Cytokine release and dynamics of leukocyte populations after CD3/TCR monoclonal antibody treatment

Abstract

Cytokine release and clinical side effects resulting from the use of OKT3 and BMA 031 monoclonal antibodies in the treatment of kidney graft recipients were evaluated and compared. The rise observed in serum levels of interferon gamma. TNF alpha, and IL-8 was similar after administration of either monoclonal antibody. Furthermore, both OKT3 and BMA 031 resulted in rapid disappearance not only of virtually all T cells, but also of substantial percentages of all major leukocyte populations from the circulation; this effect is probably due to cytokine release activating endothelial cells and thereby causing extravasation even of leukocytes not specifically recognized by the administered antibodies. Evidence has thus been obtained that BMA 031 is as potent as OKT3 in inducing unequivocal signs of T cell activation in vivo. However, while OKT3 therapy was accompanied by adverse side effects in our study as in previous ones, we saw no such reactions in any of the patients receiving BMA 031. This contrast might be due to different mechanisms of leukocyte activation possibly inducing other mediators in the case of OKT3, which then, in combination with the cytokines, could generate treatment-associated morbidity.

Application of dual affinity retargeting molecules to achieve optimal redirected T-cell killing of B-cell lymphoma

“…mAbs directed against a common determinant on the TCR␣/␤ chain have also been applied, and have shown promise in the treatment of autoimmune disease, 31 although only anti-CD3 mAbs are currently approved or under development. 32 Because TCR␣/␤ has a somewhat more limited expression than CD3⑀, and in some studies has shown a lower potential for side effects when targeted therapeutically, 33 it was of interest to ascertain whether redirecting killing via TCR retargeting would have similar or different effects as CD3. The CD3-signaling subunit of the TCR is composed of 4 elements in a ␦⑀/␥⑀/ configuration.…”

Exacerbation of Established Collagen‐Induced Arthritis in Mice Treated with An Anti—T Cell Receptor Antibody

“…There are several possible explanations for this unexpected result. First, it has been demonstrated that an in vivo injection of BMA-031, MAb to human TCRdp, gives rise to a massive systemic release of several cytokines, such as TNFa, IFNy, IL-2, and IL-8 (26,27). Similarly, we have recently confirmed that high levels of circulating TNFa, JFNy, and IL-2 were detected in mice immediately after H57-597 injection, as well as after 145-2C 11 injection (manuscript in preparation).…”

Reactive oxygen product formation after Fcγ receptor‐mediated neutrophil activation by monomeric mouse IgG2a: implications for the generation of first dose effects after OKT3 treatment

“…This is manifested by systemic release of several cytokines including IL-2, IL-6, IL-8,TNF-a and IFN-y [l-31. Another mAb, BMA031, which is specific for a common epitope of the d B T cell receptor [4], is similarly able to induce the release of cytokines into the circulation when given as a single 50-mg dose in a prophylactic protocol [3]. Its administration, however, is not followed by initial side effects as observed after OKT3 [3,5,6].…”

“…Another mAb, BMA031, which is specific for a common epitope of the d B T cell receptor [4], is similarly able to induce the release of cytokines into the circulation when given as a single 50-mg dose in a prophylactic protocol [3]. Its administration, however, is not followed by initial side effects as observed after OKT3 [3,5,6]. Since a potent T cell activating property of BMA031, when the mAb is used at the appropriate dose, can also be substantiated by cytokine release and cell proliferation in vifro [7], we, therefore, looked for further possible differences between these two mAb.…”