scholarly journals The Anti-Tumor Activity of Igm-8444, an Agonistic Death Receptor 5 (DR5) IgM Antibody, Is Sensitized in Combination with Chemotherapy and Bcl-2 Inhibitors in NHL and AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Beatrice T. Wang ◽  
Thomas J. Matthew ◽  
Ling Wang ◽  
Tasnim Kothambawala ◽  
Susan E. Calhoun ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Single Agent ◽  
Mouse Tumor ◽  
Targeted Agents ◽  
Publicly Traded ◽  
Tumor Models ◽  
In Vivo Efficacy

Background: Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF) receptor superfamily that multimerizes when bound to its ligand, TNF-related apoptosis inducing ligand (TRAIL), to activate the extrinsic apoptotic pathway. DR5 is broadly expressed on solid and hematologic cancers and has been targeted with both recombinant TRAIL and agonistic antibodies in the clinic. However, these therapeutics have been unsuccessful due to lack of efficacy or hepatotoxicity. We have developed IGM-8444, a pentameric IgM with 10 binding sites specific for DR5, that multimerizes DR5 to selectively and potently induce tumor cell apoptosis while maintaining tolerability. We have previously presented the in vitro and in vivo efficacy of IGM-8444 in solid tumor models, demonstrating low picomolar potency across multiple tumor cell lines, strong tumor regressions in cell line and patient derived xenograft mouse tumor models, and dose-dependent increases in apoptotic biomarkers. Here, we evaluate the activity of IGM-8444 in hematologic malignancies in combination with chemotherapy or targeted agents including Bcl-2 inhibitors targeting the intrinsic apoptotic pathway. Methods: Human hematologic cancer cell lines and primary human hepatocytes were evaluated in vitro for dose-dependent IGM-8444-induced cytotoxicity. Cell lines were further evaluated using IGM-8444 in combination with chemotherapy or targeted agents including Bcl-2 inhibitor ABT-199. In vivo efficacy was evaluated using IGM-8444 in combination with ABT-199 in cell line-derived xenograft mouse tumor models. Results: In a previous cancer cell line screen profiling single agent IGM-8444 cytotoxicity across 190 solid and hematologic cell lines, 25 (13%) were classified as highly responsive and 75 (39%) as moderately responsive to IGM-8444 induced cell death. Here the in vitro activity of IGM-8444 was evaluated across a subset of 32 NHL and AML cell lines. 5/21 (24%) of NHL cell lines and 5/11 (45%) of AML cell lines tested were classified as highly responsive or moderately responsive to IGM-8444-induced cytotoxicity. The DOHH-2 and JEKO1 NHL cell lines were amongst the most sensitive, with growth-normalized EC50 values as low as 0.03 ng/mL (0.03 pM) for JEKO1. Combinations with chemotherapy including cytarabine and doxorubicin or targeted agents such as Bcl-2 inhibitor ABT-199 resulted in synergistic in vitro cytotoxicity in multiple cell lines, as determined by Bliss synergy scores. IGM-8444 demonstrated minimal to no in vitro cytotoxicity to primary human hepatocytes at doses several log-fold higher than efficacious doses, and this favorable in vitro safety profile was maintained in combination with chemotherapeutic agents and ABT-199. Combination of IGM-8444 with ABT-199 also resulted in synergistic in vivo efficacy. In a DOHH-2 NHL model, IGM-8444 and ABT-199 showed modest tumor growth inhibition as single agents. However the combined treatment regimen led to tumor regressions during the first 2 weeks of treatment, with 3 of 10 animals showing a partial response and 2 of 10 animals achieving a complete response. The combined treatment also extended median overall survival compared to the control group, which was a significant improvement compared to either agent alone. Collectively, these results provide a strong rationale for simultaneously targeting the extrinsic and intrinsic apoptotic pathways to achieve enhanced efficacy. Conclusions: These data support the clinical development of IGM-8444 in hematological malignancies as a single agent, in combination with standard of care chemotherapy, and in combination with targeted agents that impact the intrinsic signaling pathway such as Bcl-2 inhibitor ABT-199. Initiation of a Phase I clinical study evaluating the safety of IGM-8444 is anticipated in 2020. Disclosures Wang: IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Matthew:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Wang:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Kothambawala:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Calhoun:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Humke:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Sinclair:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company. Keyt:IGM Biosciences Inc: Current Employment, Current equity holder in publicly-traded company.

