DC101 / Eli Lilly - LARVOL DELTA

Junctional Adhesion Molecule a (JAM-A) Maintains Vascular Endothelial Barrier Integrity through c-Src/Stat3-Dependent Suppression of Inhibitor of DNA-Binding 1 (Id1) (ASH 2024) - "When both Jam-A null and WT mice were pretreated with anti-VEGFR2 (DC101; 200μg/kg) a function blocking antibody or isotype specific (200μg/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."

Cardiovascular • Heart Failure • Hypertension • CSK • ID1 • STAT3 • VTN

Combination potential of EO-3021, a CLDN18.2 vc-MMAE ADC, with VEGFR2 or PD1 inhibition in preclinical models of CLDN18.2-expressing cancers (ESMO-IO 2024) - P1 | "The current treatment landscape of gastric/GEJ cancer includes the combination of a fluoropyrimidine and platinum-based chemotherapy with an anti-PD1 inhibitor in the first line and paclitaxel with the VEGFR2 inhibitor ramucirumab in second line metastatic setting...We conducted preclinical studies to evaluate the anti-tumor activity of EO-3021 with an anti-PD1 or VEGFR2 inhibitor.Methods Mice bearing NUGC4-hCLDN18.2 gastric tumors (CrownBio) were treated with a ramucirumab surrogate, DC101 (BioXCell; 20 mg/kg twice-weekly), EO-3021 (2 mg/kg once-weekly), or the combination...An update on durability of CRs, details on the immune infiltrate in mice from the EO-3021 + anti-PD1 study, and comparisons to the ADCC/CDC-inducing CLDN18.2 mAb, zolbetuximab, will be presented.Conclusions Each of the combinations provided a more robust anti-tumor response compared to the single agents. Results from preclinical studies support the planned clinical evaluation of EO-3021 in..."

Preclinical • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • CLDN18

Hyaluronidase improves the efficacy of nab-paclitaxel after prolonged angiogenesis inhibition in preclinical models for esophagogastric cancer. (PubMed, Biomed Pharmacother) - "These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC."

Journal • Preclinical • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD31 • PECAM1

Deletion of Junctional Adhesion Molecule a (JAM-A) Renders Protection to Mice from Severe Sepsis in a Sex Dependent Manner (ASH 2023) - "To evaluate if the increased VEGF levels were responsible for the rapid clearance of bacteria in the peritoneum due to efficient leukocyte transmigration, we pretreated WT mice with DC101, an anti-VEGFR2 antibody or isotype specific IgG (200μg/kg)... Endothelial Jam-A plays an important role in regulating sepsis in female mice. Jam-A may suppress the protective function of female sex hormones. Although, VEGF positively contribute to bacteremia by enhancing endothelial permeability, the role of Jam-A in suppressing sex hormone function is independent of VEGF in mice."

Preclinical • Cardiovascular • Hematological Disorders • Infectious Disease • Septic Shock • Thrombocytopenia • Thrombosis

EFFICACY OF VEGFR2-TARGETED THERAPY AFTER ATEZOLIZUMAB AND BEVACIZUMAB COMBINATION THERAPY IN HEPATOCELLULAR CARCINOMA (AASLD 2023) - "Ramucirumab, an anti-VEGFR2 antibody, has been shown to be effective for advanced HCC with high AFP levels, but its efficacy after ABC therapy is unclear. The anti-VEGFR2 antibody not only inhibits angiogenesis but also suppresses cancer stem cells and activates tumor immunity, and it might be effective in AFP-positive advanced HCC after ABC therapy."

Clinical • Combination therapy • IO biomarker • Gastrointestinal Cancer • Gene Therapies • Hepatocellular Cancer • Oncology • Solid Tumor • CD8 • TIGIT

Fibroblast growth factor inhibition by molecular-targeted agents mitigates immunosuppressive tissue microenvironment in hepatocellular carcinoma. (PubMed, Hepatol Int) - "In this study, we showed that cabozantinib activated the innate immune system, and lenvatinib and AZD4547, which commonly inhibit FGFR signaling, altered TIME to a hot immune state by downregulating lipid metabolism-related genes. These findings support the therapeutic use of combination immunotherapies."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Metabolic Disorders • Oncology • Solid Tumor • CD8 • FOXP3 • GZMB • ITGAX • KDR • PD-1 • PD-L1

Triple therapy (binimetinib, bevacizumab, pembrolizumab) modulates the tumor immune microenvironment in microsatellite stable colorectal cancer PDXs in a humanized mice model (SITC 2022) - "For each PDX we generated humanized mice cohorts treated with vehicle, binimetinib, binimetinib/pembrolizumab combination, or binimetinib/pembroliumab/bevacizumab/DC101. Ethics Approval The human cord blood samples were generously provided as de-identified donors from Clinimmune Cord Blood Bank (Aurora, CO). All procedures and mouse husbandry were performed in accordance with IACUC protocols approved by the University of Colorado Denver Institutional Animal Care and Use Committee in the Office of Laboratory of Animal Resources (OLAR), a facility approved by the American Association for Laboratory Animal Care."

