Anaphylactic hypersensitivity reaction after repeat OKT3 treatment

Werier, Joel; Cheung, AlanH.S.; Matas, A. J.

doi:10.1016/0140-6736(91)93028-8

Cited by 17 publications

(6 citation statements)

References 3 publications

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“…Indeed, anaphylaxis caused by antidrug antibodies has been observed in patients retreated with OKT3 (mouse anti-CD3) and basiliximab (chimeric anti-CD25). [64][65][66] Careful immune monitoring of sera from these patients may have detected high levels of antidrug IgE antibodies and could have precluded these patients from receiving another dose of antibody. Although the foreign and chimeric natures of OKT3 and basiliximab, respectively, were considered the primary reasons for anaphylaxis upon retreatment, it is interesting that both OKT3 and basiliximab target and modulate the function of T lymphocytes.…”

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confidence: 99%

Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice

Murphy

Burey

Beebe

et al. 2014

Blood

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• Repeated doses of agonist antibodies targeting the costimulatory receptors GITR and OX40 result in anaphylaxis in mice.• Anaphylaxis caused by the GITR agonist antibody DTA-1 is dependent on GITR, IL-4, basophils, and plateletactivating factor.Immunotherapy for cancer using antibodies to enhance T-cell function has been successful in recent clinical trials. Many molecules that improve activation and effector function of T cells have been investigated as potential new targets for immunomodulatory antibodies, including the tumor necrosis factor receptor superfamily members GITR and OX40. Antibodies engaging GITR or OX40 result in significant tumor protection in preclinical models. In this study, we observed that the GITR agonist antibody DTA-1 causes anaphylaxis in mice upon repeated intraperitoneal dosing. DTA-1-induced anaphylaxis requires GITR, CD4 1 T cells, B cells, and interleukin-4. Transfer of serum antibodies from DTA-1-treated mice, which contain high levels of DTA-1-specific immunoglobulin G1 (IgG1), can induce anaphylaxis in naive mice upon administration of an additional dose of DTA-1, suggesting that anaphylaxis results from anti-DTA-1 antibodies. Depletion of basophils and blockade of platelet-activating factor, the key components of the IgG1 pathway of anaphylaxis, rescues the mice from DTA-1-induced anaphylaxis. These results demonstrate a previously undescribed lethal side effect of repetitive doses of an agonist immunomodulatory antibody as well as insight into the mechanism of toxicity, which may offer a means of preventing adverse effects in future clinical trials using anti-GITR or other agonist antibodies as immunotherapies. (Blood. 2014;123(14):2172-2180) IntroductionImmune modulation using monoclonal antibodies has a significant impact on the overall survival of patients with cancer, based on the results of clinical trials using antibodies to block CTLA-4 and PD-1. [1][2][3][4][5][6] In an approach that differs from using antibodies to mitigate immune checkpoint, agonist monoclonal antibodies can be used to directly stimulate T-cell function. Antibodies that engage members of the tumor necrosis factor receptor (TNFR) superfamily have shown promising tumor protection in preclinical models. 3,[7][8][9][10][11][12][13] Glucocorticoid-induced TNFR-related (GITR) is a costimulatory receptor in the TNFR superfamily with high homology to the other TNFR superfamily members OX40, 4-1BB, and CD27.14 GITR and OX40 are expressed primarily on activated CD41 and CD8 1 effector T cells as well as on CD4 1 Foxp3 1 regulatory T cells (Tregs). 15,16Engagement of GITR and OX40 through agonist monoclonal antibodies results in increased T-cell activation, cytokine secretion, proliferation, and survival. [17][18][19][20][21][22][23] We and others have shown that the GITR agonist antibody DTA-1 and the OX40 agonist antibody OX86 are very effective antitumor therapies in murine tumor models by increasing antitumor CD4 1 and CD8 1 T-cell effector function as well as destabilizing and causing apoptosis of Tregs i...

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confidence: 99%

Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice

Murphy

Burey

Beebe

et al. 2014

Blood

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“…[13][14][15] Anaphylactic reactions were reported in patients after retreatment with OKT3. [5][6][7][8][9] Symptoms included cardiovascular collapse, cardiorespiratory arrest, loss of consciousness, hypotension, shock, tingling, angioedema, bronchospasm, and urticaria. 3 These symptoms resemble some of the severe manifestations of CRS, although anaphylaxis occurs immediately, usually within 10 minutes after OKT3 administration, and often responds to epinephrine.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Rare anaphylactic reactions have occurred in patients exposed to OKT3 and are mediated by anti-OKT3 IgE antibodies. [5][6][7][8][9] Anaphylactoid reactions are not antibody mediated and can occur within seconds of administration of a mast cell secretogogue. 10…”

Section: (Pharmacotherapy 2000;20(1):100-104)mentioning

confidence: 99%

Anaphylactoid Reaction to Muromonab‐CD3 in a Pediatric Renal Transplant Recipient

et al. 2000

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Muromonab-CD3 (OKT3), a murine IgG2a antibody directed against the T3 (CD3) complex on mature lymphocytes, triggers adverse immune reactions. Anaphylactic reactions have occurred in patients exposed to OKT3 and are mediated by anti-OKT3 IgE antibodies. The reactions are not antibody mediated and can occur within seconds of administration of a mast cell secretogogue. A renal transplant recipient became hypotensive and hypoxic immediately after receiving her first dose of OKT3 and required advanced life support. Serum antibody tests were negative for anti-OKT3 IgG, IgE, and antimouse protein antibodies. To our knowledge, this is the first published report of a patient with an anaphylactoid reaction to the initial infusion of OKT3.

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“…Anaphylaxis induced by ADAs against mDTA-1 and OX-86 have already been characterized in preclinical and clinical studies (Werier et al, 1991;Abramowicz et al, 1992;Baudouin et al, 2003;Murphy et al, 2014), Although, the manifestations of immunogenicity in preclinical models are generally not considered predictive to humans, our results suggest that close attention to the appearance of ADA responses should be given when administering T-cell agonists. Anti-GITR agonist antibodies are already in the clinic as monotherapy and in combination with anti-PD-1.…”

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confidence: 87%

The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice

Brunn

Mauze

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Administration of biologics to enhance T-cell function is part of a rapidly growing field of cancer immunotherapy demonstrated by the unprecedented clinical success of several immunoregulatory receptor targeting antibodies. While these biologic agents confer significant anti-tumor activity through targeted immune response modulation, they can also elicit broad immune responses potentially including the production of anti-drug antibodies (ADAs). DTA-1, an agonist monoclonal antibody against GITR, is a highly effective anti-tumor treatment in preclinical models. We demonstrate that repeated dosing with murinized DTA-1 (mDTA-1) generates ADAs with corresponding reductions in drug exposure and engagement of GITR on circulating CD31 CD4 1 T cells, due to rapid hepatic drug uptake and catabolism. Mice implanted with tumors after induction of preexisting mDTA-1 ADA show no anti-tumor efficacy when given 3 mg/kg mDTA-1, an efficacious dose in naive mice. Nonetheless, increasing mDTA-1 treatment to 30 mg/kg in ADA-positive mice restores mDTA-1 exposure and GITR engagement on circulating CD3

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Anaphylactic hypersensitivity reaction after repeat OKT3 treatment

Cited by 17 publications

References 3 publications

Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice

Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice

Anaphylactoid Reaction to Muromonab‐CD3 in a Pediatric Renal Transplant Recipient

The Role of Anti-Drug Antibodies in the Pharmacokinetics, Disposition, Target Engagement, and Efficacy of a GITR Agonist Monoclonal Antibody in Mice

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