scholarly journals Small Molecule-Induced, Selective STAT3 Degradation Leads to Anti-Tumor Activity in STAT3-Dependent Heme Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3803-3803
Author(s):  
Fred Csibi ◽  
Nan Ji ◽  
Bin Yang ◽  
Karen Yuan ◽  
Michele Mayo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Ternary Complex ◽  
Target Genes ◽  
E3 Ligase ◽  
Target Protein ◽  
Therapeutic Modality ◽  
Employment Equity ◽  
Equity Ownership ◽  
Anti Tumor Activity

Targeted protein degradation mediated by small molecule degraders represents a new and exciting therapeutic modality to target difficult-to-drug oncogenic proteins including transcription factors. These molecules bind to both the target protein and an E3 ligase, enabling the formation of a ternary complex that leads to ubiquitination and subsequent degradation of the target protein by the proteasome. STAT3 (signal transducers and activators of transcription 3) is a transcription factor and a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated serine/threonine kinases, and phosphylated STAT3 (pSTAT3) then forms dimers that translocate into the nucleus, binds to DNA, and regulate transcription. STAT3 is frequently mutated and activated in numerous cancers including clinically aggressive hematologic malignancies with high unmet medical need. Mechanistically, aberrant activation of STAT3 has been directly linked to the promotion of cancer cell survival, proliferation and immune evasion, thus making it a highly attractive target for oncology. Potent and selective agents specifically and directly targeting STAT3 have remained elusive, however. Herein we report the discovery of a potent and selective STAT3 heterobifunctional degrader, KYM-003, which displays strong anti-tumor activity in models of STAT3-dependent heme malignancies. KYM-003 degrades STAT3 via an E3 ligase-dependent mechanism. It strongly binds to STAT3 and a E3 ligase, leading to the formation of the a productive ternary complex, which leads to ubiquitination of STAT3 and subsequent proteasomal degradation. KYM-003 robustly degraded STAT3 in a number of primary cells or cell lines with DC50 < 100 nM. Degradation was highly selective for STAT3 vs >10,000 other detected proteins (including all other STAT family members) in cell lines and human PBMCs. Degradation of STAT3 by KYM-003 led to significant downregulation of STAT3 target genes, such as SOCS3, MYC, and PIM1. Importantly, total STAT3 and pSTAT3 levels in tumors were reduced by >90% for at least 24 hours after a single dose of KYM-003 and repeated dosing of KYM-003 showed dose-dependent antitumor activity in xenograft models of heme malignancies. Collectively, our data demonstrates that KYM-003 is a potent and selective STAT3 degrader that exhibited strong anti-tumor activity in vitro and in vivo. These data support STAT3 degraders as a new and exciting therapeutic opportunity in heme malignancies. Disclosures Csibi: kymera Therapeutics: Employment, Equity Ownership. Ji:Kymera Therapeutics: Employment, Equity Ownership. Yang:Kymera Therapeutics: Employment, Equity Ownership. Yuan:Kymera Therapeutics: Employment, Equity Ownership. Mayo:kymera Therapeutics: Employment, Equity Ownership. Rong:Kymera Therapeutics: Employment, Equity Ownership. Rusin:Kymera Therapeutics: Employment, Equity Ownership. Sharma:kymera Therapeutics: Employment, Equity Ownership. Loh:Kymera Therapeutics: Employment, Equity Ownership. Li:Kymera Therapeutics: Employment, Equity Ownership. Townson:Kymera Therapeutics: Employment, Equity Ownership. Chen:kymera therapeutics: Employment, Equity Ownership. Kamadurai:Kymera Therapeutics: Employment, Equity Ownership. Walker:Kymera Therapeutics: Employment, Equity Ownership. Gollob:Kymera Therapeutics: Employment, Equity Ownership. Mainolfi:Kymera Therapeutics: Employment, Equity Ownership.

TK216, a Novel, Small Molecule Inhibitor of the ETS-Family of Transcription Factors, Displays Anti-Tumor Activity in AML and DLBCL

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4035-4035 ◽  
Author(s):  
Katayoun Jessen ◽  
Eric Moseley ◽  
Elaine Yee Lin Chung ◽  
Lauren Otuski ◽  
Chiara Tarantelli ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Lines ◽  
Small Molecule ◽  
Ewing Sarcoma ◽  
Family Members ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Ets Family ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract The ETS family of transcription factors is critical for development, differentiation, proliferation, and plays an important role in apoptosis and tissue remodeling. Transcriptional consequences of ETS protein deregulation by overexpression, gene fusion, and modulation by RAS/MAPK and PI3K signaling are linked to alterations in normal cell functions, and lead to increased proliferation, sustained angiogenesis, invasion, and metastasis. Overexpressed ETS proteins and ETS family fusion proteins have been reported in acute myeloid leukemia (AML) and diffuse large B cell lymphoma (DLBCL). In DLBCL, the 11q24.3 region has been identified as a recurrent lesion and a contributor to the pathogenesis of disease, leading to the deregulation of ETS family members, ETS1 and FLI1. Additionally, in AML, the overexpression and translocations of ERG, an ETS family member, has been shown to be associated with poor prognosis in complex or normal karyotypes. TK216 is a first in class, small molecule that directly binds EWS-FLI1 inhibiting the biological activity of ETS-family transcription factor oncoproteins and is currently under clinical investigation in patients with Ewing sarcoma (NCT02657005). The EWS1-FLI1 is a fusion protein that has been shown to be the driver of Ewing Sarcoma (ES). In preclinical potency models, TK216 blocked the binding between EWS-FLI1 and RNA helicase A, showed a significant transcriptional decrease in COS7 cells transfected with a EWS-FLI1 responsive promoter (EC50 < 100 nM), and inhibited the proliferation of A4573 cells (EWS-FLI1 expressing Ewing sarcoma cell line) at nanomolar concentrations (EC50 < 200 nM). Here we show that TK216 has anti-proliferative effects, causes cell cycle arrest, and induces apoptosis in a panel of AML and DLBCL cell lines with deregulated ETS family members. We report an upregulation of FLI1 and/or ERG ETS family members in 5 of 5 myeloid cell lines evaluated (HL60, Kasumi-1, ML-2, MOLM-13, and MOLM-16). Treatment with TK216 showed a decrease in cellular viability and induced dose-dependentapoptosis of cells at 48 hours. Similarly, in a panel of DLBLC cell lines (TMD8, HBL1, U2932, DOHH2, WSUDLCL2 and OCI-Ly18), TK216 treatment resulted in a decrease in cellular proliferation and an increase in apoptosis. In vivo efficacy studies in xenograft models of DLBCL are underway; the preliminary anti-tumor activity that is being seen is encouraging and consistent with our in vitro findings. We believe that our findings provide compelling evidence of the utility and potential efficacy of TK216 in the treatment of AML and DLBCL by targeting the aberrant expression and translocations in the ETS-family of transcription factors, which contribute to the pathogenesis of the disease. Disclosures Jessen: Oncternal: Employment. Otuski:Oncternal: Employment, Equity Ownership. Breitmeyer:Oncternal: Employment, Equity Ownership. Freddo:Oncternal: Employment, Equity Ownership. Toretsky:Oncternal: Research Funding. Lannutti:Oncternal: Employment, Equity Ownership.