IO biomarker • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD4 • CD8 • FOXP3 • HAVCR2 • IFNG • IL2RA • SIRPA • TMB • TNFA

DC101, an anti-VEGFR2 agent, promotes high-endothelial venule formation and immune infiltration versus SAR131675 and fruquintinib. (PubMed, Biochem Biophys Res Commun) - "Moreover, DC101 enhanced the infiltration of dendritic cells and B cells, and local HEV formation. In conclusion, our data indicate that DC101 may be a better choice for the combined clinical application of ICIs and anti-angiogenic agents."

IO biomarker • Journal • Immune Modulation • Melanoma • Oncology • Solid Tumor • CD31 • CD8 • FLT4 • GZMB • HIF1A • IFNG • KDR • PD-1 • PD-L1 • PECAM1 • PTPRC

Activation of GCN2 by HC-7366 results in significant antitumor efficacy as monotherapy and in combination with multiple standard of care agents in various solid cancer models (AACR 2023) - P1 | "Furthermore, HC-7366 showed significant benefit in colorectal models when combined with DC101 (anti-VEGFR2 antibody), 5-fluorouracil (chemotherapy), alpelisib (PI3Kα inhibitor), or trametinib (MEK1/2 inhibitor). ATF4 and JUN transcriptional activity was enhanced with HC-7366 treatment consistent with activation of ISR. Collectively, our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity across multiple solid tumor models as a monotherapy or in combination with standard of care agents."

Clinical • Combination therapy • Monotherapy • Preclinical • Oncology • Sarcoma • Solid Tumor • ATF4 • E2F1 • HIF1A • PIK3CA • PSAT1

MYC mediates enhanced lactate reutilization and resistance to anti-angiogenesis therapy in preclinical models of LKB1-deficient NSCLC (AACR 2023) - "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."

IO biomarker • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • MYC • STK11

Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody. (PubMed, J Immunother Cancer) - "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."

IO biomarker • Journal • Preclinical • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD4 • CD8 • GPC3 • IL2RA

Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody (J Immunother Cancer) - "BVZ significantly reduced serum VEGF levels in mice. BVZ or DC101 increased high endothelial venules (HEVs) in the TME and substantially enhanced (2.1–8.1 fold) BsAb-driven T cell infiltration into neuroblastoma and osteosarcoma xenografts, which was preferential for CD8(+) TILs versus CD4(+) TILs, leading to superior antitumor effects in multiple CDX and PDX tumor models without added toxicities."

Preclinical • Neuroblastoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Hypoxia reduction in combination with anti-angiogenic therapy remodels the PDAC microenvironment (SITC 2022) - P1 | "Results We find that Evofosfamide with anti-VEGFR-2 (DC101) significantly extends mouse survival. 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."

Combination therapy • IO biomarker • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • CD8 • PD-L1

Derazantinib, an inhibitor of fibroblast growth factor receptors 1-3, increases the efficacy of paclitaxel combined with a VEGFR2-antibody in murine syngeneic tumor models (AACR-NCI-EORTC 2022) - P1b/2 | "DZB is also in a phase-2 trial for gastric cancer (GC), where it is combined with the current standard-of-care (SoC) paclitaxel and the VEGFR2-antibody (Ab), ramucirumab...When the mean tumor size was at least 80 mm3, mice were treated with vehicles (po, ip and iv), DZB alone (35 or 75 mg/kg, po, qd), paclitaxel (15 mg/kg, iv, qw) or the VEGFR2-Ab, DC101 (10 mg/kg, ip, 2qw)... DZB is well-tolerated when combined with paclitaxel and a VEGFR2-Ab in murine syngeneic models, and shows an additive effect in the orthotopic breast models. These data support the ongoing clinical trial with DZB in GC (FIDES-03, NCT04604132). No"

Preclinical • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CSF1R • FGFR

Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment (AACR 2022) - P1 | "While these studies highlight hypoxia reduction as therapeutically tractable, we lack complete understanding of the contribution of the tumor vasculature to hypoxia reduction therapy, as well as the downstream consequences of hypoxia reduction on the cellular composition of the tumor microenvironment and the responsiveness to immunotherapy.We used a transplantable, orthotopic pancreatic tumor model derived from Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre mice and a syngeneic prostate tumor model to study tumor responses to hypoxia-reduction, anti-angiogenic therapy, and combination immunotherapy.We find that Evofosfamide with anti-VEGFR-2 (DC101) significantly extends mouse survival. Put together, these data indicate that targeted hypoxic reduction with anti-angiogenic therapy remodels the pancreatic tumor microenvironment. In this setting, CD40 agonist over PD-1 blockade provides an additive benefit in prolonging mouse survival."

