DC101 / Eli Lilly 
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  • ||||||||||  DC101 / Eli Lilly
    Junctional Adhesion Molecule a (JAM-A) Maintains Vascular Endothelial Barrier Integrity through c-Src/Stat3-Dependent Suppression of Inhibitor of DNA-Binding 1 (Id1) (Halls G-H (San Diego Convention Center)) -  Nov 6, 2024 - Abstract #ASH2024ASH_6887;    
    When both Jam-A null and WT mice were pretreated with anti-VEGFR2 (DC101; 200?g/kg) a function blocking antibody or isotype specific (200?g/kg) IgG1 as a control, we found that the vascular permeability was significantly reduced (P<0.00003) in Jam-A null mice, compared to the WT, indicating that the observed permeability is dependent on VEGFR2...Interestingly, we found that inhibition of c-Src or Stat3 or overexpression of JAM-A in HUVECs attenuates Id1 expression. Our results suggest that JAM-A positively regulates vascular integrity by suppressing levels of VEGFR2 expression on ECs through downregulation of Id1 transcriptional factor thus maintaining EC barrier function.
  • ||||||||||  Avastin (bevacizumab) / Roche, DC101 / Eli Lilly
    Preclinical, Journal, IO biomarker:  Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody. (Pubmed Central) -  Mar 30, 2023   
    In conclusion, our data indicate that DC101 may be a better choice for the combined clinical application of ICIs and anti-angiogenic agents. VEGF blockade using specific antibodies against VEGF or VEGFR2 increased HEVs in the TME and cytotoxic CD8(+) TILs, significantly improving the therapeutic efficacy of EAT strategies in preclinical models, supporting the clinical investigation of VEGF blockades to further enhance BsAb-based T cell immunotherapies.
  • ||||||||||  DC101 / Eli Lilly
    MYC mediates enhanced lactate reutilization and resistance to anti-angiogenesis therapy in preclinical models of LKB1-deficient NSCLC (Section 10; Poster Board #4) -  Mar 14, 2023 - Abstract #AACR2023AACR_2795;    
    Finally, we injected KL murine tumor cells into immunocompetent mice, and randomly treated them with vehicle or the VEGF blocking antibody, DC101...Collectively, our data indicates that in LKB1-deficient tumors, upregulation of MYC promotes tumor cell metabolic reprogramming and that targeting MYC or MCT4 can inhibit lactate reutilization and enhance the efficacy of anti-angiogenic agents. These findings provide insight into the mechanisms driving the aggressive phenotype of KRAS-mutant LKB1-deficient tumors and identify a novel therapeutic strategy for targeting this patient population.
  • ||||||||||  evofosfamide (TH 302) / Molecular Templates, ImmunoGenesis
    Hypoxia reduction in combination with anti-angiogenic therapy remodels the PDAC microenvironment (Hall C) -  Oct 6, 2022 - Abstract #SITC2022SITC_1450;    
    P1
    This combination relieves hypoxic stress and simultaneously reinvigorates T cell function, but may facilitate de novo MDSC infiltration. Future work will determine the underlying factors that shape the tumor immune microenvironment and influence immunotherapy responses.
  • ||||||||||  DC101 / Eli Lilly, H3B-6527 / Eisai
    Journal:  Combined inhibition of FGFR4 and VEGFR signaling enhances efficacy in FGF19 driven hepatocellular carcinoma. (Pubmed Central) -  Jul 13, 2022   
    Mechanistic studies showed that the combination resulted in enhanced efficacy through increased anti-angiogenic and anti-tumorigenic activities. Overall, our results indicate that this combination can be a highly effective treatment option for FGF19 driven HCC patients, and provide preclinical validation of a combination that can be readily tested in the clinical setting.
  • ||||||||||  DC101 / Eli Lilly
    Journal:  Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression. (Pubmed Central) -  May 29, 2022   
    Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.
  • ||||||||||  DC101 / Eli Lilly
    Journal:  Role of angiogenesis in beta-cell epithelial-mesenchymal transition in chronic pancreatitis-induced diabetes. (Pubmed Central) -  Mar 15, 2022   
    Inhibition of angiogenesis by specific antisera for vascular endothelial growth factor receptor 2 (VEGFR2), DC101, did not alter the loss of beta-cells and the fibrotic process in PDL-pancreas...Thus, our data suggest that angiogenesis promotes beta-cell survival in the inflamed pancreas, while suppression of angiogenesis turns beta-cell EMT into apoptotic beta-cell death. This finding could be informative during development of intervention therapies for CPRD.
  • ||||||||||  DC101 / Eli Lilly
    Journal, CAR T-Cell Therapy, PD(L)-1 Biomarker, IO biomarker:  VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding. (Pubmed Central) -  Jan 7, 2022   
    In this setting, CD40 agonist over PD-1 blockade provides an additive benefit in prolonging mouse survival. This study represents the first example of impaired function of a vasculature-targeted CAR by an angiogenic ligand and rationalizes the use of combinatorial therapies that target the tumor vasculature and augment CAR-T cell effector function.
  • ||||||||||  DC101 / Eli Lilly
    Preclinical, Journal:  Optical scattering as an early marker of apoptosis during chemotherapy and antiangiogenic therapy in murine models of prostate and breast cancer. (Pubmed Central) -  Nov 4, 2021   
    We utilized SFDI to monitor responses of PC3/2G7 prostate tumors and E0771 mammary tumors to treatment with cyclophosphamide or the antiangiogenic agent DC101 for up to 49 days...These optical parameters outperformed tumor volume and several functional parameters (e.g., oxygen saturation and hemoglobin concentration) as an early predictive biomarker of treatment response. Quantitative diffuse optical scattering is thus a promising new early marker of treatment response, which does not require radiation or exogenous contrast agents.