scholarly journals CC-92480 Is a Novel Cereblon E3 Ligase Modulator with Enhanced Tumoricidal and Immunomodulatory Activity Against Sensitive and Resistant Multiple Myeloma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1812-1812 ◽  
Author(s):  
Antonia Lopez-Girona ◽  
Courtney G. Havens ◽  
Gang Lu ◽  
Emily Rychak ◽  
Derek Mendy ◽  
...  
Keyword(s):  
Cell Lines ◽  
Acquired Resistance ◽  
E3 Ligase ◽  
Immunomodulatory Activity ◽  
Employment Equity ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Equity Ownership ◽  
Induction Of Apoptosis ◽  
Low Levels

Lenalidomide- and pomalidomide-based therapies are effective drugs in the treatment of patients with multiple myeloma (MM), however most patients with MM eventually relapse or become resistant. CC-92480, a novel cereblon (CRBN) E3 ligase modulator (CELMoD) with multiple activities including potent immunomodulation and single-agent antiproliferative effects, is being investigated in a phase 1 clinical trial (CC-92480-MM-001; NCT03374085) for patients with relapsed/refractory MM (RRMM). The present study investigates the preclinical data and mechanism of action of CC-92480 in MM models. CELMoD agents bound to CRBN confer differentiated substrate-degradation specificity on the CRL4CRBN E3 ubiquitin ligase. CRBN-modulator agents mediate destruction of Ikaros and Aiolos, transcription factors that contribute to myeloma cell survival. CC-92480 was found to produce rapid, deep, and sustained degradation of Ikaros and Aiolos, with superior antimyeloma activity. Accordingly, in a CRBN protein competitive binding assay, CC-92480 displaced a Cy-5-labeled CELMoD analog from CRBN with a 50% inhibitory concentration (IC50) value of 0.03 μM, whereas lenalidomide competed with an IC50 value of 1.27 μM in the same assay, demonstrating a higher binding affinity of CC-92480 for CRBN. Additionally, CC-92480 promoted the recruitment of Ikaros to the CRBN E3 ligase complex more effectively than pomalidomide in 2 orthogonal CRBN/Ikaros binding assays; it also triggered a more extensive cellular ubiquitination of Ikaros, and a faster, more efficient depletion of cellular Ikaros and Aiolos than pomalidomide. In various MM cell lines, including those with acquired resistance to lenalidomide or pomalidomide and low levels of CRBN, CC-92480 produced robust degradation of Ikaros and Aiolos followed by strong reduction of 2 additional and highly critical transcription factors, c-Myc and interferon regulatory factor 4, which are linked to the induction of apoptosis as measured by cleaved caspase-3. The tumoricidal activity of CC-92480 was shown to be CRBN dependent, since the effect was prevented by complete loss of CRBN or by the stabilization of Ikaros and Aiolos. CC-92480 displayed broad and potent antiproliferative activity across a panel of 20 MM cell lines that are either sensitive, have acquired resistance, or are refractory to lenalidomide or pomalidomide; the cell lines also contained diverse chromosomal translocations and oncogenic drivers typically found in MM patients. Approximately half of the MM cell lines evaluated were highly sensitive to CC-92480, with IC50 values for antiproliferative activity ranging from 0.04 to 5 nM; only 2 cell lines had IC50 values > 100 nM. CC-92480 inhibits cell proliferation and induces apoptosis in MM cell lines that are not sensitive to lenalidomide or pomalidomide. This panel of cell lines includes both refractory cell lines and resistant cell lines generated through continuous exposure to lenalidomide and pomalidomide that acquired low levels of CRBN protein or mutations in the CRBN gene. CC-92480 also induced deep destruction of Ikaros and Aiolos in cultures of peripheral blood mononuclear cells (PBMCs), which led to the activation of T cells and increased production of the cytokines interleukin-2 and interferon gamma. These responses occurred at the range of CC-92480 concentrations that show potent tumoricidal effect against MM cells. The T cell activation and enhanced cytokine production by CC-92480 led to the potent and effective immune-mediated killing of MM cells in co-cultures with PBMCs. CC-92480 is a potent antiproliferative and proapoptotic novel CELMoD with enhanced autonomous cell-killing activity in MM cells that are either sensitive, resistant, or have acquired resistance to lenalidomide and pomalidomide. CC-92480 has a unique and rapid degradation profile stemming from the enhanced efficiency to drive the formation of a protein-protein interaction between Ikaros and Aiolos and CRBN, inducing cytotoxic effects in a CRL4CRBN-dependent fashion that leads ultimately to the induction of apoptosis, even in the context of low or mutated CRBN protein. Additionally, similar to lenalidomide, CC-92480 conserves immunomodulatory activity against MM cells. These data support the clinical investigation of CC-92480 in patients with RRMM. Disclosures Lopez-Girona: Celgene Corporation: Employment. Havens:Pfizer: Employment, Equity Ownership; Celgene: Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Rychak:Celgene Corporation: Employment, Equity Ownership. Mendy:Celgene Corporation: Employment. Gaffney:Celgene: Employment. Surka:Celgene: Employment, Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Matyskiela:Celgene corporation: Employment. Khambatta:Celgene: Employment. Wong:Celgene Corporation: Employment, Equity Ownership. Hansen:Celgene Corporation: Employment. Pierce:Celgene Corporation: Employment, Equity Ownership. Cathers:Global Blood Therapeutics (GBT): Employment; Celgene Corporation: Equity Ownership. Carmichael:Celgene plc: Employment, Equity Ownership.

