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Cited by 209Radiopharmaceutical Chemistry and ApplicationsMonoclonal and Polyclonal Antibodies ResearchBiochemical and Structural Characterization

Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting

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Rossi, Edmund A., Goldenberg, David M., Cardillo, Thomas M., McBride, William J., Sharkey, Robert M., Chang, Chien-Hsing·2006·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0600982103PMC PMC1447525
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Abstract

We describe a platform technology, termed the dock and lock method, which uses a natural binding between the regulatory subunits of cAMP-dependent protein kinase and the anchoring domains of A kinase anchor proteins for general application in constructing bioactive conjugates of different protein and nonprotein molecules from modular subunits on demand. This approach could allow quantitative and site-specific coupling of many different biological substances for diverse medical applications. The dock and lock method is validated herein by producing bispecific, trivalent-binding complexes composed of three stably linked Fab fragments capable of selective delivery of radiotracers to human cancer xenografts, resulting in rapid, significantly improved cancer targeting and imaging, providing tumor/blood ratios from 66 ± 5 at 1 h to 395 ± 26 at 24 h.

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  • TF2 is a 157 kDa bsAb built using the DNL method, devoid of Fc fragment, comprising two Fab fragments derived from humanized anti-human CEA mAb hMN-14 and one Fab fragment from humanized mAb h679 that strongly binds the hapten HSG.

    “The first described bsAb built using the DNL method was a molecule of 157 kDa, devoid of Fc fragment, comprising two Fab fragments derived from humanized anti-human CEA mAb hMN-14 and one Fab fragment from humanized mAb h679 that is able to strongly bind the hapten histamine-succinyl-glycine (HSG).”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [61]

  • In xenografted nude mice, TF2 produced exceptionally high tumor blood ratios ranging from 13 at 0.5 h to 395 at 24 h, with high tumor uptake of 30% ID/g, whereas levels in blood and normal tissues except kidney were <1% ID/g at 1 h after injection.

    “Exceptionally high tumor blood ratios were observed, ranging from 13 at 0.5 h to 395 at 24 h, with high tumor uptake of 30% ID/g, whereas the levels in blood and normal tissues, except kidney, were <1% ID/g at 1 h after injection.”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [61]

  • The DNL method relies on the spontaneous association of a dimer of the 45 amino acids peptide DDD2 with the 21 residues peptide AD2.

    “It relies on the spontaneous association of a dimer of the 45 amino acids peptide DDD2, derived from the regulatory subunit of human cAMP-dependent protein kinase (PKA) with the 21 residues peptide AD2, derived from the anchoring domains (AD) of human A kinase anchor proteins (AKAPs).”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [61]

  • DNL can be used to efficiently create any kind of bsAb, but was so far used to create bispecific molecules dedicated to radioimmunotherapy.

    “This can be used to efficiently create any kind of bsAb, but was so far used to create bispecific molecules dedicated to radioimmunotherapy.”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [61]

  • Upon association, two disulfide bonds are created, resulting in a covalent complex that is stable for more than a week at 37°C in human serum.

    “Upon association, two disulfide bonds are created, resulting in a covalent complex that is stable for more than a week at 37°C in human serum.”

    From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [61]

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Research works printed but not linked: 2

  1. [20]Gegner, J. A. &amp; Dahlquist, F. W. (1991) Proc. Natl. Acad. Sci. USA 88, 750-754.
  2. [25]Terskikh, A. V., Le Doussal, J.-M., Crameri, R., Fisch, I., Mach, J.-P. &amp; Kajava, A. V. (1997) Proc. Natl. Acad. Sci. USA 94, 1663-1668.

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Authors
Rossi, E. A., Goldenberg, D. M., Cardillo, T. M., McBride, W. J., Sharkey, R. M., & Chang, C.-H.
Affiliations
  • IBC Pharmaceuticals (India) (IN)
  • Immunomedics (United States) (US)
  • Center for Molecular Medicine and Immunology (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2006-05-02
Volume
103
Issue
18
Pages
6841-6846
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0600982103
PMC
PMC1447525
OpenAlex
W2037803066
Cited by
209
References
33
Citations by year
2026: 1 · 2024: 7 · 2023: 10 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 11 · 2017: 7 · 2016: 6 · 2015: 11 · 2014: 15 · 2013: 14 · 2012: 22
FWCI
12.13
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
Keywords
cAMP-dependent protein kinase regulatory subunit, A-kinase anchoring proteins, protein-protein binding, protein conjugation, tumor targeting, tumor imaging, tumor-to-blood ratio, tumor xenografts
MeSH terms
Amino Acid Sequence, Animals, Diagnostic Imaging, Humans, Immunoglobulin Fab Fragments, Mice, Nude, Molecular Sequence Data, Neoplasm Transplantation, Neoplasms, Protein Binding, Transplantation, Heterologous, Reproducibility of Results, Cyclic AMP-Dependent Protein Kinases, Protein Subunits, Multiprotein Complexes, Mice

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