BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nerves, with significant unmet treatment needs. Clinical trials in CIDP are challenging; thus, new trial designs are needed. We present design of an open-label phase 2 study (NCT04658472) evaluating efficacy and safety of SAR445088, a monoclonal antibody targeting complement C1s, in CIDP. METHODS: This phase 2, proof-of-concept, multicenter, open-label trial will evaluate the efficacy, and safety of SAR445088 in 90 patients with CIDP across three groups: (1) currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-Treated); (2) refractory to SOC (SOC-Refractory); and (3) naïve to SOC (SOC-Naïve). Enrolled participants undergo a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B). In part A, the primary endpoint for the SOC-Treated group is the percentage of participants with a relapse after switching from SOC to SAR445088. The primary endpoint for the SOC-Refractory and SOC-Naïve groups is the percentage of participants with a response, compared to baseline. Secondary endpoints include safety, tolerability, immunogenicity, and efficacy of SAR445088 during 12-week overlapping period (SOC-Treated). Part B evaluates long-term safety and durability of efficacy. Data analysis will be performed using Bayesian statistics (predefined efficacy thresholds) and historical data-based placebo assumptions to support program decision-making. INTERPRETATION: This innovative trial design based on patient groups and Bayesian statistics provides an efficient paradigm to evaluate new treatment candidates across the CIDP spectrum and can help accelerate development of new therapies.

• Keywords
• Bayesian analysis, CIDP, SAR445088, complement C1s, complement classical pathway, trial design,
• MeSH
• Bayes Theorem MeSH
• Polyradiculoneuropathy, Chronic Inflammatory Demyelinating * drug therapy   MeSH
• Adrenal Cortex Hormones therapeutic use   MeSH
• Complement C1s MeSH
• Humans MeSH
• Antibodies, Monoclonal MeSH
• Proof of Concept Study MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Clinical Trial, Phase II MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adrenal Cortex Hormones MeSH
• Complement C1s MeSH
• Antibodies, Monoclonal MeSH

Donor-specific antibodies (DSA) cause antibody-mediated rejection (AMR); however, their pathogenic role has not yet been adequately investigated after liver transplantation. The aim of our study was to analyse the clinical significance of DSA and complement-binding DSA for the prediction of AMR after liver transplantation. Our cohort included 120 liver recipients with assessed protocol biopsies one year post-transplant. All patients had defined HLA-specific and complement-binding (C1q + and C3d+) antibodies before and in regular intervals after transplantation. The incidence of DSA was evaluated in relation with clinical and histopathological data in the liver allografts. A higher occurrence of acute AMR was observed in recipients with preformed complement-binding DSA to HLA Class I antigens. Patients who developed chronic AMR had more frequently de novo-produced antibodies against HLA Class II antigens (P = 0.0002). A correlation was also found between de novo-formed C1q + and C3d+-binding antibodies to HLA Class II antigens and the development of chronic AMR (P = 0.043). Our study implies that preformed complement-binding DSA to HLA Class I antigens are related to increased risk of acute antibody-mediated rejection, while chronic AMR is more frequent in patients with de novo-produced antibodies to HLA Class II antigens after liver transplantation.

• Keywords
• C4d deposits, HLA, complement-binding, donor-specific antibodies, rejection,
• MeSH
• Tissue Donors MeSH
• HLA Antigens MeSH
• Isoantibodies MeSH
• Complement C1q MeSH
• Humans MeSH
• Graft Survival MeSH
• Graft Rejection MeSH
• Retrospective Studies MeSH
• Liver Transplantation * adverse effects   MeSH
• Kidney Transplantation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• HLA Antigens MeSH
• Isoantibodies MeSH
• Complement C1q MeSH

The aim of our study was to evaluate the relevance of complement-binding donor-specific antibodies (DSA) for prediction of antibody-mediated rejection (AMR) after liver transplantation. Sera from 123 liver transplant recipients were retrospectively defined for HLA specificity and complement-fixing activity using the single antigen beads, C1q and C3d techniques. Liver-recipients' sera were tested before transplantation, 3, 6 months and 1 year after transplantation. Patients were followed up for graft survival and rejection incidence for 1 year after transplantation. All patients with pretransplant complement-binding DSA developed severe AMR after transplantation, while three recipients out of four, who produced de novo complement-fixing DSA, developed AMR. Definition of DSA with respect to complement-fixing activity may provide clinically relevant information about the risk of AMR after liver transplantation.