scholarly journals CDK9 Inhibition Reverses Resistance to ABT-199 (GDC-0199) By Down-Regulating MCL-1

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2161-2161 ◽  
Author(s):  
Jun Chen ◽  
Sha Jin ◽  
Paul Tapang ◽  
Stephen K Tahir ◽  
Morey Smith ◽  
...  
Keyword(s):  
Clin Oncol ◽  
Cell Lines ◽  
Small Molecule ◽  
Hodgkin’S Lymphoma ◽  
Acquired Resistance ◽  
Hematologic Malignancies ◽  
Hodgkin's Lymphoma ◽  
Employment Equity ◽  
Non Hodgkin's Lymphoma ◽  
Equity Ownership

Abstract All authors are employees of AbbVie and participated in the design, conduct, and interpretation of these studies. AbbVie and Genentech provided financial support for these studies and participated in the review and approval of this publication. The BCL-2-selective inhibitor ABT-199 has demonstrated efficacy in numerous preclinical models of hematologic malignancies without causing thrombocytopenia, a dose-limiting toxicity associated with the BCL-2/BCL-XL inhibitor navitoclax (Souers et al. 2013. Nat. Med. 19, 202-208). ABT-199 has also demonstrated clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) (Seymour et al. 2014. J. Clin. Oncol. 32, 448s; Davids et al. 2014. J. Clin. Oncol. 32, 544s). Despite these encouraging early clinical data, some subjects do not respond to ABT-199 or progress while on treatment. Pre-clinical models indicate that both intrinsic and acquired resistance may be a consequence of MCL-1 expression. Consequently, we have explored potent and selective small molecule inhibitors of CDK9, a kinase known to maintain the expression of MCL-1 through its role in p-TEFb-mediated transcription. Inhibition of CDK9 resulted in the rapid loss in RNA polymerase II phosphorylation (Serine 5) and MCL-1 expression that was closely followed by the induction of apoptosis in MCL-1-dependent cell lines, a cellular response that could be rescued by overexpression of BCL-2. Substantial synergy was observed between CDK9 inhibitors and ABT-199 in a number of hematologic cell lines with intrinsic or acquired resistance to ABT-199. Direct inhibition of MCL-1 with the small molecule BH3 mimetic A-1210477 was also highly synergistic with ABT-199, further validating the utility of co-inhibiting MCL-1 and BCL-2 function simultaneously in ABT-199 resistant tumors. Importantly, the CDK9 inhibitor-ABT-199 combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in xenograft models of non-Hodgkin’s lymphoma (NHL) and acute myelogenous leukemia (AML). These data indicate that CDK9 inhibitors may be highly efficacious when used in combination with ABT-199 for the treatment of hematologic malignancies. Disclosures Chen: Abbvie: Employment, Equity Ownership. Jin:Abbvie: Employment, Equity Ownership. Tapang:abbvie: Employment, Equity Ownership. Tahir:abbvie: Employment, Equity Ownership. Smith:abbvie: Employment, Equity Ownership. Xue:abbvie: Employment, Equity Ownership. Zhang:abbvie: Employment, Equity Ownership. Gao:abbvie: Employment, Equity Ownership. Tong:abbvie: Employment, Equity Ownership. Clark:abbvie: Employment, Equity Ownership. Ricker:abbvie: Employment, Equity Ownership. Penning:abbvie: Employment, Equity Ownership. Albert:abbvie: Employment, Equity Ownership. Phillips:abbvie: Employment, Equity Ownership. Souers:abbvie: Employment, Equity Ownership. Leverson:abbvie: Employment, Equity Ownership.

scholarly journals Preclinical Development of an Anti-CD38 Antibody-Drug Conjugate for Treatment of Hematological Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5621-5621 ◽  
Author(s):  
Lingna Li ◽  
Wenyong Tong ◽  
Megan Lau ◽  
Katherine Fells ◽  
Tong Zhu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Cell Binding ◽  
Antibody Drug Conjugate ◽  
Employment Equity ◽  
Cd38 Expression ◽  
Equity Ownership ◽  
Anti Tumor Activity ◽  
Antibody Drug

