PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

Woo, Jacky; Vierboom, Michel; Kwon, Hakju; Chao, Debra T.; Ye, Shiming; Li, Jianmin; Lin, Karen; Tang, Irene; Belmar, Nicole A.; Hartman, Taymar; Breedveld, Elia; Vexler, Vladimir; Hart, Bert A. ’t; Law, Debbie A.; Starling, Gary C.

doi:10.1186/ar4400

Cited by 19 publications

(16 citation statements)

References 37 publications

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“…In the PDL241 study, the development of a strong neutralizing ADA response was also observed in the majority of monkeys treated with the monoclonal antibody, with reduced exposure and strong infusion reactions as a consequence [ 19 ]. It is conceivable that in this rhesus model, the Mamu-B26 negative genotype, possibly in combination with the complete Freund’s adjuvant in the inoculum, renders animals immunologically hypersensitive, as it does with chicken collagen type II.…”

Section: Discussionmentioning

confidence: 99%

“…However, animals that were unimpeded by interfering ADA showed marked clinical treatment improvements. A similar subgroup analysis for efficacy was performed in the PDL241 study [ 19 ]. The effect of ALX-0061 on CRP seemed to be more pronounced than its clinical effect.…”

Section: Discussionmentioning

confidence: 99%

“…CIA-susceptible adult, healthy rhesus monkeys ( Macaca mulatta ; BPRC) were selected on basis of the absence of the dominant major histocompatibility complex (MHC) class I resistance marker Mamu-B26 , as identified by serotyping [ 17 – 19 ]. CIA was evoked by immunization with 5 mg of chicken type II collagen (MD Biosciences, St Paul, MN, USA), dissolved in 0.1 M acetic acid to a final concentration of 10 mg/mL, and mixed with an equal volume of complete Freund’s adjuvant (CFA; DIFCO, Detroit, MI, USA).…”

Section: Methodsmentioning

confidence: 99%

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The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis

Roy¹,

Ververken²,

Beirnaert³

et al. 2015

Arthritis Res Ther

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147

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IntroductionThe pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of different diseases, including rheumatoid arthritis (RA). ALX-0061 is a bispecific Nanobody® with a high affinity and potency for IL-6 receptor (IL-6R), combined with an extended half-life by targeting human serum albumin. We describe here the relevant aspects of its in vitro and in vivo pharmacology.MethodsALX-0061 is composed of an affinity-matured IL-6R-targeting domain fused to an albumin-binding domain representing a minimized two-domain structure. A panel of different in vitro assays was used to characterize the biological activities of ALX-0061. The pharmacological properties of ALX-0061 were examined in cynomolgus monkeys, using plasma levels of total soluble (s)IL-6R as pharmacodynamic marker. Therapeutic effect was evaluated in a human IL-6-induced acute phase response model in the same species, and in a collagen-induced arthritis (CIA) model in rhesus monkeys, using tocilizumab as positive control.ResultsALX-0061 was designed to confer the desired pharmacological properties. A 200-fold increase of target affinity was obtained through affinity maturation of the parental domain. The high affinity for sIL-6R (0.19 pM) translated to a concentration-dependent and complete neutralization of sIL-6R in vitro. In cynomolgus monkeys, ALX-0061 showed a dose-dependent and complete inhibition of hIL-6-induced inflammatory parameters, including plasma levels of C-reactive protein (CRP), fibrinogen and platelets. An apparent plasma half-life of 6.6 days was observed after a single intravenous administration of 10 mg/kg ALX-0061 in cynomolgus monkeys, similar to the estimated expected half-life of serum albumin. ALX-0061 and tocilizumab demonstrated a marked decrease in serum CRP levels in a non-human primate CIA model. Clinical effect was confirmed in animals with active drug exposure throughout the study duration.ConclusionsALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0651-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis

Roy¹,

Ververken²,

Beirnaert³

et al. 2015

Arthritis Res Ther

Self Cite

147

View full text Add to dashboard Cite

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“…Histopathology was performed as described previously [33]. The severity of histological changes was graded by a pathologist blinded to the study as published by Pettit et al [34].…”