Coltuximab Ravtansine (SAR3419) Demonstrates Enhanced Activity in Combination with Bendamustine, Gemcitabine and Novel Targeted Agents Such As PI3K Inhibitors in Pre-Clinical Models of Relapsed and/or Refractory Non-Hodgkins Lymphoma (NHL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5125-5125
Author(s):  
Callum M Sloss ◽  
Katie O'Callaghan ◽  
Jutta Deckert ◽  
Jenny Tsui ◽  
Leanne Lanieri ◽  
...  
Keyword(s):  
Cell Lines ◽  
Single Agent ◽  
Targeted Agents ◽  
Employment Equity ◽  
Pi3k Inhibitors ◽  
Xenograft Models ◽  
Equity Ownership ◽  
Chemotherapy Agents

Abstract Introduction: Relapsed/refractory B-cell NHL remains an area of significant medical need. CD19 is broadly expressed on B-cell malignancies making it an ideal target for antibody-drug conjugate (ADC) based therapy. Coltuximab ravtansine is a CD19-targeting ADC consisting of a CD19-targeting antibody conjugated to the maytansinoid anti-mitotic DM4. In preclinical studies, coltuximab ravtansine has shown potent, targeted activity against NHL cell lines and xenograft models. In early clinical trials, it has been well tolerated and has shown promising signs of efficacy as both a single agent and in combination with rituximab. In the STARLYTE Phase 2 trial coltuximab ravtansine monotherapy resulted in an ORR of 44% in R/R-DLBCL that included an ORR of 21% in hard-to-treat primary refractory patients (NCT01472887). Here we describe studies aimed at the identification of combination partners for coltuximab ravtansine to further optimize clinical benefit to R/R-NHL patients. We are employing a dual approach where we investigate combination of coltuximab ravtansine with multiple, novel targeted therapy partners whilst in parallel also investigating the combination of coltuximab ravtansine with chemotherapies commonly used in the late stage R/R-NHL setting. Methods: Coltuximab ravtansine and the DM4 payload were evaluated in a high throughput screen both as single agents and in combination with a selection of novel, emerging targeted agents across a panel of twenty NHL cell lines. The combinations were evaluated in a dose-response matrix and a statistical method was used to identify combination synergies significantly superseding baseline additivity values. The in vivo efficacy of coltuximab ravtansine was additionally assessed in combination with various clinically relevant chemotherapy agents in subcutaneous xenograft models of NHL. Results: Coltuximab ravtansine and DM4 both showed potent single agent activity against the entire panel of NHL cell lines with median GI50's of 770pM and 100pM, respectively. We observed a significant correlation in the cell line sensitivity of the two compounds suggesting that sensitivity to coltuximab ravtansine is driven, at least in part, by inherent sensitivity of cells to the cytotoxic effects of the DM4 payload. In vitro combination studies for coltuximab ravtansine were performed to identify targets or pathways that result in the most prominent combination effects across the cell line panel. Analysis of the in vitro combination dose-matrix revealed particularly strong synergy between coltuximab ravtansine and various inhibitors of the PI3K/AKT/mTOR axis. Studies to examine the synergism between coltuximab ravtansine and PI3K inhibitors in in vivo models of NHL are ongoing. In order to further determine the utility of coltuximab ravtansine as part of a potential combination regimen for the treatment of R/R-NHL, we assessed the combination of coltuximab ravtansine with the chemotherapy agents bendamustine and gemcitabine in vivo. As gemcitabine is typically used in combination we assessed the efficacy of a coltuximab ravtansine with rituximab and gemcitabine in vivo. In both cases the combination with coltuximab ravtansine was significantly more efficacious than the standard-of-care alone arms. Conclusions: Coltuximab ravtansine demonstrates synergistic activity in combination with multiple PI3K pathway inhibitors across a large panel of NHL cell lines. Additionally, we have shown that combination of coltuximab ravtansine with clinically relevant late stage treatments such as bendamustine and rituximab + gemcitabine is more efficacious than the chemotherapy regimens alone. These results support the continued development of coltuximab ravtansine in R/R-NHL in combination with chemotherapy regimens and suggest that a combination of coltuximab ravtansine with PI3K inhibitors may also be of interest in the clinical setting. Disclosures Sloss: ImmunoGen, Inc.: Employment, Equity Ownership. O'Callaghan:ImmunoGen, Inc.: Employment, Equity Ownership. Deckert:ImmunoGen, Inc.: Employment, Equity Ownership. Tsui:ImmunoGen, Inc.: Employment, Equity Ownership. Lanieri:ImmunoGen, Inc.: Employment, Equity Ownership. Romanelli:ImmunoGen, Inc.: Employment, Equity Ownership.

