Nonhuman primate responses to murine and humanized OKT4A

Area of Science:

• Immunology
• Transplantation immunology
• Monoclonal antibody therapy

Background:

• A nonhuman primate antimurine response (MAMA) occurs in cynomolgus monkeys receiving murine OKT4A for renal allografts.
• This antixenogeneic response is not inhibited by cyclosporine, total-lymphoid irradiation, or donor bone marrow preparation.

Purpose of the Study:

• To investigate if humanized OKT4A monoclonal antibodies (mAbs) can alter the antimurine basis of the MAMA response.
• To evaluate the impact of humanized mAb construction on MAMA and therapeutic mAb levels in allograft recipients.

Main Methods:

• Administered murine OKT4A and two types of humanized OKT4A (chimeric and CDR-grafted) to cynomolgus renal allograft recipients.
• Assessed MAMA by measuring serum reactivity to murine and humanized mAbs.
• Quantified serum levels of humanized OKT4A over time.

Main Results:

• MAMA was detected in all recipients of both murine and humanized OKT4A.
• Sera from humanized OKT4A recipients showed no reactivity to other murine mAbs, unlike recipients of murine OKT4A.
• Serum levels of humanized OKT4A were maintained for longer periods (12-24 days) compared to murine OKT4A (<12 days).

Conclusions:

• Humanized OKT4A construction may reduce cross-reactivity in MAMA and potentially mitigate anti-idiotypic responses in future clinical trials.
• Humanized mAb design can influence the duration of therapeutic mAb levels, suggesting a potential advantage in allograft treatment.
• Anti-idiotypic reactivity may be less consequential for the clinical use of humanized mAbs in allograft recipients.