Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers

Wu, Anna M.; Chen, Wengang; Raubitschek, Andrew; Williams, Lawrence E.; Neumaier, Michael; Fischer, Rainer; Hu, Shi-zhen; Odom‐Maryon, Tamara; Wong, Jeffrey Y.C.; Shively, John E.

doi:10.1016/1380-2933(95)00027-5

Cited by 174 publications

(114 citation statements)

References 33 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…More recently, the formation of V H -V L oriented scFv antibodies with <3 residue linkers to predominantly dimeric molecules has been described [13,14]. Several studies have shown that in comparison with monovalent counterparts, multivalent scFv fragments exhibited increased functional antigen binding affinity [12,15], favorable in vivo retention within tumor tissue [7,16,17], and markedly slower clearance from the bloodstream [6,18]. These properties suggest multivalent scFv fragments to be excellent candidates for the fusion with small antineoplastic effector molecules.…”

Section: Introductionmentioning

confidence: 99%

Antigen binding and stability properties of non‐covalently linked anti‐CD22 single‐chain Fv dimers

Arndt¹,

Krauß²,

Rybak³

2004

FEBS Letters

View full text Add to dashboard Cite

By varying linker length and domain orientation three multivalent derivatives of a monovalent anti-CD22 single-chain fragment variable (scFv) antibody were generated. Shortening the linker of the V H -V L oriented scFv to 5 or 0 residues resulted in the formation of diabodies or a mixture of tetramers and trimers, respectively. Unexpectedly, a V L -0-V H scFv assembled to homogenous dimers, remained substantially more stable than the V H -5-V L diabody when incubated in human serum at 37°C, and retained its dimeric state when concentrated up to 4 mg/ml. These properties suggest the V L -0-V H scFv could become an attractive vehicle for the selective delivery of multiple effector molecules to CD22 + tumor cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Antigen binding and stability properties of non‐covalently linked anti‐CD22 single‐chain Fv dimers

Arndt¹,

Krauß²,

Rybak³

2004

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…A second antigen binding site in the same molecule creates a large avidity effect, which makes the apparent affinity of such bivalent antibody species much higher. ScFv dimers, including non-covalently associated diabodies, have indeed been reported to show superior imaging characteristics of solid tumours than their monovalent counterparts (Adams et al, 1993;Tai et al, 1995;Wu et al, 1996), mainly because of the slower off-rate of these avid molecules. Our cloned scFv antibody fragments already show a variable degree of…”

Section: Discussionmentioning

confidence: 99%

High-affinity recombinant phage antibodies to the pan-carcinoma marker epithelial glycoprotein-2 for tumour targeting

Roovers

Henderikx²,

Helfrich³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary The tumour-associated antigen epithelial glycoprotein-2 (EGP-2) is a promising target for detection and treatment of a variety of human carcinomas. Antibodies to this antigen have been successfully used in patients for imaging of small-cell lung cancer and for adjuvant treatment of minimal residual disease of colon cancer. We describe here the isolation and complete characterization of high-affinity singlechain variable fragments (scFv) to the EGP-2 antigen. First, the binding kinetics of four murine whole antibodies directed to EGP-2 (17-1A, 323/A3, MOC-31 and MOC-1 61) were determined using surface plasmon resonance (SPR). The MOC-31 antibody has the lowest apparent off-rate, followed by MOC-161 and 323/A3. The V-genes of the two MOC hybridomas were cloned as scFv in a phage display vector and antigen-binding phage were selected by panning on recombinant antigen. The scFvs compete with the original hybridoma antibodies for binding to antigen and specifically bind to human carcinomas in immunohistochemistry. MOC-31 scFv has an off-rate which is better than those of the bivalent 17-1A and 323/A3 whole antibodies, providing it with an essential characteristic for tumour retention in vivo. The availability of these high-affinity anti-EGP-2 antibody fragments and of their encoding V-genes creates a variety of possibilities for their future use as tumour-targeting vehicles.

show abstract

“…Using parameters derived from the literature their simulations were in qualitative and quantitative agreement with a variety of experimental datasets including kinetics and dose dependence of Ab uptake into spheroids [37][38][39][40][41][42] and biodistribution of Abs and Ab fragments into tumor xenografts as a function of affinity, molecular weight, and elimination half-life. 4,[43][44][45] During an initial loading phase, intratumoral diffusion competes with systemic clearance, and bound Ab moves toward the tumor core, whereas the concentration of free Ab at the tumor surface remains high. Low-affinity Abs penetrate more deeply into the tumor than high-affinity Abs.…”

Section: Physical Properties Of Ab Constructs That Favor Tumor Exposurementioning

confidence: 99%

Antibody constructs in cancer therapy

Beckman

Weiner

Davis³

2007

Cancer

249

View full text Add to dashboard Cite

Whereas over 85% of human cancers are solid tumors, of the 8 monoclonal antibodies (mAbs) currently approved for cancer therapy, 25% are directed at solid tumor surface antigens (Ags). This shortfall may be due to barriers to achieving adequate exposure in solid tumors. Advancements in tumor biology, protein engineering, and theoretical modeling of macromolecular transport are currently enabling identification of critical physical properties for antitumor Abs. It is now possible to structurally modify Abs or even replace full Abs with a plethora of Ab constructs. These constructs include Fab and Fab 0 2 fragments, scFvs, multivalent scFvs (e.g., diabodies and tribodies), minibodies (e.g., scFv-CH3 dimers), bispecific Abs, and camel variable functional heavy chain domains. The purpose of the article is to provide investigators with a conceptual framework for exploiting the recent scientific advancements. The focus is on 2 properties that govern tumor exposure: 1) physical properties that enable penetration of and retention by tumors, and 2) favorable plasma pharmacokinetics. It is demonstrated that manipulating molecular size, charge, valence, and binding affinity can optimize these properties.These manipulations hold the key to promoting tumor exposure and to ultimately creating successful Ab therapies for solid tumors.

show abstract

Tumor localization of anti-CEA single-chain Fvs: improved targeting by non-covalent dimers

Cited by 174 publications

References 33 publications

Antigen binding and stability properties of non‐covalently linked anti‐CD22 single‐chain Fv dimers

Antigen binding and stability properties of non‐covalently linked anti‐CD22 single‐chain Fv dimers

High-affinity recombinant phage antibodies to the pan-carcinoma marker epithelial glycoprotein-2 for tumour targeting

Antibody constructs in cancer therapy

Contact Info

Product

Resources

About