CD38 is a validated target for the treatment of multiple myeloma (MM). Daratumumab (Darzalex®), an anti-CD38 monoclonal antibody (mAb), has shown great clinical efficacy and has been approved for multiple myeloma treatment. However, both primary refractoriness and development of resistance to daratumumab therapy have been reported. Based on the therapeutic benefits of this CD38 antibody, we developed a CD38-targeting antibody-drug conjugate (ADC), employing a fully human anti-CD38 antibody STI-6129, identified from Sorrento's G-MAB® antibody library, and proprietary linker-toxin technology. The toxin payload is duostatin 5.2 (Duo.5.2), a microtubule inhibitor, conjugated to STI-6129 via a non-polyethylene glycol linker resulting in our lead ADC CD38-077. Cell binding studies showed that it specifically binds to CD38-positive tumor cells but not CD38-negative cell lines. The cell binding was proportional to the CD38 expression level on the cell surface. The ADC was internalized into CD38-positive cells at a rate comparable to that of the unconjugated antibody, indicating that conjugation did not change the binding characteristics of STI-6129 to its antigen. In cytotoxicity studies, CD38-077 exhibited a CD38-dependent cytotoxic activity against a panel of CD38-expressing tumor cell lines and was more potent in cells with high CD38 expression. The cytotoxic effect of CD38-077 was also examined against human PBMC cells, as it has been reported that certain types of the immune cells express CD38. The result indicated that normal PBMC cells were generally insensitive to the ADC up to 1 µM following 120 hr exposure. We investigated the anti-tumor activity of CD38-077 in xenograft animal models of Burkitt's lymphoma and two different multiple myeloma (MM) cell lines. The studies evaluated different dose levels and dosing regimens, including single dose and multiple doses at various intervals. The data showed that the ADC has a broad, potent and CD38-dependent in vivo efficacy in all three xenograft tumor models examined. In a pharmacokinetic study in naïve mice, CD38-077 was found to be stable, with T1/2 of about 7-11 days, comparable to that of the unconjugated STI-6129 antibody. In summary, CD38-077 exhibits strong anti-tumor activity in vitro and in vivo. The ADC showed specific activity towards CD38-expressing tumors but was less active against CD38-expressing normal PBMC cells, which express relatively low levels of CD38 level and where internalization was not detectable. These results warrant further development exploration of CD38-077. Disclosures Li: Concortis Biotherapeutics: Employment, Equity Ownership. Lau:Levena Biopharma: Employment, Equity Ownership. Fells:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zhu:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties. Sun:Levena Biopharma: Employment, Equity Ownership. Kovacs:Levena Biopharma: Employment, Equity Ownership. Khasanov:Levena Biopharma: Employment, Equity Ownership. Yan:Levena Biopharma: Employment, Equity Ownership. Deng:Levena Biopharma: Employment, Equity Ownership. Takeshita:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Li:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties; Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Concortis Biotherapeutics: Employment, Equity Ownership, Patents & Royalties.

Preclinical Development of Triptolide Derivative MRx102 as a Therapeutic Agent for Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3271-3271
Author(s):  
John M. Fidler ◽  
Jinhua An ◽  
John H. Musser ◽  
Duncan H. Mak ◽  
Bing Carter ◽  
...  
Keyword(s):  
Drug Development ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Employment Equity ◽  
Toxicology Study ◽  
Leukemia Cell Lines ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract Abstract 3271 Acute Myeloid Leukemia (AML) is the most common form of adult acute leukemia and the second most common childhood leukemia. AML has the lowest survival rate among leukemias, and the frequency is increasing as the population ages. Current therapies are inadequate, and a need exists for better therapeutic agents to treat AML, both as initial treatment for newly diagnosed patients and for those who have failed current therapy and relapsed. Natural products, such as taxol, have shown activities in a variety of disease states, including cancer. Triptolide is a natural product diterpenoid derived from Tripterygium wilfordii Hook f, and has shown anti-cancer activity in a broad range of solid tumors in preclinical models. It induces apoptosis in various leukemic cell lines and primary AML blasts (Carter, B et al, Blood 2006). Derivatives of triptolide with improved pharmacokinetics and bioavailability offer the opportunity to optimize the activity of triptolide for clinical application in AML. MRx102 is a triptolide derivative that is more hydrophobic than triptolide. It has potent in vitro cytotoxic activity with human tumor and leukemia cell lines, an unusual result for triptolide derivatives because they are usually much less active in vitro than the parent compound. Designed as a prodrug, MRx102 exerts cytotoxic activity with human AML cell lines and other human leukemia cell lines without pre-incubation with plasma esterases (IC50 of 51.0 and 37.1 nM with MV4-11 AML cells at 48 and 72 hours, respectively, ∼55% and ∼36% of the activity of triptolide, respectively). MRx102 decreases the viable CD34+ blasts of AML patient samples (a mean of 79.8 ± 8.8% specific apoptosis at 100 nM, n=3), and overcomes the apoptosis protection by co-cultivated stromal cells (with a similar mean of 74.1 ± 8.5%). MRx102 shows dose-dependent anti-tumor activity with the MV4-11 cell line in nude mouse human AML tumor xenografts. After 42 days of MRx102 dosing at 1.35 mg/kg/day i.p., tumor volume was inhibited by 99.7%. Tumors removed from several mice appeared to be Matrigel pellets rather than vascularized tumors, suggesting that many of the tumors were completely eliminated. In studies with the OCI-AML3 human AML cell line xenograft model, the group receiving MRx102 at 1.35 mg/kg/day i.p. showed similar high activity, with mean tumor volume reduced by as much as 99.2% on day 23 compared to the vehicle control group. Tumors of 7 of 10 mice were smaller than the day 0 volumes at the day 28 end of the study. As part of drug development, toxicology testing with MRx102 was initiated with an acute single dose rat toxicology study with no deaths and no adverse signs up to the top dose of 3.0 mg/kg MRx102 in DMSO/PBS administered i.v. The maximum tolerated dose (MTD) is greater than 3 mg/kg of MRx102, and the no observable adverse effect level (NOAEL) is at least 3 mg/kg. A 7-day subacute rat toxicology study of MRx102 showed no deaths and no adverse signs up to the top dose of 1.5 mg/kg/day MRx102 in DMSO/PBS administered daily i.v. for 7 days. The histopatholgy report shows no findings related to administration of the test article. The MRx102 MTD is greater than 1.5 mg/kg/day, and the NOAEL is at least 1.5 mg/kg/day. Previously observed NOAELs for related compounds have been less than 0.1 mg/kg/day. The current studies show potent anti-tumor activity as well as an unusually positive safety profile for MRx102 when compared to triptolide and other triptolide derivatives. Further MRx102 drug development is underway, with the intention of submitting an Investigational New Drug application to the Food and Drug Administration leading to clinical evaluation of MRx102 in AML patients. Updated results on current drug development activities will be presented at the meeting. This work is supported in part by NCI SBIR Contract HHSN261200900061C to MyeloRx LLC. Disclosures: Fidler: MyeloRx LLC: Employment, Equity Ownership, PI for an NCI Contract to MyeloRx LLC, Patents & Royalties. An:MyeloRx LLC: Employment, Equity Ownership, participant in research under an NCI SBIR Contract to MyeloRx LLC. Musser:MyeloRx LLC: Employment, Equity Ownership, Patents & Royalties, participant in research under an NCI SBIR Contract to MyeloRx LLC. Mak:MyeloRx LLC: participant in research under an NCI SBIR Contract to MyeloRx LLC. Carter:MyeloRx LLC: participant in research under an NCI SBIR Contract to MyeloRx LLC. Andreeff:MyeloRx LLC: Consultancy, participant in research under an NCI SBIR Contract to MyeloRx LLC.

