Antigen Specificity and Tumour Targeting Efficiency of a Human Carcinoembryonic Antigen-specific ScFv and Affinity-matured Derivatives

Overview

Journal Br J Cancer

Specialty Oncology

Date 1998 Jul 31

PMID 9683291

Citations 11

Authors

H Jackson

L Bacon

R B Pedley

E Derbyshire

A Field

J Osbourn

D Allen

Affiliations

Soon will be listed here.

Abstract

We have examined the biological properties of CEA6, a human carcinoembryonic antigen (CEA)-specific single-chain Fv (scFv) isolated by phage display, and five related clones derived by affinity maturation and selected for improved off-rate (Koff). All clones bind strongly and specifically to CEA-positive human tumours by immunocytochemistry and show negligible cross-reactivity with normal colon. Flow cytometry of scFv on human liver cells indicates a shift in fine epitope specificity resulting from mutagenesis. All monomeric scFv have been radioiodinated, retaining effectively full binding activity. A single intravenous injection into nude mice bearing human colon tumour xenografts confirms tumour targeting in all cases. As reported in other studies, the kidney is the main route of elimination of scFv at early time points. Tumour binding of the parental antibody CEA6 consistently gives the highest tumour-blood ratios at 24 h (mean 16:1). Clone TO6D11, which has a sevenfold reduced Koff relative to CEA6, showed no difference in tumour uptake at 24 h but persisted at the tumour site for longer than CEA6. This study demonstrates a possible correlation between binding affinity and tumour residence time when examined in this model.

Citing Articles

Improvement of antibody affinity by introduction of basic amino acid residues into the framework region.

Fukunaga A, Maeta S, Reema B, Nakakido M, Tsumoto K Biochem Biophys Rep. 2018; 15:81-85.

PMID: 30073208 PMC: 6068084. DOI: 10.1016/j.bbrep.2018.07.005.

Optimization and comparison of CD4-targeting lipid-polymer hybrid nanoparticles using different binding ligands.

Cao S, Jiang Y, Levy C, Hughes S, Zhang H, Hladik F J Biomed Mater Res A. 2017; 106(5):1177-1188.

PMID: 29271128 PMC: 6038932. DOI: 10.1002/jbm.a.36315.

Multivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans.

Broecker F, Hanske J, Martin C, Baek J, Wahlbrink A, Wojcik F Nat Commun. 2016; 7:11224.

PMID: 27091615 PMC: 4838876. DOI: 10.1038/ncomms11224.

Identification of an antibody fragment specific for androgen-dependent prostate cancer cells.

Williams R, Hajiran C, Nayeem S, Sooter L BMC Biotechnol. 2014; 14:81.

PMID: 25186190 PMC: 4158339. DOI: 10.1186/1472-6750-14-81.

Impact of intrinsic affinity on functional binding and biological activity of EGFR antibodies.

Zhou Y, Goenaga A, Harms B, Zou H, Lou J, Conrad F Mol Cancer Ther. 2012; 11(7):1467-76.

PMID: 22564724 PMC: 4209485. DOI: 10.1158/1535-7163.MCT-11-1038.

References

Perelson A, Oster G . Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-non-self discrimination. J Theor Biol. 1979; 81(4):645-70. DOI: 10.1016/0022-5193(79)90275-3. View

Vaughan T, Williams A, Pritchard K, Osbourn J, Pope A, Earnshaw J . Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nat Biotechnol. 1996; 14(3):309-14. DOI: 10.1038/nbt0396-309. View

Munro S, Pelham H . An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell. 1986; 46(2):291-300. DOI: 10.1016/0092-8674(86)90746-4. View

Hinoda Y, Neumaier M, Hefta S, Drzeniek Z, Wagener C, Shively L . Molecular cloning of a cDNA coding biliary glycoprotein I: primary structure of a glycoprotein immunologically crossreactive with carcinoembryonic antigen. Proc Natl Acad Sci U S A. 1988; 85(18):6959-63. PMC: 282098. DOI: 10.1073/pnas.85.18.6959. View

Colcher D, Bird R, Roselli M, HARDMAN K, Johnson S, Pope S . In vivo tumor targeting of a recombinant single-chain antigen-binding protein. J Natl Cancer Inst. 1990; 82(14):1191-7. DOI: 10.1093/jnci/82.14.1191. View

