Pharmacokinetic and Pharmacodynamic Analysis of Circulating Biomarkers of Anti-NRP1, a Novel Antiangiogenesis Agent, in Two Phase I Trials in Patients with Advanced Solid Tumors

Yan, Xin; Li, Jessica; Wu, Jenny Q.; Kinard, Rashell; Weekes, Colin D.; Patnaik, Amita; LoRusso, Patricia; Brachmann, Rainer K.; Tong, Raymond K.; Yan, Yibing; Watts, Ryan J.; Bai, Shuang; Hegde, Priti S.

doi:10.1158/1078-0432.ccr-12-1652

Cited by 34 publications

(26 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to our results, Xin et al . have also reported increased plasma NRP-1 in metastatic breast cancer patients compared to healthy controls 13 , although we additionally show a significant upregulation in non-metastatic breast cancer patients compared to controls as well. NRP-1 expression has been correlated to metastasis in tumor tissue from prostate cancer patients only, not breast cancer 28 .…”

Section: Discussionsupporting

confidence: 57%

“…Apart from the full-length isoform of NRP-1, it is also present as soluble isoforms generated by alternative splicing 12 . Blocking NRP-1 with an anti-NRP-1 antibody increased the circulating levels of the soluble PlGF, VEGF and NRP-1 in advanced solid tumors in a phase I clinical trial 13 . An alternative VEGF receptor involved in lymphangiogenesis, VEGFR3, was shown to interact with the VEGFR2/NRP-1 complex on VEGF-C binding to activate AKT signaling 14 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuropilin-1 Associated Molecules in the Blood Distinguish Poor Prognosis Breast Cancer: A Cross-Sectional Study

Belič

Al-Zeheimi

Bakheit

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Circulating plasma and peripheral blood mononuclear (PBMCs) cells provide an informative snapshot of the systemic physiological state. Moreover, they provide a non-invasively accessible compartment to identify biomarkers for personalized medicine in advanced breast cancer. The role of Neuropilin-1 (NRP-1) and its interacting molecules in breast tumor tissue was correlated with cancer progression; however, the clinical impact of their systemic levels was not extensively evaluated. In this cross-sectional study, we found that circulating and tumor tissue expression of NRP-1 and circulating placental growth factor (PlGF) increase in advanced nodal and metastatic breast cancer compared with locally advanced disease. Tumor tissue expression of NRP-1 and PlGF is also upregulated in triple negative breast cancer (TNBC) compared to other subtypes. Conversely, in PBMCs, NRP-1 and its interacting molecules SEMA4A and SNAI1 are significantly downregulated in breast cancer patients compared to healthy controls, indicating a protective role. Moreover, we report differential PBMC expression profiles that correlate inversely with disease stage (SEMA4A, SNAI1, PLXNA1 and VEGFR3) and can differentiate between the TNBC and non-TNBC tumor subtypes (VEGFR3 and PLXNA1). This work supports the importance of NRP-1-associated molecules in circulation to characterize poor prognosis breast cancer and emphasizes on their role as favorable drug targets.

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Neuropilin-1 Associated Molecules in the Blood Distinguish Poor Prognosis Breast Cancer: A Cross-Sectional Study

Belič

Al-Zeheimi

Bakheit

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Further, tumor vascular density is decreased when anti-NRP1 B is combined with murine anti-VEGF (12), which may, therefore, make NRP1 a potential target for improving the efficacy of anti-VEGF therapy. Anti-NRP1, a novel antiangiogenesis agent, has been used in two phase I trials in patients with metastatic breast cancer (31). …”

Section: Discussionmentioning

confidence: 99%

Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma

Lü

Cheng

Zhang

et al. 2015

Molecular Medicine Reports

View full text Add to dashboard Cite

Neuropilin 1 (NRP1), a receptor of vascular endothelial growth factor (VEGF), promotes angiogenesis, tumor growth, tumor invasion and metastasis. However, the function of NRP1 in melanoma progression, as well as the effect of NRP1 expression on the prognosis of patients with melanoma remains unknown. In the present study, NRP1 expression was examined in 460 cases of melanocytic lesions (28 common nevi, 51 dysplastic nevi, 250 primary melanoma and 131 metastatic melanoma) at different stages, using a tissue microarray. The correlation of NRP1 expression with melanoma progression, and its prognostic value in patients with melanoma was examined. In addition, the correlation between matrix metalloproteinase 2 (MMP2) and NRP1 expression in patients with melanoma was analyzed. The results demonstrated that NRP1 expression was significantly increased in primary (56%) and metastatic melanoma (62%), compared with common nevi (11%) and dysplastic nevi (24%). Notably, increased NRP1 expression was correlated with a poorer overall, and disease specific, 10-year survival (P=0.03 and P=0.002, respectively). Multivariate Cox regression analyses indicated that NRP1 is an independent prognostic marker for melanoma. Furthermore, a significant positive correlation between NRP1 and MMP2 expression in melanoma biopsies was observed, and their concomitant expression was closely correlated with melanoma patient survival, further supporting the hypothesis that the expression of NRP1 is associated with melanoma invasion and metastasis. In conclusion, increased NRP1 expression is associated with disease progression and reduced survival in patients with melanoma, and is a promising prognostic molecular marker for this disease.

show abstract

“…The ECD binds its soluble targets VEGF-A and PlGF, which are known to have low ng/mL and pg/mL circulating concentrations in the blood of normal animals, respectively. 20,21 The ECD was fused via a flexible glycine-serine linker of the same length to the C-terminal end of the HC each of the 3 mAb partners. The C-terminal HC position was initially selected for the fusion configuration of the ECD protein domain for each of the mAbs because this theoretically allowed the bispecific constructs increased target binding accessibility such that the mAbs could engage their targets concomitantly with protein binding its antigen.…”

Section: Design Rational For Bsabsmentioning

confidence: 99%

“…Similarly, peripheral concentrations of the ECD antigens, including vascular endothelial growth factor (VEGF-A) and placental growth factor (PlGF) are in the low ng/mL and pg/ mL range in normal animals, and these would not be predicted to influence the clearance of the D2 domain ECD used to construct the IgG-ECD constructs at the doses administered. 20,21 Each of the IgG components of the bispecific molecules were also targeted to soluble ligands having low/no significant peripheral levels in cynomolgus monkeys, with the exception of G2 used to make G2-ECD. The mAb portion of G2-ECD had interactions with a cell surface receptor and the shed soluble domain of the same receptor, and thus its pharmacokinetics were examined at doses known to saturate TMDD.…”

Section: Introductionmentioning

confidence: 99%

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Datta‐Mannan

Croy

Schirtzinger

et al. 2016

mAbs

View full text Add to dashboard Cite

(2016) Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys, mAbs, 8:5, 969-982, DOI: 10.1080/19420862.2016 To link to this article: https://doi.org/10. 1080/19420862.2016 ABSTRACT Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgGscFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.

show abstract

Pharmacokinetic and Pharmacodynamic Analysis of Circulating Biomarkers of Anti-NRP1, a Novel Antiangiogenesis Agent, in Two Phase I Trials in Patients with Advanced Solid Tumors

Cited by 34 publications

References 29 publications

Neuropilin-1 Associated Molecules in the Blood Distinguish Poor Prognosis Breast Cancer: A Cross-Sectional Study

Neuropilin-1 Associated Molecules in the Blood Distinguish Poor Prognosis Breast Cancer: A Cross-Sectional Study

Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Contact Info

Product

Resources

About