scholarly journals SL-501, a Next-Generation Targeted Therapy Directed to the IL-3 Receptor (IL-3R), Possesses Preclinical Anti-Tumor Activity Against Hodgkin’s and Non-Hodgkin’s Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4500-4500 ◽  
Author(s):  
Janice Chen ◽  
Vince Macri ◽  
Pedro Herrera ◽  
Christopher Brooks ◽  
Eric Rowinsky
Keyword(s):  
Targeted Therapy ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Next Generation ◽  
Employment Equity ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract While Hodgkin’s lymphoma (HL) is among the most curable lymphomas, a significant percentage of patients relapse after frontline therapy or have primary refractory disease. Patients that remain resistant after second or third line chemotherapy or autologous stem cell transplantation (ASCT) have very limited treatment options. Non-Hodgkin’s lymphoma (NHL) comprises a wide array of clinical subtypes, which have indolent to aggressive clinical courses. Multiple lines of chemotherapy and ASCT are part of the NHL treatment strategy, but indolent forms frequently recur, and patients can develop resistance to therapies that were previously effective. The prognosis for patients with HL and NHL who fail to achieve durable remission with approved therapeutics or transplantation is poor. Therefore, new treatment strategies for such patients are desperately needed. The interleukin-3 receptor (IL-3R) alpha chain (CD123) is overexpressed on the tumor bulk and cancer stem cells (CSCs) of multiple hematologic malignancies. In particular, CD123 has been shown to be upregulated on a variety of leukemias and lymphomas, including HL and certain NHLs. We previously showed that SL-401, a novel IL-3R-targeted therapy comprised of IL-3 fused to a truncated diphtheria toxin payload, possesses cytotoxic activity against IL-3R-expressing HL and NHL cells. SL-501 is a next-generation IL-3R targeted therapy with increased binding affinity for the IL-3R and enhanced potency against both tumor bulk and CSCs of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Here, the anti-tumor activity of SL-501 against HL and NHL cells was investigated. Our flow cytometry assessment of CD123 showed that the receptor was expressed on two nodular sclerosing HL cell lines (L-428 and HDLM2), one mixed cellularity HL line (L-1236), and two mantle cell lymphoma lines (Mino and JeKo-1). CD123 was expressed to varying extents, ranging from high expression in HDLM-2 (99.5%) and L-428 (89.1%), to moderate-to-low expression in Mino (25.4%), L-1236 (19.5%) and JeKo-1 (2.9%). In this study, the activity of SL-501 was tested against this panel of cell lines. Cell were treated with SL-501 (range: 6.3 pM – 1.5 mM) for 48 hours and then assessed for viability using the CellTiter Glo® in vitro cytotoxicity assay. We found that SL-501 reduced the viability of all cell lines tested in a dose-dependent fashion. In particular, SL-501 showed very high potency against the HDLM2 and L-1236 lines, with IC50 values in the sub-nanomolar range (0.139 nM and 0.191 nM, respectively). SL-501 was also cytotoxic against L-428, JeKo-1, and Mino cell lines, with IC50s of 91 nM, 97 nM, and 116 nM, respectively. Taken together, these findings demonstrate that SL-501, a novel next-generation IL-3R-targeted therapeutic, possesses potent in vitro anti-cancer activity against a variety of HL and NHL cell lines. Additional functional studies are ongoing. These promising results provide a rationale for further development of SL-501 in HL and NHL. Disclosures Chen: Stemline Therapeutics: Employment, Equity Ownership. Macri:Stemline Therapeutics: Employment, Equity Ownership. Herrera:Stemline Therapeutics: Employment. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Rowinsky:Stemline Therapeutics: Consultancy, Employment, Equity Ownership.

scholarly journals Diffuse Large B Cell Lymphoma (DLBCL) Expresses ROR1 and a ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Tumor Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2565-2565
Author(s):  
Mohammad Hojjat-Farsangi ◽  
Amineh Ghaderi ◽  
AmirHossein Daneshmanesh ◽  
Jemina Lehto ◽  
Ali Moshfegh ◽  
...  
Keyword(s):  
Cell Lines ◽  
Small Molecule ◽  
Stromal Cells ◽  
Research Funding ◽  
Cytotoxic Effect ◽  
Advanced Disease ◽  
Annexin V ◽  
Employment Equity ◽  
2Nd Generation ◽  
Equity Ownership

