A Novel Strategy To Reduce the Immunogenicity of Biological Therapies

Somerfield, J; Hill-Cawthorne, Grant A.; Lin, Andrew C.; Zandi, Michael S; McCarthy, Claire; Jones, Joanne L.; Willcox, M.; Shaw, David M; Thompson, Sara; Compston, Alastair; Hale, Geoff; Waldmann, Herman; Coles, Alasdair

doi:10.4049/jimmunol.1000422

Cited by 62 publications

(58 citation statements)

References 31 publications

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“…If persistent, neutralizing antibodies become problematic in patients who have received multiple alemtuzumab cycles. We have shown that pre-treatment with an altered version of alemtuzumab, which no longer binds to its target, can effectively induce tolerance to alemtuzumab itself [24].…”

Section: Immunogenicitymentioning

confidence: 97%

“…These were all detected as a result of thyroid ultrasound scanning of patients with biochemical thyroid dysfunction in which context papillary carcinomas are recognized as "incidental" [23]. In the extension of the phase 2 trial, 1 patient died from non-EBV associated Burkitt's lymphoma, and another patient who received alemtuzumab developed Castleman's disease, a pre-lymphomatous condition, and is now in remission after R-CHOP (rituximab, cyclophosphamide, doxyrubicin, prednisolone) [24].…”

Section: Malignancymentioning

confidence: 99%

“…However, because the interval between treatment cycles is at least 1 year, such antibodies usually become undetectable before the next cycle [24]. If persistent, neutralizing antibodies become problematic in patients who have received multiple alemtuzumab cycles.…”

Section: Immunogenicitymentioning

confidence: 99%

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Alemtuzumab Therapy for Multiple Sclerosis

Coles

2013

Neurotherapeutics

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Alemtuzumab is a humanized monoclonal antibody that is administered daily for 5 days, and then no further therapy is required for 12 months. It causes rapid and prolonged lymphocyte depletion; the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells. Although previously licensed for the treatment of B-cell chronic lymphocytic leukemia, it is now been considered for licensing in the treatment of multiple sclerosis (MS). From a disappointing experience with alemtuzumab in progressive MS, Alastair Compston and I argued that immunotherapies should be given early in the course of the disease. In a unique program of drug development in MS, alemtuzumab has been compared in 1 phase 2 trial and 2 phase 3 trials with the active comparator interferon beta-1a. In all trials, alemtuzumab was more effective in suppressing relapses than interferon beta-1a. In one phase 2 and one phase 3 trial, alemtuzumab also reduced the risk of accumulating disability compared with interferon beta-1a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy. The safety issues are infusion-associated reactions largely controlled by methylprednisolone, antihistamines, and antipyretics; mild-to-moderate infections (with 3 opportunistic infections from the open-label experience: 1 case each of spirochaetal gingivitis, pyogenic granuloma, and Listeria meningitis); and autoimmunity. Usually autoimmunity is directed against the thyroid gland, but causes (1 %) immune thrombocytopenia, and in a few cases antiglomerular basement membrane syndrome. Alemtuzumab is an effective therapy for early relapsing-remitting MS, offering disability improvement at least to 5 years after treatment. Its use requires careful monitoring so that potentially serious side effects can be treated early and effectively.

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Section: Immunogenicitymentioning

confidence: 97%

Section: Malignancymentioning

confidence: 99%

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Alemtuzumab Therapy for Multiple Sclerosis

Coles

2013

Neurotherapeutics

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“…28 Finally, T-cell epitopes embedded within antibody CDRs, such as those described for golimumab, are also capable of stimulating cytokine release through their T-cell stimulating potential. 4 Anti-drug-antibody responses and CRS may appear as separate issues, but (anti-αβTCR antibody), may provide this T-cell targeting profile.…”

Section: Monoclonal Antibody Therapy In Oncologymentioning

confidence: 99%

“…7,8,22 Adalimumab can have up to 89% HAHA incidence, even though it is a fully human antibody. 4,7,8,13,14,16,17,[23][24][25][26][27][28][29][30] The generation of anti-drug-antibodies is usually regarded as a negative outcome, with reductions in efficacy an obvious concern. However, in some instances the formation of high HAMA titers have correlated with increased therapeutic efficacy of certain antibodies.…”

Section: Introductionmentioning

confidence: 99%

Have we overestimated the benefit of human(ized) antibodies?

Getts

McCarthy³

et al. 2010

mAbs

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Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab

et al. 2017

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IMPORTANCE Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.OBJECTIVE To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS. DESIGN, SETTING, AND PARTICIPANTS Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016. MAIN OUTCOMES AND MEASURES Tabulated data from T-and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.RESULTS Alemtuzumab depleted CD4 + T cells by more than 95%, including regulatory cells (−80%) and CD8 + T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19 + B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19 + memory B cells that may underpin efficacy in MS.CONCLUSIONS AND RELEVANCE Although blockade of memory T and B cells may limit MS, rapid CD19 + B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell-depleting agents.

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A Novel Strategy To Reduce the Immunogenicity of Biological Therapies

Cited by 62 publications

References 31 publications

Alemtuzumab Therapy for Multiple Sclerosis

Alemtuzumab Therapy for Multiple Sclerosis

Have we overestimated the benefit of human(ized) antibodies?

Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab

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