The in vivo characteristics of genetically engineered divalent and tetravalent single-chain antibody constructs

Wittel, Uwe A.; Jain, Maneesh; Goel, Apollina; Chauhan, Subhash C.; Colcher, David; Batra, Surinder K.

doi:10.1016/j.nucmedbio.2004.11.003

Cited by 34 publications

(20 citation statements)

References 15 publications

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“…Monoclonal antibodies in the format of scFvs are the smallest stable fragment of an antibody still able to bind to the antigen. They combine the advantage of a fully human sequence to that of small size, which allows better tumor penetration compared with full-length mAbs and production in large quantities by recombinant technology in bacterial systems without the need of animal immunization (42). In addition, scFvs can be modified in their size, pharmacokinetics, immunogenicity, specificity, valency, and effector functions to improve affinity and stability and reduce the rapid blood clearance (45).…”

Section: Discussionmentioning

confidence: 99%

“…We engineered the scFvs C7 directed against CD99 (26) to develop a bivalent antigen-binding molecule (dAbd C7) characterized by a doubled valency and a molecular mass of about 55-60 kDa to reduce the too fast clearance typical of monomers and increase tumor retention (42,43). ELISA and Annexin V-PI assays demonstrated the higher avidity and activity of dAbd C7 over scFv C7, respectively ( Supplementary Fig.…”

Section: Development Of Human Anti-cd99 C7 Diabodymentioning

confidence: 99%

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CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

Guerzoni

Fiori²,

Terracciano

et al. 2015

Clinical Cancer Research

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Purpose: The paucity of new drugs for the treatment of Ewing sarcoma (EWS) limits the cure of these patients. CD99 has a strong membranous expression in EWS cells and, being also necessary for tumor survival, is a suitable target to aim at. In this article, we described a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) directed against CD99 of potential clinical application.Experimental Design: In vitro and in vivo evaluation of cell death and of the molecular mechanisms triggered by anti-CD99 agents were performed alone or in combination with doxorubicin to demonstrate efficacy and selectivity of the new dAbd C7.Results: The dAbd C7 induced rapid and massive EWS cell death through Mdm2 degradation and p53 reactivation. Mdm2 overexpression as well as silencing of p53 in p53wt EWS cells decreased CD99-induced EWS cell death, whereas treatment with nutlin-3 enhanced it. Furthermore, cell death was associated with induction of p21, bax, and mitochondrial depolarization together with substantial inhibition of tumor cell proliferation. Combined treatment of anti-CD99 dAbd C7 with doxorubicin was additive both in vitro and in vivo against EWS xenografts. Normal mesenchymal stem cells showed no p53 activation and were resistant to cell death, unless transformed by EWS-FLI, the oncogenic driver of EWS.Conclusions: These results indicate that dAbd C7 is a suitable candidate tool to target CD99 in patients with EWS able to spare normal stem cells from death as it needs an aberrant genetic context for the efficient delivery of CD99-triggered cell death.

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Section: Discussionmentioning

confidence: 99%

Section: Development Of Human Anti-cd99 C7 Diabodymentioning

confidence: 99%

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

Guerzoni

Fiori²,

Terracciano

et al. 2015

Clinical Cancer Research

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“…For instance, the use of anti-IgG antibodies or protein A/G as cross-linking agents is commonly used in vitro because of ease and simplicity, but this approach is not well suited for in vivo applications. Alternatively, multivalent antibodies or fragments can be readily generated by protein expression technology; however, in vivo application of these constructs is challenging (7,12). Recently, the research group led by Alan Epstein developed a dextran polymer formulation of rituximab that promoted hyper-cross-linking -induced apoptosis of CD20 + lymphoma cells (4).…”

Section: Introductionmentioning

confidence: 99%

Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs

Chiu¹,

Edwards²,

Kapanen³

et al. 2007

Molecular Cancer Therapeutics

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“…In a separate study by another group, using a tag-free anti-CD45 scFv, the uptake and binding by the liver was much lower at only < 5% of the injected dose [123]. Other studies, however, have not demonstrated an increase in liver uptake of scFvs that contain a poly-his tag [124,125]. Taken together, these results further suggest that the PK/BD of scFv fragments or scFv conjugates may be influenced by molecular tags within the constructs.…”

Section: Effect Of Scfv Tagsmentioning

confidence: 93%

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

Cheng

Allen

2010

Expert Opinion on Drug Delivery

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Importance of the field-Targeted liposomal drugs represent the next evolution of liposomal drug delivery in cancer treatment. In various preclinical cancer models, antibody-targeted PEGylated liposomal drugs have demonstrated superior therapeutic effects over their non-targeted counterparts. Single chain Fv (scFv) has gained popularity in recent years as the targeting agent of choice over traditional targeting agents such as monoclonal antibodies (mAb) and antibody fragments (e.g., Fab′).Areas covered in this review-This review is focused mainly on advances in scFv-targeted liposomal drug delivery for the treatment of cancers, based on a survey of the recent literature, and on experiments done in a murine model of human B-lymphoma, using anti-CD19 targeted liposomes targeted with whole mAb, Fab′ fragments and scFv fragments.What the reader will gain-This review examines the recent advances in PEGylated immunoliposomal drug delivery, focusing on scFv fragments as targeting agents, in comparison with Fab′ and mAb.Take home message-For clinical development, scFv are potentially preferred targeting agents for PEGylated liposomes over mAb and Fab′, owing to factors such as decreased immunogenicity, and pharmacokinetics/biodistribution profiles that are similar to non-targeted PEGylated (Stealth ® ) liposomes.

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The in vivo characteristics of genetically engineered divalent and tetravalent single-chain antibody constructs

Cited by 34 publications

References 15 publications

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

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