Biomarker • IO biomarker • Tumor microenvironment • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • CD40 • CD8 • KRAS • PD-L1 • PDX1 • TP53

Angiogenic inhibitor pre-administration improves the therapeutic effects of immunotherapy. (PubMed, Cancer Med) - "When combined with an ICI and paclitaxel, only DC101 pre-administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre-administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration."

IO biomarker • Journal • Immune Modulation • Lung Cancer • Oncology • Solid Tumor • CD8 • KDR • PD-L1

THE CURRENT MTAs FOR HEPATOCELLULAR CARCINOMA HAVE DIFFERENT EFFECTS ON THE TUMOR IMMUNE MICROENVIRONMENT -A COMPREHENSIVE IMMUNOHISTOCHEMISTRICAL ANALYSIS- (AASLD 2022) - " We have established an immune syngeneic orthotopic HCC mouse model inoculating Hep-55.1C cells into the left liver lateral lobe of C57BL/6 mice (n=5-6/group) and treated with the MTAs (lenvatinib (LEN), sorafenib (SORA), regorafenib, cabozantinib, DC101/an anti-mouse VEGFR-2 antibody)) for 2 weeks... In the orthotopic xenograft mice model for HCC, LEN and AZD4547, which commonly inhibit FGFR signaling, altered the TIME from cold to hot. The findings obtained from this study support the therapeutic concept in the era of multi-MTAs including ICIs."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • AXL • CD8 • FOXP3 • ITGAX • PD-1 • PD-L1

Combined inhibition of FGFR4 and VEGFR signaling enhances efficacy in FGF19 driven hepatocellular carcinoma. (PubMed, Am J Cancer Res) - "Using HCC relevant xenograft and PDX models, we show that Lenvatinib, an approved multi-kinase inhibitor, strongly enhanced the efficacy of FGFR4 inhibitor H3B-6527...This cell non-autonomous mode of action was further supported by strong in vivo combination efficacy with the mouse specific VEGFR2 antibody, DC101, which cannot cell-autonomously inhibit pathways in human xenografts. 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."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • FGF19 • FGFR4

Increased lung metastasis with sevoflurane in breast cancer surgery is associated with VEGF and elevated vascular permeability by VEGF in a mouse model of human breast cancer. (ASCO 2022) - "The sevoflurane-promoted breast cancer lung metastasis is reversed by DC101, an antibody targeting mouse VEGFR-2. Our results show that the inhaled anesthetic sevoflurane during surgical removal of primary tumor alter the course of metastasis through regulating secretion of VEGF and associated vascular remodeling. The mechanistic study of general anesthetics on cancer cell metastasis establishes the causal link and could provide the potential therapeutic intervention and guide the clinical trials."

Preclinical • Anesthesia • Breast Cancer • Oncology • Solid Tumor • IL6 • KDR • VEGFA

Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression. (PubMed, Mol Psychiatry) - "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."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • VEGFA

Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition. (PubMed, Clin Cancer Res) - "High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome."

Journal • Immunology • Oncology

Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages. (PubMed, J Immunother Cancer) - "Regorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immune Modulation • Immunology • Inflammation • Liver Cancer • Oncology • Solid Tumor • CREB1 • KLF4

Augmenting experimental gastric cancer activity of irinotecan through liposomal formulation and antiangiogenic combination therapy. (PubMed, Mol Cancer Ther) - "The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). PK characterization in GAC xenografts demonstrated that compared to IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy."

Combination therapy • Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy (SITC 2021) - "Results We find that anti-VEGFR-2 (DC101) in combination with TH-302 demonstrates a cooperative benefit to combat both orthotopically implanted pancreatic cancer and transplantable prostate cancer. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted hypoxia reduction with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC."

IO biomarker • Gastrointestinal Cancer • Genito-urinary Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Prostate Cancer • Solid Tumor • CD40 • CD8 • PD-L1

Role of angiogenesis in beta-cell epithelial-mesenchymal transition in chronic pancreatitis-induced diabetes. (PubMed, Lab Invest) - "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."

Journal • Diabetes • Fibrosis • Metabolic Disorders • Pancreatitis • KDR • TGFB1