BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer <i>In Vivo</i>

Li, Chong; Yang, Zhao; Du, Ying; Tang, Haidong; Hu, Deqing; Fan, Zusen

doi:10.1158/1078-0432.ccr-13-3397

Cited by 42 publications

(41 citation statements)

References 41 publications

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“…Both the α3β1 and α5β1 integrin family members may be of particular relevance in the context of re-seeding of tumor cells post-TURBT in NMIBC. In addition to the efficacy results shown here, the notion that integrins mediate UCC seeding is further supported by earlier work where α5β1-specific and α3β1-specific ECM-blocking oligopeptides used in combination were able to effectively inhibit orthotopic MB49 tumor implantation (11) and in another more recent report where shRNA knockdown of α3 resulted in impaired establishment of human T24 UCCs in a subcutaneous xenograft model (13).…”

Section: Discussionsupporting

confidence: 82%

“…Re-seeding may be facilitated, in part, by the interaction of tumor cell integrins with extracellular matrix (ECM) components including fibronectin, laminin, and collagen, all of which are likely to be exposed at the surgical site following resection. Previous reports have indicated that specific mammalian integrins, particularly integrin heterodimer family members alpha3beta1 (α3β1) and alpha5beta1 (α5β1), are implicated as being required for the attachment of tumor cells to the ECM and establishment of tumors in the urothelium in vivo (11)(12)(13).…”

Section: Been Previously Characterized As An Integrin-specific Oncolymentioning

confidence: 99%

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A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival

Hancock

McGuire

Tsuji

et al. 2016

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Abstract. Background/Aim: VAX014 minicells (VAX014) Bladder cancer ranks second amongst newly diagnosed urothelial carcinomas worldwide, is the sixth leading cause of cancer death and the fourth most common malignancy of men in developed countries (1). Current estimates suggest that as many as 75-80% of patients with bladder cancer present for the first time with localized non-muscle invasive bladder cancer (NMIBC). It is further estimated that of those newly diagnosed NMIBC cases, 70% present with what the European Association of Urologists classifies as low-risk disease (2).Current recommended clinical practice for the treatment of low-risk NMIBC is cystoscopic transurethral resection of bladder tumor (TURBT) followed by an immediate postoperative intravesical instillation of a chemotherapeutic agent. Without adjuvant treatment, as many as 35.8% of patients treated for low-risk NMIBC will suffer recurrence within 2 years (3). There have been several studies and meta-analyses published indicating that the immediate postoperative instillation of adjuvant therapy may lead to a decrease in the overall risk of recurrence of up to 39%, with absolute reduction in recurrence rates as high as 17% (4). While clearly effective in reducing recurrence, several recently conducted surveys have revealed that immediate single-dose post-operative adjuvant therapy is not consistently administered (5, 6). A prominently cited reason among those clinicians who do not administer immediate post-operative chemotherapy is that the potential for systemic exposure and agent-associated toxicity outweighs the clinical benefit, especially in cases where bladder perforation is suspected. The perceived clinical benefit-torisk ratio argument seems justified given that while patients with low-and intermediate-risk NMIBC have a high rate of recurrence, the initial risk of progression is low (0.8% and 6% at 5 years, respectively) (2). However, the risk of progression increases with the number and interval of recurrences, so any initial prevention or delay of recurrence would be of clear benefit (2). Moreover, because of the high rate of recurrence, frequent monitoring and treatment are required, making NMIBC one of the most expensive cancer types to treat over the course of the disease (7). Therefore, an effective agent for use in the immediate post-operative setting would impart considerable pharmacoeconomic benefit. Recent failures in mid-and late-stage clinical trials highlight the unmet clinical need for the development of new agents that can be safely administered in the immediate post-operative setting (8).