scholarly journals Targeted Inhibition of PI3K α/δ Is Synergistic with BCL-2 Blockade in Genetically Defined Subtypes of DLBCL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 39-39
Author(s):  
Kamil Bojarczuk ◽  
Kirsty Wienand ◽  
Jeremy A. Ryan ◽  
Linfeng Chen ◽  
Mariana Villalobos-Ortiz ◽  
...  
Keyword(s):  
Tumor Growth ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Research Funding ◽  
Single Agent ◽  
Research Report ◽  
Genetic Bases

Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease that is transcriptionally classified into germinal center B-cell (GCB) and activated B-cell (ABC) subtypes. A subset of both GCB- and ABC-DLBCLs are dependent on B-cell receptor (BCR) signaling. Previously, we defined distinct BCR/PI3K-mediated survival pathways and subtype-specific apoptotic mechanisms in BCR-dependent DLBCLs (Cancer Cell 2013 23:826). In BCR-dependent DLBCLs with low baseline NF-κB activity (GCB tumors), targeted inhibition or genetic depletion of BCR/PI3K pathway components induced expression of the pro-apoptotic HRK protein. In BCR-dependent DLBCLs with high NF-κB activity (ABC tumors), BCR/PI3K inhibition decreased expression of the anti-apoptotic NF-κB target gene, BFL1. Our recent analyses revealed genetic bases for perturbed BCR/PI3K signaling and defined poor prognosis DLBCL subsets with discrete BCR/PI3K/TLR pathway alterations (Nat Med 2018 24:679). Cluster 3 DLBCLs (largely GCB tumors) exhibited frequent PTEN deletions/mutations and GNA13 mutations. Cluster 5 DLBCLs (largely ABC tumors) had frequent MYD88L265P and CD79B mutations that often occurred together. These DLBCL subtypes also had different genetic mechanisms for deregulated BCL2 expression - BCL2 translocations in Cluster 3 and focal (18q21.33) or arm level (18q) BCL2 copy number gains in Cluster 5. These observations prompted us to explore the activity of PI3K inhibitors and BCL2 blockade in genetically defined DLBCLs. We utilized a panel of 10 well characterized DLBCL cell line models, a subset of which exhibited hallmark genetic features of Cluster 3 and Cluster 5. We first evaluated the cytotoxic activity of isoform-specific, dual PI3Kα/δ and pan-PI3K inhibitors. In in vitro assays, the PI3Kα/δ inhibitor, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. We next assessed the transcriptional abundance of BCL2 family genes in the DLBCLs following copanlisib treatment. In BCR-dependent GCB-DLBCLs, there was highly significant induction of the pro-apoptotic HRK. In BCR-dependent ABC-DLBCLs, we observed significant down-regulation of the anti-apoptotic BFL1 protein and another NF-κB target gene, BCLxL (the anti-apoptotic partner of HRK). We then used BH3 profiling, to identify dependencies on certain BCL2 family members and to correlate these data with sensitivity to copanlisib. BCLxL dependency significantly correlated with sensitivity to copanlisib. Importantly, the BCLxL dependency was highest in DLBCL cell lines that exhibited either transcriptional up-regulation of HRK or down-regulation of BCLxL following copanlisib treatment. In all our DLBCL cell lines, PI3Kα/δ inhibition did not alter BCL2 expression. Given the genetic bases for BCL-2 deregulation in a subset of these DLBCLs, we next assessed the activity of the single-agent BCL2 inhibitor, venetoclax, in in vitro cytotoxicity assays. A subset of DLBCL cell lines was partially or completely resistant to venetoclax despite having genetic alterations of BCL2. We postulated that BCR-dependent DLBCLs with structural alterations of BCL2 might exhibit increased sensitivity to combined inhibition of PI3Kα/δ and BCL2 and assessed the cytotoxic activity of copanlisib (0-250 nM) and venetoclax (0-250 nM) in the DLBCL cell line panel. The copanlisib/venetoclax combination was highly synergistic (Chou-Talalay CI<1) in BCR-dependent DLBCL cell lines with genetic bases of BCL2 deregulation. We next assessed copanlisib and venetoclax activity in an in vivo xenograft model using a DLBCL cell line with PTENdel and BCL2 translocation (LY1). In this model, single-agent copanlisib did not delay tumor growth or improve survival. Single-agent venetoclax delayed tumor growth and improved median survival (27 vs 51 days, p<0.0001). Most notably, we found that the combination of copanlisib and venetoclax delayed tumor growth significantly longer than single-agent venetoclax (p<0.0001). Additionally, the combined therapy significantly increased survival in comparison with venetoclax alone (median survival 51 days vs not reached, p<0.0013). Taken together, these results provide in vitro and in vivo pre-clinical evidence for the rational combination of PI3Kα/δ and BCL2 blockade and set the stage for clinical evaluation of copanlisib/venetoclax therapy in patients with genetically defined relapsed/refractory DLBCL. Disclosures Letai: AbbVie: Consultancy, Other: Lab research report; Flash Therapeutics: Equity Ownership; Novartis: Consultancy, Other: Lab research report; Vivid Biosciences: Equity Ownership; AstraZeneca: Consultancy, Other: Lab research report. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.

