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Impact of antibody framework residue V-H-71 on the stability of a humanised anti-MUC1 scFv and derived immunoenzyme

  1. Author:
    Krauss, J.
    Arndt, M. A. E.
    Zhu, Z.
    Newton, D. L.
    Vu, B. K.
    Choudhry, V.
    Darbha, R.
    Ji, X.
    Courtenay-Luck, N. S.
    Deonarain, M. P.
    Richards, J.
    Rybak, S. M.

  2. Author Address

    Rybak, SM, NCI, Dev Therapeut Program, Frederick, MD 21702 USA NCI, Dev Therapeut Program, Frederick, MD 21702 USA. NCI, SAIC, Frederick, MD 21702 USA. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Antisoma Res Ltd, Ealing W5 3QR, England. Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. NCI, Dev Therapeut Program, Frederick, MD 21702 USA.
    1. Year: 2004
  2. Journal: British Journal of Cancer
    1. 90
    2. 9
    3. Pages: 1863-1870
  4. Type of Article: Article
  1. Abstract:

    Anti-MUC1 single-chain Fv ( scFv) fragments generated from the humanised antibody huHMFG1 had adequate antigen-binding properties but very poor stability irrespective of the applied linker or domain orientation. Mutagenesis of heavy-chain framework residue V-H-71, previously described as a key residue for maintaining the CDR-H2 main-chain conformation and thus important for antigen binding, markedly stabilised the scFv while having only a minor effect on the binding affinity of the molecule. Because of its improved stability, the engineered fragment exhibited immunoreactivity with tumour cells even after 7 days of incubation in human serum at 37degreesC. It also showed, in contrast to the wild-type scFv, a concentration-dependent binding to the target antigen when displayed on phage. When fusing the scFv to the recombinant ribonuclease rapLRI, only the fusion protein generated with the stable mutant scFv was able to kill MUC1(+) tumour cells with an IC50 of 80 nM. We expect this novel immunoenzyme to become a promising tool for the treatment of MUC1(+) malignancies

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