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Section: Discussionsupporting

confidence: 82%

Section: Been Previously Characterized As An Integrin-specific Oncolymentioning

confidence: 99%

A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival

Hancock

McGuire

Tsuji

et al. 2016

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“…Tumor specimens were fixed in 10% buffered formalin and embedded in paraffin as described (20). The immunosignals were detected using the ABC kit.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

“…Among these hybridomas, we identified several antibodies, including BCMab1 and BCMab37, which were determined to recognize the BCSC surface antigens, aberrantly glycosylated integrin a3b1 and CD47, respectively. We previously showed that the BCMab1 antibody was also generated by T24 cell immunization, recognizing the aberrantly glycosylated integrin a3b1 on bladder cancer cells (20). The aberrantly glycosylated integrin a3b1 is highly expressed in bladder cancer tissues.…”

Section: Cd44mentioning

confidence: 99%

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GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells

Yang

et al. 2016

Cancer Research

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The existence of bladder cancer stem cells (BCSC) has been suggested to underlie bladder tumor initiation and recurrence. Sonic Hedgehog (SHH) signaling has been implicated in promoting cancer stem cell (CSC) self-renewal and is activated in bladder cancer, but its impact on BCSC maintenance is unclear. In this study, we generated a mAb (BCMab1) against CD44 þ human bladder cancer cells that recognizes aberrantly glycosylated integrin a3b1. The combination of BCMab1 with an anti-CD44 antibody identified a BCMab1þ cell subpopulation as BCSCs with stem cell-like properties. Gene expression analysis revealed that the hedgehog pathway was activated in the BCMab1 þ CD44 þ subpopulation and was required for BCSC self-renewal. Furthermore, the glycotransferase GALNT1 was highly expressed in BCMab1 þ CD44 þ cells and correlated with clinicopathologic features of bladder cancers. Mechanistically, GALNT1 mediated O-linked glycosylation of SHH to promote its activation, which was essential for the selfrenewal maintenance of BCSCs and bladder tumorigenesis. Finally, intravesical instillation of GALNT1 siRNA and the SHH inhibitor cyclopamine exerted potent antitumor activity against bladder tumor growth. Taken together, our findings identify a BCSC subpopulation in human bladder tumors that appears to be responsive to the inhibition of GALNT1 and SHH signaling, and thus highlight a potential strategy for preventing the rapid recurrence typical in patients with bladder cancer.

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A novel monoclonal antibody KMP1 has potential antitumor activity of bladder cancer by blocking CD44 in vivo and in vitro

et al. 2018

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Bladder cancer becomes a serious medical and social concern due to its high recurrence and mortality rates. Thus, it is urgent to search a novel prognostic biomarker and targeted therapy with high sensitivity and specificity. In this study, we used the human bladder cancer cell line EJ as an immunogen to generate a novel mouse monoclonal antibody KMP1 that specifically bound to bladder cancer, and then, the antitumor effect of KMP1 against bladder cancer was investigated both in vivo and in vitro. The results showed that expression of the KMP1 epitope is consistent with clinical severity and prognosis of bladder cancer. Furthermore, KMP1 not only significantly inhibited the proliferation, migration, and adhesion of EJ cells in vivo, but also suppressed the xenograft tumor growth in nude mice compared with the control group treated with mIgG. Subsequently, the underlying mechanism of KMP1 against bladder cancer was explored via antigen affinity chromatography and mass spectrometry. CD44 located on the cytomembrane was found as the antigen of KMP1. Using RNA interference technology to knock down CD44 expression, we further identified that KMP1 has the antitumor activity by binding to CD44 and blocking its functions. In conclusion, KMP1 might be valuable for development as a promising specific diagnostic biomarker or targeted agent for bladder cancer.

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BCMab1, A Monoclonal Antibody against Aberrantly Glycosylated Integrin α3β1, Has Potent Antitumor Activity of Bladder Cancer In Vivo

Cited by 42 publications

References 41 publications

A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival

A Single Intravesical Instillation of VAX014 Inhibits Orthotopic Superficial Bladder Tumor Implantation to Increase Survival

GALNT1-Mediated Glycosylation and Activation of Sonic Hedgehog Signaling Maintains the Self-Renewal and Tumor-Initiating Capacity of Bladder Cancer Stem Cells

A novel monoclonal antibody KMP1 has potential antitumor activity of bladder cancer by blocking CD44 in vivo and in vitro

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