scholarly journals A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

2021 ◽  
Vol 14 (12) ◽  
pp. 1322
Author(s):  
Belinda L. Sun ◽  
Lin Tang ◽  
Xiaoguang Sun ◽  
Alexander N. Garcia ◽  
Sara M. Camp ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Monoclonal Antibody ◽  
Cancer Progression ◽  
Unmet Need ◽  
Scid Mice ◽  
Therapeutic Effects ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Humanized Monoclonal Antibody

Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa.

scholarly journals N2E4, a Monoclonal Antibody Targeting Neuropilin-2, Inhibits Tumor Growth and Metastasis in Pancreatic Ductal Adenocarcinoma via Suppressing FAK/Erk/HIF-1α Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Li Wang ◽  
Lanlan Wang ◽  
Shengyu Wang ◽  
Zonglang Zhou ◽  
Zongjunlin Liu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Progression ◽  
Unmet Need ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Pancreas Carcinoma ◽  
Antibody Targeting

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with extremely limited treatment; the effective targeting strategy stays an urgent unmet need. Neuropilin-2 (NRP2), a multifunctional transmembrane non-tyrosine-kinase glycoprotein, enhances various signal transduction pathways to modulate cancer progression. However, the application value of NRP2 as a therapeutic target in pancreatic cancer is still unclear. Here, we detected the elevated NRP2 was associated with the poor prognosis of pancreas carcinoma. The mouse monoclonal antibody targeting NRP2 (N2E4) that could specifically bind to PDAC cells was developed. Moreover, N2E4 inhibits PDAC proliferation, migration, and invasion in vitro, and repressed growth and metastasis in vivo. Mechanistically, the effect of N2E4 was mainly related to the blocking of interaction between NRP2 with integrinβ1 to inhibit FAK/Erk/HIF-1a/VEGF signaling. Therefore, N2E4 has the potential for targeting therapy of PDAC. This study lays a foundation for the future development of NRP2-based targeted therapy for PDAC.

scholarly journals Organic Nanocarriers for Bevacizumab Delivery: An Overview of Development, Characterization and Applications

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4127
Author(s):  
Aline de Cristo Soares Alves ◽  
Franciele Aline Bruinsmann ◽  
Silvia Stanisçuaski Guterres ◽  
Adriana Raffin Pohlmann
Keyword(s):  
Monoclonal Antibody ◽  
Physicochemical Characterization ◽  
Vascular Endothelial ◽  
Organic Nanoparticles ◽  
Humanized Monoclonal Antibody ◽  
Angiogenesis Process ◽  
Endothelial Growth Factor ◽  
Drug Pharmacokinetics

Bevacizumab (BCZ) is a recombinant humanized monoclonal antibody against the vascular endothelial growth factor, which is involved in the angiogenesis process. Pathologic angiogenesis is observed in several diseases including ophthalmic disorders and cancer. The multiple administrations of BCZ can cause adverse effects. In this way, the development of controlled release systems for BCZ delivery can promote the modification of drug pharmacokinetics and, consequently, decrease the dose, toxicity, and cost due to improved efficacy. This review highlights BCZ formulated in organic nanoparticles providing an overview of the physicochemical characterization and in vitro and in vivo biological evaluations. Moreover, the main advantages and limitations of the different approaches are discussed. Despite difficulties in working with antibodies, those nanocarriers provided advantages in BCZ protection against degradation guaranteeing bioactivity maintenance.

scholarly journals A Partially Humanized Monoclonal Antibody to Human IFN-γ Inhibits Cytokine Effects both In Vitro and In Vivo

2002 ◽  
Vol 55 (3) ◽  
pp. 284-292 ◽  
Author(s):  
S. Fiorentini ◽  
G. De Panfilis ◽  
G. Pasolini ◽  
C. Bonfanti ◽  
A. Caruso
Keyword(s):  
Monoclonal Antibody ◽  
Humanized Monoclonal Antibody ◽  
Ifn Γ

Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 1810-1817 ◽  
Author(s):  
Ciaran D. Scallan ◽  
Haiyan Jiang ◽  
Tongyao Liu ◽  
Susannah Patarroyo-White ◽  
Jurg M. Sommer ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Clinical Success ◽  
Circulatory System ◽  
Scid Mice ◽  
Factor Ix ◽  
Human Immunoglobulin ◽  
Transduction Efficiency ◽  
Therapeutic Effects

Long-term cures of hemophilia B have been achieved using AAV2 delivering the factor IX gene to the liver of adeno-associated virus (AAV)–naive hemophilic animals. However, the clinical success of this approach requires overcoming pre-existing AAV neutralizing antibodies prevalent in humans. To better define the inhibition of neutralizing antibodies on AAV2-mediated liver transduction, we developed an in vivo passive immunity model. SCID mice were first reconstituted to a defined neutralizing titer with pooled plasma-derived human immunoglobulin. AAV2-FIX vectors then were administered to the liver, and the transduction efficiency was measured by plasma FIX levels. Unexpectedly, AAV2 neutralizing titers lower than 1:10 were sufficient to neutralize 4 to 20 × 1012 vg/kg of AAV2 vectors in vivo, a capacity that was underestimated by in vitro neutralizing assays. We also evaluated strategies to evade neutralization, including the use of alternative delivery routes, infusion parameters, empty capsids, and alternative AAV serotypes 6 and 8. The results indicate that low AAV2 neutralizing titers can be inhibitory to the tested human and primate AAV vectors delivered into the circulatory system. Therefore, novel nonprimate AAV vectors or compartmentalized delivery may offer more consistent therapeutic effects in the presence of pre-existing AAV neutralizing antibodies.

