Radiolabeled
antibodies have shown promise for the treatment of
lymphoma and for solid
tumor targeting.
Campath-1H is a humanized
monoclonal antibody that reacts with the
CD52 antigen present on human lymphoid and myeloid cells.
Campath-1H is a gamma1 (G1) isotype that induces
lymphopenia via an Fc-mediated mechanism(s). Isotype switches were engineered, and the resulting
antibodies were expressed in NS0 mouse myeloma cells and biosynthetically radiolabeled with [35S]
methionine. The forms included G1, G4, and a G4 variant that contained
alanine substitutions at (EU numbering) Leu-235, Gly-237, and Glu-318. All isotypes bound
antigen equivalently as assessed by target cell binding in vitro. The G4 variant had a greatly reduced capacity to interact with
Fc receptor by virtue of reduced binding to THP-1 human myeloid cells and by a 1000-fold increase in EC50 to intermediate antibody-dependent cellular cytotoxicity. The pharmacokinetics of the isotypes were compared in CD-1 (nu/nu) mice bearing an experimental
antigen-expressing
tumor. The plasma half-life and
tumor uptake were increased for the G4 variant. The G4 variant showed significantly less spleen, liver, and bone uptake but similar uptake in the lung, kidney, and stomach and lower tissue-to-blood ratios. Immunogenicity was assessed after repeated monthly administrations of unlabeled antibody in BALB/c mice. A 50% reduction in the incidence of anti-
globulin response was observed for the G4 variant. These properties suggest that
antibodies with reduced
Fc receptor interaction merit additional study as potential targeting vehicles relative to other isotypes for
radioimmunotherapy or situations where diminished normal tissue binding contributes to efficacy.