Background: Receptor tyrosine kinase (RTK) (ROR1) is normally expressed during embryogenesis but absent in most normal tissues. However, ROR1 is overexpressed in several cancers (onco-fetal RTK) and of importance for various tumor cell functions such as proliferation and survival. In patients with diffuse large B-cell lymphomas (DLBCL) there is a great medical need to develop new treatment alternatives for those not responding to primary treatment as well as for patients with relapse as effective treatments are warranted. Inhibition of ROR1 by a small molecule ROR1 inhibitor (KAN0439834) abrogated downstream kinase activities as well as induced apoptosis of various tumor cells as CLL and pancreatic carcinoma (Leukemia, Oct;32(10):2291-2295, 2018) (PLoS One. 13(6): e0198038, 2018). A 2nd generation of ROR1 inhibitor (KAN0441571C) has been synthesized with the aim to bind to the ROR1-TK domain and inhibit ROR1 signaling. Aim: To examine the expression of ROR1 in DLBCL cell lines (RC-KB, SUDHL4, MS, OCL-LY3, U2932) and in patients´ samples at different stages of DLBCL as well as effects of KAN0441571C on survival of DLBCL cells and ROR1 signaling. Methods: Flow cytometry, tissue microarray and immunohistochemistry assays were used to check ROR1 expression. MTT and Annexin V/PI assays were applied to analyse cytotoxicity and apoptosis of KAN0441571C alone or in combination with ibrutinib (BTK inhibitor) and venetoclax (BCL-2 inhibitor) on DLBCL cell lines. Western blot was performed to evaluate ROR1 phosphorylation and associated signaling pathways. DLBCL cells were also cultured with HS-5 stromal cells (ROR1 neg.) to evaluate the apoptosis inhibitory effects of stromal cells. Results: ROR1 expression was significantly more frequently noted in patients with advanced disease (Richter´s, transformation, transformed follicular lymphoma and refractory DLBCL) compared to less advanced disease (recurrent or de novo DLBCL) (p=0.0001). In primary refractory and relapsing DLBCL 5-years survival was 45% in ROR1- patients (n=17) while in ROR1+ patients (n=16) the corresponding figure was <10% (p= 0.0335). KAN0441571C induced a dose-dependent cytotoxic effect in all ROR1+ DLBCL cell lines (EC50=50-100 nM) while no effect could be noted in the ROR1- U2932 cell line (EC50>10000 nM). EC50 for venetoclax in the ROR1+ DLBCL cell lines varied between 100 and 500 and 5000 - 10000 nM for ibrutinib. In comparison to venetoclax, KAN0441571C induced a similar or significantly higher cytotoxic effect. KAN0441571C and venetoclax seemed to be the most promising drug combination approaching 100% killing at the EC50 dose for each drug. Apoptosis was confirmed by Annexin V/PI staining as well as by downregulation of BCL-2 and MCL-1 as well as cleavage of PARP and caspase 3. KAN0441571C dephosphorylated ROR1 as well as the co-receptor LRP6 and the SRC protein which binds to phosphorylated ROR1. The downstream molecules PI3Kδ/AKT/mTOR was also dephosphorylated and the transcription factor CREB. CK1δ and GSK3B were also dephosphorylated and β-catenin downregulated indicating involvement of both the non-canonical and canonical Wnt pathways. When DLBCL and HS-5 cells (ROR1 neg.) were co-cultured, HS-5 cells could partially prevent induction of apoptosis of DLBCL cells at low concentrations of KAN0441571C, while at higher concentrations the presence of stromal cells was less effective. Zebrafish embryos transplanted with the OCI-Ly3 cell line were treated for 3 days with KAN0441571C (25-1000 nM). No toxic effects of the drug could be noted. A significant dose and time-dependent decrease in the tumor area were noted. Conclusion: KAN0441571C is the 2nd generation of a novel class of ROR1-inhibiting small molecule drugs. The molecule was more effective in inducing apoptosis of DCBCL cells than venetoclax or ibrutinib. New anti-cancer drugs with other mechanisms of action than those clinically available for DLBCL are warranted to improve the prognosis. ROR1 inhibitors in combination with other targeted drugs as venetoclax and ibrutinib might improve the therapeutic effects. KAN0441571C may be a novel drug candidate which needs further exploration in DLBCL. Disclosures Lehto: Kancera AB: Employment. Vågberg:Kancera AB: Employment. Olsson:Kancera AB: Employment. Löfberg:Kancera AB: Employment. Norström:Kancera AB: Employment. Schultz:Kancera AB: Employment, Equity Ownership. Norin:Kancera AB: Employment. Olin:Kancera AB: Employment, Equity Ownership. Österborg:Kancera AB: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; BeiGene: Research Funding. Mellstedt:Kancera AB: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals CC-92480, a Novel Cereblon E3 Ligase Modulator, Is Synergistic with Dexamethasone, Bortezomib, and Daratumumab in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1815-1815
Author(s):  
Lilly Wong ◽  
Rama Krishna Narla ◽  
Jim Leisten ◽  
Daniel Bauer ◽  
Matthew Groza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Synergistic Effect ◽  
Cell Viability ◽  
Cell Lines ◽  
E3 Ligase ◽  
Proteasome Activity ◽  
Employment Equity ◽  
Equity Ownership

