response under sub-optimal CAR-T cell dosages were also greatly enhanced as assessed by both B-ALL and T-ALL mouse xenograft models. GC502 CAR functionality comparison to single CAR products with proven clinical efficacies GC502 and GC027 were compared for their CD7 CAR function to assess their anti-HvG activities. GC502 and GC027 exhibited comparable toxicities towards pan T cells and similar efficacies in a highly malignant T-ALL mouse model. The CD19 CAR functionality of GC502 were evaluated and compared to a 2 nd generation CD19 CAR product comprising a FMC63 scFv and a 4-1BB-CD3ȥ signaling domain. In a Raji based B-ALL mouse xenograft model, both products rapidly eliminated cancer cells. While CD19 CAR treated mice showed signs of relapse at 2 weeks post CAR-T infusion, GC502 treatment group maintained "leukemia free" status till the end of study (Day28). Conclusion GC502 was optimized for CD19/CD7 dual CAR functionality and in vivo durability. It demonstrated robust anti-tumor efficacy and promising potentials to suppress HvG. This report presents an example that the dual CAR design of GC502 may serve as a novel "off-the-shelf" CAR-T technology. Disclosures Ge: GracellBiotechnologies Ltd: Current Employment, Current equity holder in publicly-traded company. Yang: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Sun: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Chen: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Qiu: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Yin: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Shen: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Sersch: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Cao: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company. Wang: GracellBiotechnologies Inc: Current Employment, Current equity holder in publicly-traded company.

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Nx-2127, a Degrader of BTK and IMiD Neosubstrates, for the Treatment of B-Cell Malignancies

Blood ◽

10.1182/blood-2020-141461 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Daniel W Robbins ◽

Aileen Kelly ◽

May Tan ◽

Joel McIntosh ◽

Jeffrey Wu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Oral Administration ◽

B Cell ◽

T Cell Activation ◽

Cell Activation ◽

Publicly Traded ◽

B Cell Malignancies ◽

Human T Cells ◽

Baseline Levels

Bruton's tyrosine kinase (BTK) plays a key role in cell survival in B cell malignancies, such as chronic lymphocytic leukemia (CLL). Covalent inhibitors of BTK, such as ibrutinib and acalabrutinib, while effective, have been associated with the occurrence of resistance mutations. The most prevalent site of mutation, C481, renders covalent BTK inhibitors unable to form a covalent bond with BTK leading to diminished efficacy and disease progression. Small molecule-induced protein degradation offers a unique approach to target BTK for the treatment of B-cell malignancies. Chimeric Targeting Molecules (CTMs) catalyze ubiquitylation and proteasomal degradation of target proteins and are comprised of a ubiquitin ligase binding element ("harness"), a linker, and a target binding element ("hook"). NX-2127 is a CTM that contains a BTK hook linked to a cereblon (CRBN) harness. NX-2127 degrades 50% of cellular BTK (DC50) at < 5 nM across multiple cancer cell lines and in human PBMCs. BTK CTMs impair viability in the BTK-dependent ABC-DLBCL cell line, TMD8 (EC50: < 15 nM after 72 hours). Importantly, NX-2127 induces degradation of the mutated BTK-C481S in cells and inhibits proliferation of BTK-C481S mutant TMD8 cells more effectively than ibrutinib (NX-2127 EC50 values of < 30 nM versus > 1 μM for ibrutinib). Oral administration of NX-2127 in mice leads to dose-proportional exposure in plasma and BTK degradation to <10% of baseline levels in circulating and splenic B cells. In both WT TMD8 and C481S mutant xenograft models, daily oral administration of NX-2127 resulted in superior tumor growth inhibition (TGI) as compared to ibrutinib. NX-2127 also demonstrates potent degradation of BTK in cynomolgus monkeys with oral administration. Following 14 days of once daily, oral dosing in cynomolgus monkey, BTK levels are suppressed to <10% of baseline levels at doses as low as 1 mg/kg. In addition to potent BTK degradation, NX-2127 possesses IMiD-like properties through the design of the CRBN binding harness that catalyzes the degradation of CRBN neosubstrates Aiolos (IKZF3) and Ikaros (IKZF1). This activity is associated with increased T cell activation and anti-tumor effects of the IMiD drugs lenalidomide and pomalidomide. In primary human T cells, NX-2127 catalyzes the degradation of Aiolos and Ikaros with of 25 nM and 54 nM, respectively, potencies which are similar to those of lenalidomide (20 nM and 343 nM, respectively). Corresponding with such degradation, NX-2127 stimulates T cell activation as measured by increased IL-2 production in primary human T Cells in a manner similar to lenalidomide and pomalidomide. The dual activity of BTK degradation combined with immunomodulation of NX-2127 supports its development for the treatment of B-cell malignancies. Disclosures Robbins: Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kelly:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. McIntosh:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wu:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Konst:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kato:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Peng:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mihalic:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Weiss:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Perez:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tung:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kolobova:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Borodovsky:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rountree:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tenn-McClellan:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Noviski:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ye:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Basham:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ingallinera:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. McKinnell:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karr:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Powers:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Guiducci:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sands:Nurix Therapeutics: Current Employment, Current equity holder in publicly-traded company.

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