scholarly journals Pharmacologic Inhibition of the Histone Methyltransferase SETD2 with EZM0414 As a Novel Therapeutic Strategy in Relapsed or Refractory Multiple Myeloma and Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1142-1142
Author(s):  
Jennifer Totman ◽  
Dorothy Brach ◽  
Vinny Motwani ◽  
Selene Howe ◽  
Emily Deutschman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
Publicly Traded ◽  
The Past ◽  
Molecule Inhibitor

Abstract Introduction: SETD2 is the only known histone methyltransferase (HMT) capable of catalyzing H3K36 trimethylation (H3K36me3) in vivo. It plays an important role in several biological processes including B cell development and maturation, leading to the hypothesis that SETD2 inhibition in these settings could provide anti-tumor effects. The normal process of B cell development/maturation renders B cells susceptible to genetic vulnerabilities that can result in a dysregulated epigenome and tumorigenesis, including in multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL). For example, 15%-20% of MM harbors the high risk (4;14) chromosomal translocation, resulting in high expression of the multiple myeloma SET domain (MMSET) gene. MMSET is an HMT that catalyzes H3K36me1 and H3K36me2 formation and extensive scientific work has established overexpressed MMSET as a key factor in t(4;14) myeloma pathogenesis. To the best of our knowledge MMSET has eluded drug discovery efforts, however, since t(4;14) results in high levels of the H3K36me2 substrate for SETD2, inhibiting SETD2 offers promise for targeting the underlying oncogenic mechanism driven by MMSET overexpression in t(4;14) MM patients. In addition, SETD2 loss of function mutations described to date in leukemia and DLBCL are always heterozygous, suggesting a haploinsufficient tumor suppressor role for SETD2. This observation points to a key role for SETD2 in leukemia and lymphoma biology and suggests that therapeutic potential of SETD2 inhibition may also exist in these or similar settings. EZM0414 is a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2. We explored the anti-tumor effects of SETD2 inhibition with EZM0414 in MM and DLBCL preclinical studies to validate its potential as a therapy in these tumor types. Methods: Cellular proliferation assays determined IC 50 values of EZM0414 in MM and DLBCL cell line panels. Cell line-derived xenograft preclinical models of MM and DLBCL were evaluated for tumor growth inhibition (TGI) in response to EZM0414. H3K36me3 levels were determined by western blot analysis to evaluate target engagement. Combinatorial potential of SETD2 inhibition with MM and DLBCL standard of care (SOC) agents was evaluated in 7-day cotreatment in vitro cellular assays. Results: Inhibition of SETD2 by EZM0414 results in potent anti-proliferative effects in a panel of MM and DLBCL cell lines. EZM0414 inhibited proliferation in both t(4;14) and non-t(4;14) MM cell lines, with higher anti-proliferative activity generally observed in the t(4;14) subset of MM cell lines. The median IC 50value for EZM0414 in t(4;14) cell lines was 0.24 μM as compared to 1.2 μM for non-t(4;14) MM cell lines. Additionally, inhibitory growth effects on DLBCL cell lines demonstrated a wide range of sensitivity