Introduction: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) with enhanced autonomous cell-killing and immunomodulatory activity against multiple myeloma (MM) cells. CC-92480 is currently in phase 1 development in a late-line myeloma patient population (NCT03374085). Here, we sought to characterize the antitumor activity of CC-92480 in combination with dexamethasone (DEX), bortezomib (BORT), or daratumumab (DARA) in MM cell lines in vitro and xenograft mouse models in vivo. Methods: CC-92480 activity in combination with DEX was evaluated in MM cell lines. Apoptosis was measured by quantification of caspase-3 activation. The effect of BORT on CC-92480-induced Ikaros and Aiolos degradation was determined by concurrent treatment of MM cells with BORT and CC-92480. β5-site proteasome activity was also determined in the same experiment. The in vitro activity of CC-92480 in combination with BORT was characterized using washout experiments to more faithfully model the short in vivo exposure but more prolonged, gradually diminishing proteasome inhibitory activity of BORT. Apoptosis and cell viability of CC-92480 with BORT were analyzed by flow cytometry. The effect of CC-92480 on CD38 expression was also evaluated across a panel of MM cell lines. The effect of CC-92480 in combination with DARA was characterized with antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) assays. CC-92480 in combination with DEX or BORT was tested in a lenalidomide-resistant (H929-1051) xenograft mouse model. Female SCID mice were inoculated with H929-1051 cells in the right hind leg. For the DEX combination, groups of tumor-bearing mice (n = 9-10) were dosed with vehicle, DEX, or CC-92480 once daily (QD), or CC-92480 in combination with DEX throughout the study, starting when the tumor volumes reached approximately 115 mm3. For combination with BORT, mice (n = 9-10/group) were dosed with vehicle, CC-92480, or BORT, or the CC-92480 and BORT combination starting when the tumor volumes reached approximately 500 mm3. CC-92480 was administered orally QD for 3 days and BORT as a single intravenous dose. Tumor volumes were measured twice a week for the duration of the studies. Results: CC-92480 synergized with DEX in reducing cell viability and potentiated DEX-induced apoptosis in a concentration-dependent manner in MM cell lines. Of note, the combination showed activity at concentrations of both DEX and CC-92480 that had minimal activity as single agents. In the xenograft model with H929-1051 cells, the combination of CC-92480 and DEX significantly inhibited tumor growth (−84%) when compared with either agent alone (−34% and −20% for CC-92480 and DEX, respectively) and was classified as a synergistic effect using the fractional product method. Although proteasome activity is required for CC-92480-induced degradation of Ikaros and Aiolos, CC-92480 nevertheless maintained its ability to efficiently degrade Ikaros and Aiolos in the presence of doses of BORT that cause clinically relevant levels of proteasome inhibition. The in vitro combination of CC-92480 with BORT resulted in greater cytotoxic activity on MM cells than either single agent alone. The in vivo efficacy of CC-92480 and BORT, administered concurrently, showed a strongly synergistic effect with a near complete or complete tumor regression in every animal, and 6 of 9 animals remained tumor-free through an observation period extending 157 days after the control group was terminated. Anti-CD38 therapies, including DARA and isatuxumab, target CD38-expressing MM cells for killing by immune cells through cytotoxic and phagocytic mechanisms. In a panel of MM cell lines, CC-92480 treatment caused increased cell surface expression of CD38 (2-3 times that of control). Pretreatment of MM cells with CC-92480 resulted in increased DARA-mediated ADCC and ADCP compared with DMSO-treated controls. Conclusions: The strong preclinical synergy in MM cell killing exhibited by CC-92480 in combination with DEX, BORT, and with an anti-CD38 antibody (DARA), highlights its potential to bring clinical benefit to patients with MM in combination with these agents and supports the rationale for testing these combinations in clinical studies. Disclosures Wong: Celgene Corporation: Employment, Equity Ownership. Narla:Celgene Corporation: Employment, Equity Ownership. Leisten:Celgene Corporation: Employment. Bauer:Celgene Corporation: Employment, Equity Ownership. Groza:Celgene Corporation: Employment, Equity Ownership. Gaffney:Celgene: Employment. Havens:Celgene: Equity Ownership; Pfizer: Employment, Equity Ownership. Choi:AnaptysBio Inc: Employment, Equity Ownership; Celgene Corporation: Equity Ownership, Other: Formerly Employed. Lopez-Girona:Celgene Corporation: Employment. Hansen:Celgene Corporation: Employment. Cathers:Celgene Corporation: Equity Ownership; Global Blood Therapeutics (GBT): Employment. Carmichael:Celgene plc: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership.

scholarly journals Elucidating the Mechanism of Action of CC-90009, a Novel Cereblon E3 Ligase Modulator, in AML Via Genome-Wide CRISPR Screen

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 405-405 ◽  
Author(s):  
Gang Lu ◽  
Christine Surka ◽  
Chin-Chun Lu ◽  
In Sock Jang ◽  
Kai Wang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mechanism Of Action ◽  
E3 Ligase ◽  
Inhibitory Effect ◽  
Growth Inhibitory Effect ◽  
Employment Equity ◽  
Growth Inhibitory ◽  
Genome Wide ◽  
A Genome ◽  
Equity Ownership

CC-90009 is a novel cereblon E3 ligase modulator (CELMoD) currently under investigation in a phase I clinical study in relapsed or refractory acute myeloid leukemia (R/R AML) (CC-90009-AML-001; NCT02848001). CC-90009 coopts the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex to target the translation termination factor G1 to S phase transition 1 (GSPT1) for ubiquitination and proteasomal degradation, resulting in rapid induction of apoptosis and growth inhibition in AML cell lines and primary patient blasts. To further elucidate the mechanism of action of CC-90009 in AML, we performed a genome-wide CRISPR/Cas9 screen to identify gene(s) whose knockout abrogate(s) the response to CC-90009 in a sensitive AML cell line. In addition to well-established key regulatory proteins required for the activity of all known cereblon modulators, which include components of the CRL4CRBN complex, E2 ubiquitin conjugating enzymes UBE2G1 and UBE2D3, and members of the neddylation and deneddylation machinery, interestingly, the screen identified the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreased the production of full-length CRBN transcript via modulating alternative splicing of CRBN mRNA, leading to significant downregulation of cereblon expression and hence diminished response to CC-90009. The screen also revealed that mTOR signaling and the integrated stress response (ISR) specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Since CC-90009 inhibits protein translation, it is reasonable to expect interactions with regulators of this pathway. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 , at least in part by reducing CC-90009 induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Loss of GCN2 significantly attenuated the growth inhibitory effect of CC-90009, and this effect can be rescued with GCN2 wild-type but not enzymatically-dead mutants. Collectively, the antitumor activity of CC-90009, a first-in-class GSPT1 degrader, in AML cell lines is mediated by multiple layers of signaling networks and machinery, the elucidation of which reveals the underlying mechanism by which CC-90009 exerts its anti-AML activity and informs on the pathways for further study of CC-90009's clinical utility. Disclosures Lu: Celgene Corporation: Employment, Equity Ownership. Surka:Celgene: Employment, Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Jang:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Rolfe:Celgene: Employment, Equity Ownership.