Section: Joint Histologymentioning

confidence: 99%

Clinical efficacy of a new CD28-targeting antagonist of T cell co-stimulation in a non-human primate model of collagen-induced arthritis

Vierboom

Breedveld

Kap

et al. 2015

Clinical and Experimental Immunology

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SummaryT cells have a central pathogenic role in the aetiopathogenesis of rheumatoid arthritis (RA), and are therefore a favoured target of immunotherapy aiming at physical or functional elimination. Here we report an efficacy test of FR104, a new co-stimulation inhibitor directly targeting CD28 on T cells, in a translationally relevant model, the rhesus monkey model of collagen-induced arthritis (CIA). As a relevant comparator we used abatacept [cytotoxic T lymphocyte antigen immunoglobulin (CTLA Ig)], an antagonist of CTLA-4 binding to CD80/86 clinically approved for treatment of RA. Treatment with either compound was started at the day of CIA induction. Although FR104 previously demonstrated a higher control of T cell responses in vitro than abatacept, both compounds were equally potent in the suppression of CIA symptoms and biomarkers, such as the production of C-reactive protein (CRP) and interleukin (IL)-6 and anti-collagen type II (CII) serum antibody (IgM/IgG). However, in contrast to abatacept, FR104 showed effective suppression of CII-induced peripheral blood mononuclear cell (PBMC) proliferation. The current study demonstrates a strong potential of the new selective CD28 antagonist FR104 for treatment of RA.

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“…These authors reported human CD4 T cell-dependent human IgM and IgG responses to immunization with neoantigens as well as with recall Ags. Although time limited owing to xenogeneic GVHD, such models have been used to investigate human B cell pathobiology (52)(53)(54) and to assess the in vivo effects of rituximab (55). We found that anti-CD83 inhibited Ag-specific IgG responses to immunization with the recall Ag TT without affecting total circulating human IgG levels (Fig.…”

Section: Discussionmentioning

confidence: 87%

CD83 Antibody Inhibits Human B Cell Responses to Antigen as well as Dendritic Cell–Mediated CD4 T Cell Responses

Wong

Baron

Seldon

et al. 2018

The Journal of Immunology

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Anti-CD83 Ab capable of Ab-dependent cellular cytotoxicity can deplete activated CD83 human dendritic cells, thereby inhibiting CD4 T cell-mediated acute graft-versus-host disease. As CD83 is also expressed on the surface of activated B lymphocytes, we hypothesized that anti-CD83 would also inhibit B cell responses to stimulation. We found that anti-CD83 inhibited total IgM and IgG production in vitro by allostimulated human PBMC. Also, Ag-specific Ab responses to immunization of SCID mice xenografted with human PBMC were inhibited by anti-CD83 treatment. This inhibition occurred without depletion of all human B cells because anti-CD83 lysed activated CD83 B cells by Ab-dependent cellular cytotoxicity and spared resting (CD83) B cells. In cultured human PBMC, anti-CD83 inhibited tetanus toxoid-stimulated B cell proliferation and concomitant dendritic cell-mediated CD4 T cell proliferation and expression of IFN-γ and IL-17A, with minimal losses of B cells (<20%). In contrast, the anti-CD20 mAb rituximab depleted >80% of B cells but had no effect on CD4 T cell proliferation and cytokine expression. By virtue of the ability of anti-CD83 to selectively deplete activated, but not resting, B cells and dendritic cells, with the latter reducing CD4 T cell responses, anti-CD83 may be clinically useful in autoimmunity and transplantation. Advantages might include inhibited expansion of autoantigen- or alloantigen-specific B cells and CD4 T cells, thus preventing further production of pathogenic Abs and inflammatory cytokines while preserving protective memory and regulatory cells.

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PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

Cited by 19 publications

References 37 publications

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis

The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis

Clinical efficacy of a new CD28-targeting antagonist of T cell co-stimulation in a non-human primate model of collagen-induced arthritis

CD83 Antibody Inhibits Human B Cell Responses to Antigen as well as Dendritic Cell–Mediated CD4 T Cell Responses

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