with IC 50 values from 0.023 μM to &gt;10 μM. EZM0414 resulted in statistically significant potent antitumor activity compared to the vehicle control in three MM and four DLBCL cell line-derived xenograft models. In the t(4;14) MM cell line-derived xenograft model, KMS-11, robust tumor growth regressions were observed at the top two doses with maximal TGI of 95%. In addition, two non-t(4;14) MM (RPMI-8226, MM.1S) and two DLBCL xenograft models (TMD8, KARPAS422) demonstrated &gt; 75% TGI; with two additional DLBCL models (WSU-DLCL2, SU-DHL-10) exhibiting &gt; 50% TGI in response to EZM0414. In all models tested, the antitumor effects observed correlated with reductions in intratumoral H3K36me3 levels demonstrating on-target inhibition of SETD2 methyltransferase activity in vivo. In vitro synergistic antiproliferative activity was also observed when EZM0414 was combined with certain SOC agents for MM and DLBCL. Conclusions: Targeting SETD2 with a small molecule inhibitor results in significantly reduced growth of t(4;14) MM, as well as non-t(4;14) MM and DLBCL cell lines, in both in vitro and in vivo preclinical studies. In addition, in vitro synergy was observed with EZM0414 and certain SOC agents commonly used in MM and DLBCL, supporting the combination of SETD2 inhibition with current MM and DLBCL therapies. This work provides the rationale for targeting SETD2 in B cell malignancies such as MM, especially t(4;14) MM, as well as DLBCL, and forms the basis for conducting Phase 1/1b clinical studies to evaluate the safety and activity of EZM0414 in patients with R/R MM and DLBCL. Disclosures Totman: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Brach: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Motwani: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Howe: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Deutschman: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Lampe: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Riera: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Tang: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Eckley: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Alford: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Duncan: Epizyme, Inc.: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Farrow: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Dransfield: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Raimondi: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Thomeius: Foghorn Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cosmopoulos: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Kutok: Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company.

scholarly journals ADG153, an Anti-CD47 Monoclonal Antibody Prodrug, Has Strong In Vivo Anti-Tumor Activity, Minimal RBC-Related and Antigen Sink Liabilities, and Extended Half Life in Comparison with Benchmark Clinical Antibodies of the Same IgG Subclass

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3342-3342
Author(s):  
Bin Cai ◽  
Aaron N Nguyen ◽  
Songmao Zheng ◽  
Jianfeng Shi ◽  
Guizhong Liu ◽  
...  
Keyword(s):  
Half Life ◽  
Mouse Tumor ◽  
Publicly Traded ◽  
Tumor Models ◽  
The Past ◽  
Macrophage Phagocytosis ◽  
Maximum Decrease ◽  
Anti Tumor Activity