  • ||||||||||  paclitaxel / Generic mfg.
    Clinical, Journal, Combination therapy:  Variable impact of three different antiangiogenic drugs alone or in combination with chemotherapy on multiple bone marrow-derived cell populations involved in angiogenesis and immunity. (Pubmed Central) -  Jul 4, 2020   
    One exception is the combination of nintedanib and docetaxel as a second-line therapy for rapidly progressing advanced NSCLC...Herein, we evaluated two different antiangiogenic TKIs (sunitinib or nintedanib) and a VEGFR-2 antibody (DC101) either alone or combined with maximum tolerated dose paclitaxel for their differential impact on the BMDC host response, evaluating four different cell types...In contrast, the effect of nintedanib on these BMDC populations was less marked, behaving closer to the VEGFR-2 antibody effects than sunitinib. The results raise the possibility that differences observed between antiangiogenic antibodies and TKIs in increasing chemotherapy efficacy could be related, at least in part, to differential effects on cells associated with local immunity within the tumor microenvironment.
  • ||||||||||  Erbitux (cetuximab) / Eli Lilly, EMD Serono
    Journal:  Adjuvant Anti-angiogenic Therapy Enhances Chemotherapeutic Uptake in a Murine Model of Head and Neck Cancer. (Pubmed Central) -  May 27, 2020   
    The 20mg/kg anti-VEGFR3 + 5mg/kg anti-VEGFR2 and 30mg/kg anti-VEGFR3 + 2.5mg/kg anti-VEGFR2 significantly (p < 0.0004) improved percent-injected cetuximab-IRDye800CW dose/gram tumor tissue compared to other groups. Adjuvant, dual anti-angiogenic therapy targeting VEGFR2 and VEGFR3 significantly enhances tumor chemotherapeutic uptake compared to control.
  • ||||||||||  Mozobil (plerixafor) / Sanofi, DC101 / Eli Lilly, vatalanib (PTK787) / Novartis, Bayer
    Preclinical, Journal:  HIF prolyl hydroxylase inhibitor FG-4497 enhances mouse hematopoietic stem cell mobilization via VEGFR2/KDR. (Pubmed Central) -  Feb 7, 2020   
    VEGFR2 was absent on mesenchymal and hematopoietic cells and was detected only in Sca1 endothelial cells in the BM. We propose that HIF PHD inhibitor FG-4497 enhances HSPC mobilization by stabilizing HIF-1α in HSPCs as previously demonstrated, as well as by activating VEGFR2 signaling in BM endothelial cells, which facilitates HSPC egress from the BM into the circulation.
  • ||||||||||  DC101 / Eli Lilly, evofosfamide (TH 302) / Molecular Templates
    Disrupting hypoxic tumor niches to sensitize pancreatic cancer to immunotherapy (Prince George's Exhibition Halls AB) -  Oct 2, 2019 - Abstract #SITC2019SITC_1193;    
    This is in part associated with re-activation of tumor endothelium to a pro-inflammatory state favoring T cell adhesion and extravasation. These results indicate that combining TH-302 mediated tissue remodeling with VEGFR-2 blockade can enhance both reduction of hypoxia and induction of tumor immunity in a refractory model of pancreatic cancer.
  • ||||||||||  lucitanib (E 3810) / Clovis, Servier
    Combination of the angiogenesis inhibitor lucitanib with immune checkpoint blockade augments anti-tumor activity in syngeneic models (Prince George's Exhibition Halls AB) -  Oct 2, 2019 - Abstract #SITC2019SITC_604;    
    Gene expression changes associated with tumor immune infiltration and increased antitumor immunity were observed in the combination-treated tumors and may contribute to the increased antitumor activity. Results from these studies support the clinical development of the combination of lucitanib and immune checkpoint blockade as a potential treatment for patients with solid tumors.
  • ||||||||||  paclitaxel / Generic Mfg., Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen, Abraxane (albumin-bound paclitaxel) / Celgene, Otsuka
    Preclinical, Journal:  Augmentation of nab-paclitaxel chemotherapy response by mechanistically diverse antiangiogenic agents in preclinical gastric cancer models. (Pubmed Central) -  Sep 12, 2019   
    ...Nab-paclitaxel increased animal survival that was further improved by the addition of antiangiogenic agents ramucirumab (or its murine version DC101), cabozantinib and nintedanib...Effects of nab-paclitaxel, a promising chemotherapeutic agent for GAC, can be enhanced by new-generation antiangiogenic agents, especially nintedanib. The data suggest that nab-paclitaxel combinations with multitargeted antiangiogenic agents carry promising potential for improving clinical GAC therapy.
  • ||||||||||  DC101 / Eli Lilly
    Biomarker, Journal, Tumor microenvironment:  Therapeutic Remodeling of the Tumor Microenvironment Enhances Nanoparticle Delivery. (Pubmed Central) -  Mar 20, 2019   
    This normalization effect results in a more organized vascular network, improves tissue perfusion, and reduces collagen density, all of which contribute to enhanced nanoparticle delivery and distribution within tumors. These findings suggest that combined vascular and ECM normalization strategies can be used to remodel the tumor microenvironment and improve nanomedicine delivery into solid tumors, which has significant implications for developing more effective combinational therapeutic strategies using cancer nanomedicine.