YTH 34.5HL

Antibody Name: YTH 34.5HL (IgG2a) Campath-1R
Reference: Riechmann, L., Clark, M., Waldmann, H. and Winter, G. "Reshaping human antibodies for therapy." Nature (1988) 332: 323-327.
Donor Antibody: rat
Acceptor Antibody: Human IgG1, IgG2, IgG3, IgG4 | human k (Campath-1H/CDw52)
Antigen: CAMPATH-1 (trademark of Wellcome Foundation) expressed on virtually all human lymphocytes and monocytes but not blood cells including haemopoietic stem cells.
Laboratory: MRC, LMB, Cambridge, UK
Design: Used structural data, but didn't build model. Noticed two unusual residues in the heavy chain (A41, P45) the latter being a packing residue, but didn't alter them.
Frameworks: VH human NEWM (published sequence not brookhaven)
VL human REI (with different human J region and mutations detailed in comments section)
CDRs: All 6 from VH and VL, Kabat Definition.
Backmutations: S27F:H S30T:H (see also comment below).
Binding: "bound to CAMPATH-1 (data not shown)" ~3-fold lower affinity
In complement lysis assay, IgG1 similar to rat mAb with G1 > G3 > G2 > G4 (non-lytic)
In ADCC, IgG1 more lytic than rat mAb.
Expression: stably transformed non-secreting rat Y0 myeloma cells
Comment: First example of "reshaped" antibody of therapeutic interest. Both heavy and light chains engineered.
NEWM has discrepancies in N-term and S27T:H T28S:H S30D:H compared to PDB structure
REI C-term sequence LQ104-105VE T107K (different J region)
Changes T39K:L Y71F:L in REI not discussed in text.
Clinical Indication: Application in problems of immunosupression. Used in non-Hodgkin lymphoma and systemic vasculitis.
See also Hale et al (1988) Lancet ii:1394-1399.
Mathieson et al (1990) New Engl. J. Med. 323:250-254.
Isaacs et al (1992) Lancet 340:748-752.

explanation of symbols and abbreviations

José Saldanha © 1997-8. Birkbeck College, London WC1E 7HX.