Abstract Binding of the CD47 membrane protein, overexpressed on many tumor types, to the SIRPα inhibitory receptor on myeloid cells results in the inhibition of the activation of macrophages and other phagocytes against tumors. Therapies targeting the CD47/SIRPα axis have shown success in various preclinical models and are now in clinical trials for both solid and hematologic malignancies. Although anti-CD47 therapies have demonstrated promising clinical activities, the expression of CD47 on many different normal human cell types, including red blood cells (RBCs), serves as a large antigen sink for anti-CD47 antibodies. Blocking CD47 on RBCs, such as by magrolimab (Hu5F9), has led to transient anemia, requiring step-up dosing in the clinic. To circumvent these challenges, we developed ADG153, a fully human anti-CD47 SAFEbody masked by conditionally activable peptides. In normal tissues, the SAFEbody masking moiety can function to block ADG153 from binding to CD47; 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 ADG153 antibody to bind to and inhibit CD47 function on tumor cells. For head-to-head comparisons, in vitro studies were performed to compare the activity of Hu5F9 and unmasked ADG153 parental antibody of the IgG4 isotype. Both antibodies (1) blocked human SIRPα from binding to human CD47, (2) had similar potencies for binding to human CD47 protein, CD47-positive tumor cell lines, and human RBCs, and (3) induced macrophage phagocytosis. In contrast, the masked ADG153 SAFEbody demonstrated significantly reduced activities (&gt;450-fold) in the same in vitro assays, showing strong masking efficiencies. Unlike Hu5F9, both the ADG153 parental and SAFEbody molecules did not cause in vitro human RBC hemagglutination. Although the ADG153 SAFEbody had significantly reduced binding to CD47 in vitro as expected, it demonstrated strong anti-tumor activity in in vivo mouse tumor models. In both the disseminated and subcutaneous CD47-positive Raji tumor models, the ADG153 SAFEbody of the IgG4 isotype showed similar anti-tumor activities to Hu5F9. However, in exploratory toxicology studies in cynomolgus monkeys, the ADG153 SAFEbody showed significantly less decreases than Hu5F9 in RBCs, hemoglobin, and hematocrit. Hu5F9 at 10 mg/kg caused ~49% maximum decrease in RBCs, while ADG153 SAFEbody at 60 mg/kg showed ~23% maximum decrease in RBCs (Panel A). Pharmacokinetic (PK) studies of single intravenous dose ADG153 SAFEbody compared to Hu5F9 in monkeys demonstrated ~8-fold longer apparent half-life and ~9-fold higher Area Under the Curve at 10 mg/kg (Panel B). Collectively, ADG153 SAFEbody is a differentiated anti-CD47 antibody that has strong in vivo anti-tumor activity with reduced RBC-related and antigen sink liabilities and favorable PK properties. This preclinical profile with an enhanced therapeutic index provides a strong rationale for advancing ADG153 SAFEbody into clinical development. Figure 1 Figure 1. Disclosures Cai: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company. Nguyen: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company; Sparcbio, LLC: Ended employment in the past 24 months. Zheng: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company; Janssen Pharmaceuticals: Ended employment in the past 24 months. 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. Luo: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Xu: Adagene Inc.: Current Employment, Current equity holder in publicly-traded company; Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months.

scholarly journals Combination effect of lapatinib with foretinib in HER2 and MET co-activated experimental esophageal adenocarcinoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Md. Sazzad Hassan ◽  
Fiona Williams ◽  
Niranjan Awasthi ◽  
Margaret A. Schwarz ◽  
Roderich E. Schwarz ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cell Line ◽  
Esophageal Adenocarcinoma ◽  
Cell Lines ◽  
Tyrosine Kinases ◽  
Single Agent ◽  
Survival Models ◽  
Her2 Positive

AbstractRecent studies have demonstrated that HER2 and MET receptor tyrosine kinases are co-overexpressed in a subset esophageal adenocarcinoma (EAC). We therefore studied the usefulness of combining HER2 and MET targeting by small-molecule inhibitors lapatinib and foretinib, respectively, both in in-vitro and in-vivo models of experimental EAC. We characterized MET and HER2 activation in a panel of human EAC cell lines, and the differential susceptibility of these EAC cell lines to single agent or combination of foretinib and lapatinib. We then explored the antitumor efficacy with survival advantage following foretinib and lapatinib monotherapy and in combination in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. The OE33 EAC cell line with strong expression of phosphorylated both MET and HER2, demonstrated reduced sensitivity to foretinib and lapatinib when used as a single agent. The co-administration of foretinib and lapatinib effectively inhibited both MET and HER2 phosphorylation, enhanced inhibition of cell proliferation and xenograft tumor growth by inducing apoptosis, and significantly enhanced mouse overall survival, overcoming single agent resistance. In the OE19 EAC cell line with mainly HER2 phosphorylation, and the ESO51 EAC cell line with mainly MET phosphorylation, profound cell growth inhibition with induction of apoptosis was observed in response to single agent with lack of enhanced growth inhibition when the two agents were combined. These data suggest that combination therapy with foretinib and lapatinib should be tested as a treatment option for HER2 positive patients with MET-overexpressing EAC, and could be a novel treatment strategy for specific EAC patients.

