C1q Binding Activity of De Novo Donor-specific HLA Antibodies in Renal Transplant Recipients With and Without Antibody-mediated Rejection

Yell, Maggie; Muth, Brenda; Kaufman, Dixon B.; Djamali, Arjang; Ellis, Thomas M.

doi:10.1097/tp.0000000000000699

Cited by 111 publications

(92 citation statements)

References 17 publications

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“…30,31 Considering the role of complement as a trigger of adaptive immunity, including B cell activation, 32 one may hypothesize that CP inhibition could modulate antibody production by CP inhibition, but the trial design and the short study period may have precluded detection of such effects on specific immunity. 30,31 Considering the role of complement as a trigger of adaptive immunity, including B cell activation, 32 one may hypothesize that CP inhibition could modulate antibody production by CP inhibition, but the trial design and the short study period may have precluded detection of such effects on specific immunity.…”

Section: Discussionmentioning

confidence: 99%

Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection—results from a first-in-patient phase 1 trial

Eskandary

Jilma

Mühlbacher

et al. 2018

American Journal of Transplantation

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The classical pathway (CP) of complement may contribute to the pathogenesis of antibody-mediated rejection (ABMR). Selective CP blockade may be a promising strategy to counteract rejection. The objective of this first-in-patient phase 1b trial was to evaluate the safety/tolerability and CP-blocking potential of 4 weekly doses (60 mg/kg) of the anti-C1s antibody BIVV009 in complement-mediated disorders. Here we describe the results in a cohort of 10 stable kidney transplant recipients (median of 4.3 years posttransplantation) with late active ABMR and features of CP activation, such as capillary C4d or complement-fixing donor-specific antibodies (DSA). During 7 weeks follow-up, no severe adverse events were reported, and BIVV009 profoundly inhibited overall and DSA-triggered CP activation in serum. Five of 8 C4d-positive recipients turned C4d-negative in 5-week follow-up biopsies, while another 2 recipients showed a substantial decrease in C4d scores. There was, however, no change in microcirculation inflammation, gene expression patterns, DSA levels, or kidney function. In conclusion, we demonstrate that BIVV009 effectively blocks alloantibody-triggered CP activation, even though short-course treatment had no effect on indices of activity in late ABMR. This initial trial provides a valuable basis for future studies designed to clarify the therapeutic value of CP blockade in transplantation. ClinicalTrials.gov NCT#02502903.

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Section: Discussionmentioning

confidence: 99%

Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection—results from a first-in-patient phase 1 trial

Eskandary

Jilma

Mühlbacher

et al. 2018

American Journal of Transplantation

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“…In line with this idea is the fact that the ability of DSAs to bind C1q or C3d in a solid-phase assay correlates with their MFI. 11,13 Another clue that DSA titer is an important factor in their ability to activate complement is in the study by Yell et al 14 which shows that most C1q binding DSAs can be converted into non-C1q binding DSAs when diluted. However, DSAs with similar MFI do not always activate the complement, 11 which indicates that, beyond the quantity, some qualitative features of antibodies also affect their ability to activate the complement.…”

mentioning

confidence: 99%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

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The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

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“…In order to activate C1q, IgG molecules must be in close proximity to typically form a hexamer [86], which requires a high concentration of antibody. Yell et al demonstrated that concentration of relatively lower MFI C1q-negative DSA to higher concentration uniformly converted them to C1q-positive, and dilution of C1q-positive DSA converted them to C1q-negative [87]. Low MFI sera may contain C1q-positive DSA, and this is explainable by the prozone effect, at least in some instances [88].…”

Section: In Vitro Complement Activation Assaysmentioning

confidence: 99%

The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies

Filippone

Farber

2016

Journal of Immunology Research

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Central to the humoral theory of transplantation is production of antibodies by the recipient against mismatched HLA antigens in the donor organ. Not all mismatches result in antibody production, however, and not all antibodies are pathogenic. Serologic HLA matching has been the standard for solid organ allocation algorithms in current use. Antibodies do not recognize whole HLA molecules but rather polymorphic residues on the surface, called epitopes, which may be shared by multiple serologic HLA antigens. Data are accumulating that epitope analysis may be a better way to determine organ compatibility as well as the potential immunogenicity of given HLA mismatches. Determination of the pathogenicity of alloantibodies is evolving. Potential features include antibody strength (as assessed by antibody titer or, more commonly and inappropriately, mean fluorescence intensity) and ability to fix complement (in vitro by C1q or C3d assay or by IgG subclass analysis). Technical issues with the use of solid phase assays are also of prime importance, such as denaturation of HLA antigens and manufacturing and laboratory variability. Questions and controversies remain, and here we review new relevant data.

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C1q Binding Activity of De Novo Donor-specific HLA Antibodies in Renal Transplant Recipients With and Without Antibody-mediated Rejection

Abstract: The C1q binding activity by de novo DSA in patients with AMR largely reflects differences in antibody strength. The C1q assay does not appear to distinguish functionally distinct DSA with clinical significance.

Cited by 111 publications

References 17 publications

Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection—results from a first-in-patient phase 1 trial

Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection—results from a first-in-patient phase 1 trial

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

The Humoral Theory of Transplantation: Epitope Analysis and the Pathogenicity of HLA Antibodies

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