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

@article{Poirier2012PreclinicalEA,  title={Preclinical Efficacy and Immunological Safety of FR104, an Antagonist Anti‐CD28 Monovalent Fab′ Antibody},  author={Nicolas Poirier and Caroline Mary and Caroline Mary and Nahzli Dilek and Nahzli Dilek and J{\'e}r{\'e}my Hervouet and J{\'e}r{\'e}my Hervouet and David Minault and David Minault and Gilles Blancho and Bernard Vanhove and Bernard Vanhove},  journal={American Journal of Transplantation},  year={2012},  volume={12},  url={https://api.semanticscholar.org/CorpusID:715661}}
It is demonstrated that FR104 is devoid of agonist activity on human T cells and thus compatible with a clinical development that might lead to higher therapeutic indexes, by sparing CTLA‐4, as compared to CD80/CD86 antagonists.

73 Citations

FR104, an Antagonist Anti‐CD28 Monovalent Fab' Antibody, Prevents Alloimmunization and Allows Calcineurin Inhibitor Minimization in Nonhuman Primate Renal Allograft

FR104 reinforces immunosuppression in calcineurin inhibitor (CNI)‐low or CNI‐free protocols, without the need of steroids, and accumulation of intragraft Tregs suggested the promotion of immunoregulatory mechanisms.

Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28

The baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo.

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

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, and there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamics activity.

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

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, and there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamics activity.

Antagonist properties of monoclonal antibodies targeting human CD28

Data indicate that monovalency is mandatory for maintaining the antagonistic activity of anti-CD28 monoclonal antibodies.

Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model

An in vivo humanized mouse model is reported to detect adverse effects in response to OKT3, Campath‐1H or the polyclonal Ab preparation anti‐thymocyte globulin and it was found that the administration of each of these Abs to humanized mice led to acute clinical symptoms such as piloerection, hypomotility and hypothermia.

Selective Blockade of CD28-Mediated T Cell Costimulation Protects Rhesus Monkeys against Acute Fatal Experimental Autoimmune Encephalomyelitis

Whether selective blockade of CD28–CD80/86 costimulatory interactions abrogates the induction of experimental autoimmune encephalomyelitis (EAE) in rhesus monkeys is investigated and FR104 treatment diminished T and B cell responses against rhMOG, significantly reduced CNS inflammation and prevented demyelination.

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation.

After the successful testing of selective CD28 antagonists in First In Human studies, this review delineates how this shift in paradigm performed in preclinical transplantation models and evaluates its clinical potential.

Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection.

The data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.

Selective blockade of CD28 on human T cells facilitates regulation of alloimmune responses.

It is demonstrated that selective CD28 blockade prolongs human skin allograft survival through a mechanism that includes a reduction in the cellular graft infiltrate and promotes Treg function in vivo and synergizes with adoptive Treg therapy to promote transplant survival.
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64 References

INDUCTION THERAPY WITH MONOCLONAL ANTIBODIES SPECIFIC FOR CD80 AND CD86 DELAYS THE ONSET OF ACUTE RENAL ALLOGRAFT REJECTION IN NON-HUMAN PRIMATES1

It is demonstrated that administering monoclonal antibodies specific for these B7 ligands can delay the onset of acute renal allograft rejection in rhesus monkeys.

Immunomodulatory Properties of FK734, a Humanized Anti-CD28 Monoclonal Antibody With Agonistic and Antagonistic Activities

FK734 is a partial agonist of CD28 signaling that can reduce human T cell alloresponses in the presence of strong costimulation by B7 molecules in vitro and can reduce T cell-mediated skin allograft rejection in vivo.

Differential effect of CD28 versus B7 blockade on direct pathway of allorecognition and self-restricted responses.

Data show that blocking CD28, while leaving CTLA4-B7 interactions undisturbed, inhibits alloreactive CD4+ T-cell expansion but does not modify the response to nominal antigens presented in the context of a self-major histocompatibility complex.

Selective CD28 Blockade Attenuates Acute and Chronic Rejection of Murine Cardiac Allografts in a CTLA‐4‐Dependent Manner

Results show that CD28 signaling during the first weeks after transplant is a pivotal mediator of pathogenic alloimmunity, and that selective CD28 blockade prolongs graft acceptance by at least two immunomodulatory mechanisms.

Mechanisms of targeting cd28 by a signaling monoclonal antibody in acute and chronic allograft rejection1

It was demonstrated that anti-CD28 monoclonal antibody was as effective as CTLA4 immunoglobulin in protecting against chronic allograft vasculopathy, suggesting that it may be clinically relevant to combine low-dose calcineurin inhibitors with CTLA 4 immunoglOBulin or anti-B7 antibodies.

Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies

It is concluded that the combination of direct enhancement of Teff cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti–CTLA- 4 antibodies during cancer immunotherapy.

A more selective costimulatory blockade of the CD28‐B7 pathway

The current understanding of this complex costimulatory pathway involving co‐stimulatory and co‐inhibitory molecules and the way the authors can manipulate these molecules to inhibit, stimulate or kill target cells is summarized in experimental preclinical models as well as in clinical trials.

CD28‐Specific Immunomodulating Antibodies: What Can Be Learned From Experimental Models?

Differences in CD28‐specific immunomodulating strategies evaluated in experimental models of transplantation and autoimmune diseases are discussed and complexity introduced in this more detailed costimulatory pathway has important implications in therapeutic interventions against human immunological diseases.

Anti‐CD28 Antibody‐Induced Kidney Allograft Tolerance Related to Tryptophan Degradation and TCR− Class II− B7+ Regulatory Cells

It is demonstrated that an initial selective blockade of CD28 generates B7+ non‐T regulatory cells and a kidney transplant tolerance sustained by the activity of IDO and iNOS, and PBMC anti‐donor reactivity could be partially restored in vitro by blocking indoleamine‐2,3‐dioxygenase (IDO) andiNOS.

CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis.

The B7 family of cell surface molecules expressed on APC provides accessory signals to T cells via either CD28 or CTLA-4, which regulates the intensity of the autoimmune response in EAE, attenuating inflammatory cytokine production and clinical disease manifestations.
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