Preclinical Efficacy and Immunological Safety of FR104, an Antagonist Anti-CD28 Monovalent Fab′ Antibody

Poirier, Nicolas; Mary, Caroline; Dilek, Nahzli; Hervouet, Jérémy; Minault, David; Blancho, Gilles; Vanhove, Bernard

doi:10.1111/j.1600-6143.2012.04164.x

Cited by 68 publications

(114 citation statements)

References 67 publications

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“…In addition, there was a good correlation among exposure, duration of CD28 RO, and suppression of a T cell-dependent Ab response in monkeys providing a measure of target engagement and a pharmacodynamic (PD) response that can be followed in the clinic. These data, combined with that of others (21,22), clearly differentiate this mechanism of CD28 inhibition from the indirect inhibition of the CD28 pathway with CTLA-4Ig. Thus, there may be immunologic diseases such as lupus or multiple sclerosis in which a molecule that spares Tregs and has enhanced inhibitory activity for CD86 may provide better efficacy than a CTLA-4Ig therapeutic.…”

mentioning

confidence: 83%

“…More recently, this same group described a humanized PEGylated anti-CD28 Fab Ab fragment (FR104) also derived from mAb 28.3 (22). Although these are relatively straightforward approaches for generating monovalent reagents from pre-existing Abs, they are limited by the affinity of the parental Ab and, in some cases, have even lower affinities than the parent (41).…”

Section: Discussionmentioning

confidence: 99%

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A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

Suchard

Davis

Kansal

et al. 2013

The Journal of Immunology

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Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4–mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell–dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.

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mentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

Suchard

Davis

Kansal

et al. 2013

The Journal of Immunology

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“…To understand the requirement of CD28 for memory T lymphocyte reactivation, we used an anti-CD28 Fab9 antagonist devoid of agonist or superagonist activity as previously reported (20,21). We first purified human naive and memory T lymphocytes from healthy volunteers and evaluated their proliferation after stimulations with alloantigens or with 55 HLA class I-and class IIrestricted peptides from CMV, EBV, influenza virus, and tetanus toxin.…”

Section: Discussionmentioning

confidence: 99%

“…FR104 is a monovalent humanized Fab9 Ab fragment antagonist of CD28, pegylated to prolong its half-life as described previously (20). Briefly, nucleotidic sequence corresponding to the V H and V L domains of the CD28.3 mAb were humanized using the des-immunization technology (Algonomics, Gent, Belgium) and fused with human CH1 and Ck Ig domains, respectively.…”

Section: Selective Cd28 Antagonist: Fr104mentioning

confidence: 99%

“…We previously described that selective monovalent CD28 versus CD80/86 antagonists differentially control human effector and regulatory memory T cell activation in vitro at the immune synapse level (19). In the present study, we evaluated a novel selective antagonist of CD28 (FR104, a humanized pegylated anti-CD28 Fab9 Ab fragment), devoid of agonist activity (20,21), in Ag-specific memory responses in vitro and in nonhuman primate models.…”

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confidence: 99%

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Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates

Poirier

Chevalier

Mary

et al. 2016

The Journal of Immunology

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Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1–dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell–mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation.

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Large Animal Models of Transplantation

Anderson

Martin

Kirk

et al. 2014

Textbook of Organ Transplantation

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Preclinical Efficacy and Immunological Safety of FR104, an Antagonist Anti-CD28 Monovalent Fab′ Antibody

Cited by 68 publications

References 67 publications

A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

A Monovalent Anti-Human CD28 Domain Antibody Antagonist: Preclinical Efficacy and Safety

Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates

Large Animal Models of Transplantation

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