Vitamin D as Radiosensitizer: A Review in Cell Line -

2020 ◽  
Vol 10 (6) ◽  
pp. 315-324
Author(s):  
Fahmi Radityamurti ◽  
Fauzan Herdian ◽  
Tiara Bunga Mayang Permata ◽  
Handoko Handoko ◽  
Henry Kodrat ◽  
...  
Keyword(s):  
Vitamin D ◽  
Cell Differentiation ◽  
Cell Line ◽  
Cell Lines ◽  
Anticancer Agent ◽  
Medical Literature ◽  
In Vitro Studies ◽  
Anti Cancer

Introduction: Vitamin D has been shown to have anti-cancer properties such as antioxidants, anti-proliferative, and cell differentiation. The property of vitamin D as an anticancer agent triggers researchers to find out whether vitamin D is useful as a radiosensitizer. Multiple studies have been carried out on cell lines in various types of cancer, but the benefits of vitamin D as a radiosensitizer still controversial. This paperwork aims to investigate the utilization of Vitamin D3 (Calcitriol) as radiosensitizer in various cell line through literature review.Methods: A systematic search of available medical literature databases was performed on in-vitro studies with Vitamin D as a radiosensitizer in all types of cell lines. A total of 11 in-vitro studies were evaluated.Results: Nine studies in this review showed a significant effect of Vitamin D as a radiosensitizer agent by promoting cytotoxic autophagy, increasing apoptosis, inhibiting of cell survival and proliferation, promoting gene in ReIB inhibition, inducing senescene and necrosis. The two remaining studies showed no significant effect in the radiosensitizing mechanism of Vitamin D due to lack of evidence in-vitro settings.Conclusion: Vitamin D have anticancer property and can be used as a radiosensitizer by imploring various mechanism pathways in various cell lines. Further research especially in-vivo settings need to be evaluated.

scholarly journals BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽  
2018 ◽  
Vol 3 (6) ◽  
pp. e000387 ◽  
Author(s):  
Chiara Tarantelli ◽  
Elena Bernasconi ◽  
Eugenio Gaudio ◽  
Luciano Cascione ◽  
Valentina Restelli ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Antitumour Activity ◽  
Single Agent ◽  
Treatment Strategies ◽  
Bet Inhibitor ◽  
Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

scholarly journals Targeting Antibody Checkpoint Fcgriib Using Monoclonal Antibody BI-1206 to Overcome Therapeutic Resistance in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Alexa A Jordan ◽  
Joseph McIntosh ◽  
Yang Liu ◽  
Angela Leeming ◽  
William Lee ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Publicly Traded ◽  
In Vivo Efficacy ◽  
Mantle Cell ◽  
Xenograft Models

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.

Bispecific anti-PD-1/PD-L1 antibody CTX-8371 to promote cellular clustering and PD-1 shedding, antitumor activity and tolerability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15056-e15056
Author(s):  
Diana I. Albu ◽  
Yan Qin ◽  
Xianzhe Wang ◽  
Vivian Li ◽  
Taeg Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Cynomolgus Monkeys ◽  
Range Finding

