Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection.
BACKGROUND
The potential therapeutic benefits of CD3 monoclonal antibodies, such as OKT3, have been limited by their immunogenicity and their propensity to activate a severe cytokine release syndrome. This has constrained the clinical use of OKT3 to the treatment of acute rejection episodes of organ allografts.


METHODS
We have humanized a rat CD3 antibody and created a single amino acid substitution in position 297 of the IgG1 heavy chain to prevent glycosylation and, consequently, binding of the therapeutic antibody to Fc receptors and to complement. This antibody has been given as first line antirejection therapy in nine kidney transplant recipients with biopsy-proven acute rejection episodes.


RESULTS
None of the patients demonstrated any antiglobulin response nor any significant cytokine release syndrome. Seven of the nine showed evidence of resolution of their rejection, although some patients experienced re-rejection.


CONCLUSIONS
These findings suggest that CD3 antibodies can be engineered to lose their toxicity while retaining their potency as immunosuppressants. Nonactivating humanized CD3 monoclonal antibodies now merit further investigation in the management of transplant patients and in therapy of autoimmune diseases.
Friend
P J
PJ
Department of Surgery, Addenbrookes Hospital, United Kingdom.
Hale
G
G
Chatenoud
L
L
Rebello
P
P
Bradley
J
J
Thiru
S
S
Phillips
J M
JM
Waldmann
H
H
D019943:Amino Acid Substitution; D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000235:genetics* / Q000627:therapeutic use*; D000888:Antibodies, Anti-Idiotypic / Q000032:analysis; D001698:Biomedical Engineering; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D006031:Glycosylation; D006084:Graft Rejection / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects; D015994:Incidence; D007239:Infections / Q000453:epidemiology / Q000209:etiology; D016030:Kidney Transplantation; D012008:Recurrence; D012074:Remission Induction
D000906:Antibodies; D000888:Antibodies, Anti-Idiotypic; D017252:CD3 Complex; D016207:Cytokines