scholarly journals A Novel Full Length Anti-FLT3 CD3 Bispecific Antibody for the Treatment of Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1445-1445 ◽  
Author(s):  
Ivana Djuretic ◽  
Veena Krishnamoorthy ◽  
Cesar Sommer ◽  
Danielle E. Dettling ◽  
Kris Poulsen ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Dendritic Cells ◽  
Cell Lines ◽  
Bispecific Antibody ◽  
Employment Equity ◽  
Equity Ownership ◽  
Low Levels ◽  
Anti Tumor Activity

Abstract FLT3 is a receptor tyrosine kinase expressed on the surface of acute myeloid leukemia (AML) patient blasts. FLT3 is the most frequently mutated gene in AML patients, and these mutations are associated with poor prognosis. Despite the development of small molecule inhibitors of FLT3 function and neutralizing FLT3 antibodies, there remains a need for antibodies that target the broad AML patient population with improved efficacy and safety. We chose to use Pfizer's proprietary full length humanized CD3 bispecific IgG molecule platform. The first step in the development was finding a suitable targeting epitope on FLT3 as not all epitopes result in optimal T cell activation in the context of CD3 binding. Through a combination of in vitro and in vivo studies, FLT3 antibodies targeting extracellular domain 4 of FLT3 were found to be more effective at AML cell depletion than other domains in the full-length bispecific IgG format, significantly outperforming the antibodies targeting the most membrane proximal region of domain 5. The final candidate antibody was engineered to have picomolar affinity for recombinant human FLT3 (<50 pM) to ensure that low levels of FLT3 present on AML (<5,000 per cell) could efficiently trigger T cell cytotoxicity. Anti-tumor activity of the final molecule was further characterized in vitro and in vivo. Three AML cell lines, Eol-1, Molm-13 and MV-411 express high, medium and low levels of FLT3, respectively, and were targeted by activated healthy donor T cells in the presence of the FLT3 bispecific with an efficiency that correlated with FLT3 surface density (EC50 range was 0.5 pM to 40 pM at E:T ratios of 1:1). Ability to target primary AML cells was confirmed in assays with primary AML blasts and autologous patient T cells (EC50s 7 - 15 nM, for E:T ratios of up to 1:50). In orthotopic xenograft models with the same set of cell lines, all three cell lines were efficiently eliminated by activated T cells in the presence of a single dose of FLT3 bispecific (dose range 10 to 100 μg/kg), confirming the anti-tumor activity of the bispecific antibody in vivo. The safety of Pfizer's FLT3 bispecific antibody was also studied in preclinical studies. We first analyzed gene expression of FLT3 and three other commonly considered AML targets (CD33, CD123, and CLL-1) in publicly available gene expression databases. FLT3 had the highest differential expression between AML and healthy tissues with blood and brain showing expression of low levels of FLT3 RNA. In tissue cross-reactivity studies, we detected little to no binding of the candidate FLT3 antibody to human brain tissue sections. In blood, the highest expression of FLT3 was in hematopoietic stem cells and progenitors, dendritic cells and monocytes consistent with previous publications and known roles of FLT3 in hematopoiesis and dendritic cell homeostasis. Of note, expression of FLT3 in monocytes and whole blood was the lowest compared to three other AML targets. To address any potential toxicities of FLT3 bispecific, we performed exploratory studies in cynomolgus monkeys. Affinity of FLT3 bispecific for cynomolgus FLT3 was ~20x lower than for human FLT3 (~1 nM), as determined in binding assays with cells expressing human and cynomolgus FLT3. No major clinical signs or toxicological findings were observed up to the highest dose level tested (3 mg/kg) following two administrations at weekly intervals. On target activity was demonstrated by nearly complete elimination of FLT3+ dendritic cells in the blood of treated monkeys two days after administration. In addition, we detected elimination of FLT3+ CD34+ stem cells in the bone marrow of treated monkeys two days after the second dose. Remarkably, both dendritic cells and FLT3+ CD34+ stem cells rebounded to baseline levels observed in control animals when analyzed at study termination, two weeks following the second dose. Consistent with minimal expression of FLT3 on healthy tissues and the presence of FLT3+ on rare blood subsets, cytokine increases typically associated with CD3 bispecific administration were minimal (only 6 to 17 and 46 to 89 fold over baseline for IFN-γ and IL-6, respectively, at the highest dose tested). In conclusion, the robust anti-tumor activity of Pfizer's FLT3 bispecific antibody combined with good tolerability in cynomolgus monkeys, reversible hematological toxicity and absence of non-hematological toxicity support its further clinical development in AML. Disclosures Djuretic: Pfizer Inc.: Employment. Krishnamoorthy:Pfizer: Employment. Sommer:Allogene Therapeutics: Employment, Equity Ownership, Patents & Royalties. Dettling:Maverick Therapeutics: Employment. Poulsen:Allogene Therapeutics: Employment, Equity Ownership. Chen:Pfizer: Employment. Hu:Pfizer: Employment. Given Chunyk:Pfizer: Employment. Lindquist:Pfizer: Employment. Potluri:Pfizer: Employment. Rickert:Pfizer: Employment. Sasu:Allogene Therapeutics: Employment, Equity Ownership, Patents & Royalties. Chaparro-Riggers:Pfizer Inc.: Employment, Patents & Royalties. Yeung:Pfizer: Employment, Patents & Royalties.

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