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4ms
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.
Preclinical • Journal
|
CD31 (Platelet and endothelial cell adhesion molecule 1) • PECAM1 (Platelet And Endothelial Cell Adhesion Molecule 1)
|
albumin-bound paclitaxel • DC101 • nitroglycerin • pegvorhyaluronidase alfa (PEGPH20)
1year
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.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • KDR (Kinase insert domain receptor) • GZMB (Granzyme B) • FOXP3 (Forkhead Box P3) • ITGAX (Integrin Subunit Alpha X)
|
PD-L1 expression • FOXP3 expression
|
sorafenib • Lenvima (lenvatinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • fexagratinib (ABSK091) • DC101
1year
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 • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2)
|
PD-L1 expression • EPCAM expression
|
Avastin (bevacizumab) • Tecentriq (atezolizumab) • Cyramza (ramucirumab) • DC101
over1year
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.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • KDR (Kinase insert domain receptor)
|
PD-L1 expression • CD8 positive
|
paclitaxel • DC101
over1year
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.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • KDR (Kinase insert domain receptor) • IFNG (Interferon, gamma) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • FLT4 (Fms-related tyrosine kinase 4) • GZMB (Granzyme B) • CD31 (Platelet and endothelial cell adhesion molecule 1) • PECAM1 (Platelet And Endothelial Cell Adhesion Molecule 1)
|
PD-L1 expression • PD-1 expression • CD31 expression • HIF1A expression
|
Fruzaqla (fruquintinib) • DC101 • SAR131675
over1year
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.
Preclinical • Journal • IO biomarker
|
CD8 (cluster of differentiation 8) • IL2RA (Interleukin 2 receptor, alpha) • CD4 (CD4 Molecule) • GPC3 (Glypican 3)
|
VEGFA expression
|
Avastin (bevacizumab) • DC101
over1year
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)
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 • Preclinical • Combination therapy
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • ATF4 (Activating Transcription Factor 4) • E2F1 (E2F transcription factor 1)
|
Mekinist (trametinib) • 5-fluorouracil • Piqray (alpelisib) • DC101 • HC-7366
over1year
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.
Preclinical • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • STK11 (Serine/threonine kinase 11)
|
KRAS mutation • STK11 mutation
|
DC101
2years
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.
PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • AXL (AXL Receptor Tyrosine Kinase) • PD-1 (Programmed cell death 1) • FOXP3 (Forkhead Box P3) • ITGAX (Integrin Subunit Alpha X)
|
sorafenib • Lenvima (lenvatinib) • Cabometyx (cabozantinib tablet) • Stivarga (regorafenib) • fexagratinib (ABSK091) • DC101
2years
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)
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
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FGFR (Fibroblast Growth Factor Receptor) • CSF1R (Colony stimulating factor 1 receptor)
|
paclitaxel • Cyramza (ramucirumab) • derazantinib (ARQ 087) • DC101
over2years
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
|
FGF19 (Fibroblast growth factor 19) • FGFR4 (Fibroblast growth factor receptor 4)
|
Lenvima (lenvatinib) • H3B-6527 • DC101
over2years
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
|
KDR (Kinase insert domain receptor) • VEGFA (Vascular endothelial growth factor A) • IL6 (Interleukin 6)
|
VEGFA elevation
|
DC101
over2years
Hypoxia reduction in tandem with anti-angiogenic therapy remodels the pancreatic tumor microenvironment (AACR 2022)
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.
PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8) • CD40 (CD40 Molecule) • PDX1 (Pancreatic And Duodenal Homeobox 1)
|
PD-L1 expression • KRAS G12D • KRAS G12
|
DC101 • evofosfamide (IMGS-101)
3years
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.
PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • CD40 (CD40 Molecule)
|
PD-L1 expression
|
DC101 • evofosfamide (IMGS-101)
over3years
VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding. (PubMed, J Immunother Cancer)
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.
Journal • CAR T-Cell Therapy • PD(L)-1 Biomarker • IO biomarker
|
PD-1 (Programmed cell death 1) • KDR (Kinase insert domain receptor) • VEGFA (Vascular endothelial growth factor A) • LAG3 (Lymphocyte Activating 3)
|
KDR expression
|
DC101
over3years
Enhanced anti-PD-1 therapy in hepatocellular carcinoma by tumor vascular disruption and normalization dependent on combretastatin A4 nanoparticles and DC101. (PubMed, Theranostics)
Furthermore, CA4-NPs + DC101 improved anti-PD-1 therapy by increasing the number of intratumoral CD8 T cells (anti-PD-1, 0.31% vs triple drug combination, 1.18%). These results reveal a novel approach to enhance anti-PD-1 therapy with VDAs + VEGF/VEGFR2 inhibitors in HCC.
Journal
|
CD8 (cluster of differentiation 8)
|
DC101
over3years
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.
Journal • PD(L)-1 Biomarker • IO biomarker
|
KLF4 (Kruppel-like factor 4) • CREB1 (CAMP Responsive Element Binding Protein 1)
|
Stivarga (regorafenib) • DC101
almost4years
Optical scattering as an early marker of apoptosis during chemotherapy and antiangiogenic therapy in murine models of prostate and breast cancer. (PubMed, Neoplasia)
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.
Journal
|
CASP3 (Caspase 3) • PCNA (Proliferating cell nuclear antigen)
|
DC101
almost4years
Efficacy of Combination Chemotherapy Using a Novel Oral Chemotherapeutic Agent, FTD/TPI, with Ramucirumab Murine Version DC101 in a Mouse Syngeneic Cancer Transplantation Model. (PubMed, J Clin Med)
TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of KRAS mutations.
Preclinical • Journal
|
KRAS (KRAS proto-oncogene GTPase) • CD31 (Platelet and endothelial cell adhesion molecule 1)
|
KRAS mutation
|
Lonsurf (trifluridine/tipiracil) • DC101
over4years
[VIRTUAL] Antitumor efficacy of a liposomal formulation of irinotecan in preclinical gastric cancer models: Augmenting its response by antiangiogenic agents (AACR-II 2020)
We evaluated the therapeutic efficacy of nal-IRI in combination with nintedanib, a tyrosine kinase inhibitor targeting FGFR, PDGFR and VEGFR, and DC101, a monoclonal antibody targeting VEGFR2 in preclinical models of GAC. In vitro cell proliferation was evaluated in three GAC cell lines (MKN-45, KATO-III and SNU-5) by WST-1 assay. nal-IRI showed greater antitumor efficacy than IRI, and its antitumor effects can be enhanced by antiangiogenic agents suggesting that this combination has potential for improving clinical GAC therapy.
Preclinical
|
KDR (Kinase insert domain receptor)
|
irinotecan • nintedanib • DC101