e15056 Background: Checkpoint blockade therapies targeting PD-1 and PD-L1 have shown great success for the treatment of various malignancies. However, a substantial fraction of patients with PD-L1-positive tumors remain unresponsive to these therapies. Novel therapy with significantly greater activity than the leading PD-1/PD-L1 inhibitors is expected to bring additional clinical benefit to patients. Here we describe the preclinical evaluation of CTX-8371, which combines anti-PD-1 and anti-PD-L1 monoclonal antibodies in one bispecific tetravalent molecule. Methods: The immune-enhancing activity of CTX-8371 was tested in vitro in T cell activation assays and tumor cell killing assay. CTX-8371 anti-tumor efficacy in vivo was assessed using mouse tumor cells expressing human PD-L1 implanted in transgenic mice humanized at the PD-1 and PD-L1 loci. CTX-8371 anti-tumor activity was also tested in xenograft tumor models. The mechanism of action of CTX-8371 was investigated in vitro using Jurkat cells expressing PD-1 or PD-L1, human PBMCs, and in vivo in tumor-bearing, chimeric PD-1/PD-L1 transgenic mice. CTX-8371 PK was determined in mice using an MSD ELISA-based assay and in cynomolgus monkeys using a qualified ELISA method. Dose range finding and toxicokinetic studies were performed in cynomolgus monkeys. Results: CTX-8371 potently enhanced T cell activation and function in vitro and showed curative efficacy as monotherapy in multiple solid tumor models, isografts or xenografts. Furthermore, CTX-8371 demonstrated superior anti-tumor efficacy compared to Keytruda or atezolizumab in checkpoint inhibitors-sensitive and resistant syngeneic mouse tumor models. Mechanistically, in addition to blocking PD-1 interaction with PD-L1, CTX-8371 bispecific antibody facilitated cell to cell bridging between cells expressing PD-1 and cells expressing PD-L1. Furthermore, we show that simultaneous binding of CTX-8371 to both PD-1 and PD-L1 resulted in long term PD-1 shedding. This suggests that CTX-8371 may prevent or overcome T cell exhaustion within the tumor microenvironment, thus providing additional advantage over existing therapies. Lastly, excellent tolerability was observed in non-human primates given 2 weekly drug infusions at up to 50 mg/kg dose. Conclusions: CTX-8371 displays multiple mechanisms of action over monoclonal PD1/PD-L1 blockade. These unique pharmacological properties of CTX-8371 could explain the enhanced T cell responses to tumor antigens and superior efficacy over current monoclonal antibody therapies. With favorable PK/PD and toxicology profiles in mice and cynomolgus monkeys, CTX-8371 warrants further advancement to clinical testing.

scholarly journals Targeted Brain Tumor Therapy by Inhibiting the MDM2 Oncogene: In Vitro and In Vivo Antitumor Activity and Mechanism of Action

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1592
Author(s):  
Surendra R. Punganuru ◽  
Viswanath Arutla ◽  
Wei Zhao ◽  
Mehrdad Rajaei ◽  
Hemantkumar Deokar ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Tumor Therapy ◽  
Single Agent ◽  
M Cell ◽  
In Vivo Antitumor Activity ◽  
The Brain

There is a desperate need for novel and efficacious chemotherapeutic strategies for human brain cancers. There are abundant molecular alterations along the p53 and MDM2 pathways in human glioma, which play critical roles in drug resistance. The present study was designed to evaluate the in vitro and in vivo antitumor activity of a novel brain-penetrating small molecule MDM2 degrader, termed SP-141. In a panel of nine human glioblastoma and medulloblastoma cell lines, SP-141, as a single agent, potently killed the brain tumor-derived cell lines with IC50 values ranging from 35.8 to 688.8 nM. Treatment with SP-141 resulted in diminished MDM2 and increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis. In intracranial xenograft models of U87MG glioblastoma (wt p53) and DAOY medulloblastoma (mutant p53) expressing luciferase, treatment with SP-141 caused a significant 4- to 9-fold decrease in tumor growth in the absence of discernible toxicity. Further, combination treatment with a low dose of SP-141 (IC20) and temozolomide, a standard anti-glioma drug, led to synergistic cell killing (1.3- to 31-fold) in glioma cell lines, suggesting a novel means for overcoming temozolomide resistance. Considering that SP-141 can be taken up by the brain without the need for any special delivery, our results suggest that SP-141 should be further explored for the treatment of tumors of the central nervous system, regardless of the p53 status of the tumor.

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