Goldenberg D, Goldenberg H, Sharkey R, Lee R, Horowitz J, Hall T . In-vivo antibody imaging for the detection of human tumors. Cancer Treat Res. 1990; 51:273-92. DOI: 10.1007/978-1-4613-1497-4_14. View

Milenic D, Yokota T, Filpula D, Finkelman M, Dodd S, Wood J . Construction, binding properties, metabolism, and tumor targeting of a single-chain Fv derived from the pancarcinoma monoclonal antibody CC49. Cancer Res. 1991; 51(23 Pt 1):6363-71. View

Schlom J, Eggensperger D, Colcher D, Molinolo A, Houchens D, Miller L . Therapeutic advantage of high-affinity anticarcinoma radioimmunoconjugates. Cancer Res. 1992; 52(5):1067-72. View

Yokota T, Milenic D, Whitlow M, Schlom J . Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res. 1992; 52(12):3402-8. View

10.

Hawkins R, Russell S, Winter G . Selection of phage antibodies by binding affinity. Mimicking affinity maturation. J Mol Biol. 1992; 226(3):889-96. DOI: 10.1016/0022-2836(92)90639-2. View

11.

Langmuir V, Mendonca H, Woo D . Comparisons between two monoclonal antibodies that bind to the same antigen but have differing affinities: uptake kinetics and 125I-antibody therapy efficacy in multicell spheroids. Cancer Res. 1992; 52(17):4728-34. View

12.

Griffiths A, Malmqvist M, Marks J, Bye J, Embleton M, McCafferty J . Human anti-self antibodies with high specificity from phage display libraries. EMBO J. 1993; 12(2):725-34. PMC: 413258. DOI: 10.1002/j.1460-2075.1993.tb05706.x. View

13.

Sharkey R, Goldenberg D, Murthy S, Pinsky H, Vagg R, Pawlyk D . Clinical evaluation of tumor targeting with a high-affinity, anticarcinoembryonic-antigen-specific, murine monoclonal antibody, MN-14. Cancer. 1993; 71(6):2082-96. DOI: 10.1002/1097-0142(19930315)71:6<2082::aid-cncr2820710625>3.0.co;2-q. View

14.

Pimm M, Gribben S . Influence of syngeneic (anti-idiotypic) antibody responses on biodistribution and tumour localisation of murine monoclonal antibodies and fragments. Anticancer Res. 1993; 13(1):241-8. View

15.

Pedley R, Boden J, Boden R, Dale R, Begent R . Comparative radioimmunotherapy using intact or F(ab')2 fragments of 131I anti-CEA antibody in a colonic xenograft model. Br J Cancer. 1993; 68(1):69-73. PMC: 1968289. DOI: 10.1038/bjc.1993.288. View

16.

Huston J, McCartney J, Tai M, Jin D, Warren F, Keck P . Medical applications of single-chain antibodies. Int Rev Immunol. 1993; 10(2-3):195-217. DOI: 10.3109/08830189309061696. View

17.

Savage P, Rowlinson-Busza G, Verhoeyen M, Spooner R, So A, Windust J . Construction, characterisation and kinetics of a single chain antibody recognising the tumour associated antigen placental alkaline phosphatase. Br J Cancer. 1993; 68(4):738-42. PMC: 1968604. DOI: 10.1038/bjc.1993.420. View

18.

Chester K, Begent R, Robson L, KEEP P, Pedley R, Boden J . Phage libraries for generation of clinically useful antibodies. Lancet. 1994; 343(8895):455-6. DOI: 10.1016/s0140-6736(94)92695-6. View

19.

Verhaar M, Chester K, Keep P, Robson L, Pedley R, Boden J . A single chain Fv derived from a filamentous phage library has distinct tumor targeting advantages over one derived from a hybridoma. Int J Cancer. 1995; 61(4):497-501. DOI: 10.1002/ijc.2910610412. View

20.

Liberatore M, Neri D, Neri G, Pini A, Iurilli A, Ponzo F . Efficient one-step direct labelling of recombinant antibodies with technetium-99m. Eur J Nucl Med. 1995; 22(11):1326-9. DOI: 10.1007/BF00801622. View