gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Molecular characterization of the anti-idiotypic immune response of a relapse-free neuroblastoma patient following antibody therapy. A possible vaccine against tumors of neuroectodermal origin?

Meeting Abstract

  • corresponding author presenting/speaker Peter Fischer - Technische Fachhochschule, Berlin, Deutschland
  • Joerg Krueger - now The Scripps Research Institute, La Jolla, CA, USA
  • Martina M. Uttenreuther-Fischer - Charité, Berlin

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPO444

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Veröffentlicht: 20. März 2006

© 2006 Fischer et al.
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Neuroblastoma treatment with chimeric anti-disialoganglioside GD2 antibody ch14.18 showed objective anti-tumor responses. Production of anti-idiotypic antibodies (Ab2) against ch14.18 (Ab1) in some cases was positively correlated with a more favorable prognosis. According to Jerne's network theory, a subset of anti-idiotypic antibodies (Ab2beta) form an 'internal image' of the antigen and induce antibodies (Ab3) against the original antigen. The molecular origin of the anti-idiotypic antibody response in tumor patients was not investigated previously. To clone anti-idiotypic antibodies, B-cells of a ch14.18-treated neuroblastoma patient with Ab2 serum reactivity were used to construct antibody phage display libraries (Methods described in Arthritis Rheum. 2000, 43:2722-2732). Upon repetitive selection of lambda and kappa Fab-phage display libraries on target antigens ch14.18 and the murine equivalent 14G2a, positive binders were enriched. Selected Ab2-clones GK2 and GK8 as well as another 38 Fab-phage clones demonstrated strong reactivity with both ch14.18 and 14G2a. Specificity and selectivity of binding was confirmed in Western blot analysis. Both anti-idiotypic clones inhibited binding of ch14.18 to tumor associated antigen GD2. Intriguingly, they were able to compete with natural patient’s antibodies, contained in his serum, for binding to 14G2a. Surprisingly, GK8-Fab alone was able to inhibit binding of all of the patient’s anti-idiotypic antibodies by 80%, suggesting that it is identical to majority of the patient’s natural anti-idiotypic antibodies. Immunization of rabbits with either GK2- and GK8-Fab or their Fab-phages clearly produced a continuous rise in Ab3-serum levels (Ab3’) in these animals, as indicated by increased GD2-binding. Thus we cloned human anti-idiotypic Fab which may be suitable as a tumor vaccine against GD2-positive tumors. Sequence analysis revealed at least 10 clones with different immunoglobulin genes. Homologies to putative VH-germline genes ranged between 94.90 % and 100 %, light chain homologies between 93.90 % and 99.60 %. An analysis of the R/S-ratio, giving the relation of replacement to silent mutations, suggested an antigen-driven selection of anti-idiotypic antibodies, triggered by ch14.18-treatment of our B-cell donor. 6/10 (60%) different clones showed an R/S-ratio above 2.9 for CDRs of their heavy chains and 6/10 (60%) for CDRs of their light chains. Taking into account that some clones appeared several times and giving a numeric relation, 32/36 (89%) clones showed somatic mutations in CDRs of VH-regions and 11/36 (31%) for CDRs of their VL-regions.