EB10, an Anti-FLT3 Monoclonal Antibody, Selectively Targets ALL Cell Lines and Primary ALL Blasts without Interfering with Normal Hematopoiesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2744-2744 ◽  
Author(s):  
Obdulio Piloto ◽  
Patrick Brown ◽  
Li Li ◽  
Bao Nguyen ◽  
Kyu-Tae Kim ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Lines ◽  
Scid Mice ◽  
Cytotoxic Agents ◽  
Radioactive Isotopes ◽  
Leukemic Cells ◽  
Class Iii ◽  
Antibody Treatment

Abstract The class III receptor tyrosine kinase, FLT3, is expressed by >90% of B-lineage acute lymphoblastic leukemias (ALL) blasts. In addition, it is expressed at extremely high levels in ALL patients with MLL-rearrangements or hyperdiploidy and sometimes mutated in these same patients. In this report, we investigated the effects of EB10, an anti-human FLT3 monoclonal antibody capable of preventing binding of FLT3 ligand (FL), on ALL cell lines and primary cells. In vitro studies, examining the ability of EB10 to inhibit FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. In some cell lines FLT3 phosphorylation was inhibited and with it, downstream activation of pathways involving MAPK, AKT, and STAT5 phosphorylation. However, several cell lines actually exhibited FLT3 activation upon antibody treatment, possibly because of antibody-mediated receptor dimerization, and subsequent activation of downstream pathways. Nevertheless, through antibody-mediated cellular cytotoxicity (ADCC) such an antibody could still prove efficacious against leukemia cells in vivo. In fact, EB10 treatment significantly prolongs survival and/or reduces engraftment of ALL cell lines and primary ALL blasts in NOD/SCID mice. This effect might be even more pronounced in a host that was less immune compromised than are NOD/SCID mice. The leukemic cells surviving EB10 treatment in the mice were characterized by FACS analysis and found to express low levels or no FLT3. In contrast to the reduction in engraftment of human ALL primary blasts, EB10 treatment of NOD/SCID mice did not reduce engraftment of human hematopoietic CD34+ cells. Taken together, these data demonstrate that EB10 is selectively cytotoxic to ALL blasts while having little effect on normal hematopoiesis. Such an antibody, either naked or conjugated to radioactive isotopes or cytotoxic agents, may prove useful in the therapy of infant ALL as well as childhood and adult ALL patients whose blasts typically express FLT3.

A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4514-4514 ◽  
Author(s):  
Kim N. Chi ◽  
Sebastien J. Hotte ◽  
Susan Ellard ◽  
Joel Roger Gingerich ◽  
Anthony Michael Joshua ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Single Agent ◽  
Castration Resistant Prostate Cancer ◽  
Disease Response ◽  
Measurable Disease ◽  
The Difference ◽  
Ecog Ps

4514 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits Hsp27 expression with in vitro and in vivo efficacy and was well tolerated with single agent activity in phase I studies. Methods: Chemotherapy-naïve pts with no/minimal symptoms were randomized to receive OGX-427 600 mg IV x 3 loading doses then 1000 mg IV weekly with P 5 mg PO BID or P only. Primary endpoint was the proportion of pts progression free (PPF) at 12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) with 32 pts/arm provides 70% power to detect the difference at 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: 38 pts have been enrolled; 1st stage of accrual completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to OGX-427+P, 15 to P), baseline median age was 71 years (53-89), ECOG PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment, and 93% had ≥5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions (chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts receiving OGX-427+P. One pt on OGX-427+P developed hemolytic uremic syndrome. A PSA decline of ≥50% occurred in 41% of pts on OGX-427+P, and 20% of pts treated with P. A measurable disease partial response was seen in 3/8 (38%) evaluable pts on OGX-427+P and 0/9 pts on P. CTC conversion from ≥5 to <5/7.5 ml occurred in 50% of pts on OGX-427+P and 31% treated with P. Thus far, in 26 evaluable pts the PPF at 12 weeks was 71% (95% CI: 42-92) in OGX-427+P treated pts and 33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical evidence for the role of Hsp27 as a therapeutic target in prostate cancer and support continued evaluation of OGX-427 for pts with CRPC. Funded by a grant from the Terry Fox Research Institute.

scholarly journals Cancer-Associated Fibroblasts in Pancreatic Cancer: Should They Be Deleted or Reeducated?

2018 ◽  
Vol 17 (4) ◽  
pp. 1016-1019 ◽  
Author(s):  
Chao Qu ◽  
Qing Wang ◽  
Zhiqiang Meng ◽  
Peng Wang
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Cancer Associated Fibroblasts

Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.

scholarly journals Independence of HIF1a and androgen signaling pathways in prostate cancer

2019 ◽  
Author(s):  
Maxine GB Tran ◽  
Becky AS Bibby ◽  
Lingjian Yang ◽  
Franklin Lo ◽  
Anne Warren ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Promote Tumor Growth ◽  
Elevated Expression

AbstractAndrogen signaling drives prostate cancer progression and is a therapeutic target. Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.

scholarly journals Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

2020 ◽  
Author(s):  
Feng Yu ◽  
Yuanyuan Lin ◽  
Xinping Xu ◽  
Weipeng Liu ◽  
Dan Tang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Prostate Cancer Progression
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