• Keywords
• C4d, HLA, antibodies, complement, crossmatch, liver transplantation, rejection,
• MeSH
• Tissue Donors MeSH
• Child MeSH
• Adult MeSH
• Transplantation, Homologous MeSH
• Isoantibodies blood   MeSH
• Complement C1q metabolism   MeSH
• Complement C3d metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Follow-Up Studies MeSH
• Graft Survival * MeSH
• Prognosis MeSH
• Graft Rejection blood   diagnosis   immunology   pathology   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Histocompatibility Testing methods   MeSH
• Liver Transplantation * MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Isoantibodies MeSH
• Complement C1q MeSH
• Complement C3d MeSH

Anti-C1q antibodies (anti-C1q) have been implicated in the pathogenesis of autoimmune diseases, including autoimmune thyroid disorders (AITD). The aim of this study was to evaluate the association between anti-C1q and thyroid function in pregnancy-associated AITD. In 96 pregnant women screened positive for AITD (thyroid dysfunction and/or antibodies against thyroperoxidase - TPOAb), anti-C1q were measured during the 9-11th gestational week and after delivery (median 16 months after delivery), and compared to the corresponding serum levels of thyroid hormones. As controls, 80 healthy pregnant women, 72 non-pregnant AITD patients and 72 blood donors were included. In the non-pregnant AITD group, two serum samples ≥ 6 months apart were analysed. Compared to blood donors, anti-C1q levels were substantially higher in all pregnant women analysed. In pregnancy, anti-C1q levels were higher in the TPOAb-positive women than in controls (37 versus 17·5%, P < 0·0001). Anti-C1q-positive pregnant women screened positive for AITD had higher thyroid-stimulating hormone (TSH) levels than anti-C1q-negative women (2·41 versus 1·94 mU/l, P = 0·01), and TSH correlated positively with anti-C1q (r = 0·226, P = 0·045) in the TPOAb-positive women. After delivery, serum levels of anti-C1q decreased in the positively screened TPOAb-negative women (8·8 versus 5·9 U/l, P = 0·002), but not in the TPOAb-positive ones, and they no longer correlated with TSH. Anti-C1q antibody levels increase during pregnancy in general and even more in the context of AITD, where they correlate with thyroid stimulating hormone levels.

• Keywords
• anti-C1q antibodies, autoimmune thyroid disease, complement, postpartum thyroiditis, pregnancy,
• MeSH
• Autoimmune Diseases immunology   MeSH
• Autoantibodies immunology   MeSH
• Biomarkers MeSH
• Adult MeSH
• Complement C1q immunology   MeSH
• Pregnancy Complications immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Thyroid Diseases immunology   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Pregnancy MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Autoantibodies MeSH
• Biomarkers MeSH
• Complement C1q MeSH

Blood-feeding insects inject potent salivary components including complement inhibitors into their host's skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases.

• MeSH
• Complement Activation drug effects   MeSH
• Insect Proteins pharmacology   MeSH
• Complement Inactivating Agents pharmacology   MeSH
• Complement Pathway, Classical drug effects   MeSH
• Complement C4 antagonists & inhibitors   immunology   metabolism   MeSH
• Complement C1 antagonists & inhibitors   immunology   metabolism   MeSH
• Humans MeSH
• Psychodidae immunology   metabolism   MeSH
• Recombinant Proteins pharmacology   MeSH
• Saliva metabolism   MeSH
• Chromatography, High Pressure Liquid MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Insect Proteins MeSH
• Complement Inactivating Agents MeSH
• Complement C4 MeSH
• Complement C1 MeSH
• Recombinant Proteins MeSH

BACKGROUND: The association of donor-specific HLA antibodies (DSA) with kidney graft failure has been addressed previously; however, the majority of studies were based on small numbers of patients with graft failure. METHODS: We investigated 83 patients with failed kidney transplants for a possible association of de novo development and persistence or loss of pre-existing DSA with graft failure. Single Antigen Bead assay-detected DSA and non-DSA antibodies were compared between patients with graft loss and matched controls with functioning grafts. RESULTS: The incidence of weak de novo DSA or non-DSA at a mean fluorescence intensity of 500 or higher was higher in the graft loss than in the nonrejector group (76% vs 40%, P < 0.001). Because of the low number of patients developing de novo DSA, the DSA results did not reach statistical significance (only 22% of patients with graft loss developed de novo DSA). However, at all cutoffs, there was a significantly higher rate of graft loss in patients with de novo non-DSA. The incidence of strong pretransplant DSA that persist after transplantation was higher in the graft loss group (10% vs 1%, P = 0.034). When C1q-binding ability in sera of rejectors and nonrejectors with posttransplant de novo or persistent DSA was compared, none of the nonrejectors demonstrated C1q positivity, whereas 43% of patients with graft loss showed C1q-positive antibodies, although not necessarily donor-specific (P < 0.001). CONCLUSIONS: Our data show that the posttransplant presence of persisting or de novo HLA antibodies, especially if C1q binding, is associated with graft loss, even if the antibodies are not specific for mismatched donor HLA.

• MeSH
• Biomarkers blood   MeSH
• Adult MeSH
• Histocompatibility MeSH
• HLA Antigens immunology   MeSH
• Isoantibodies blood   MeSH
• Complement C1q immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Predictive Value of Tests MeSH
• Graft Rejection blood   diagnosis   immunology   MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Serologic Tests MeSH
• Histocompatibility Testing methods   MeSH
• Kidney Transplantation adverse effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers MeSH
• HLA Antigens MeSH
• Isoantibodies MeSH
• Complement C1q MeSH

The role of complement has been demonstrated in experimental models of neuromyelitis optica (NMO), however, only few studies have analysed complement components longitudinally in NMO patients. We measured serum or plasma concentrations of anti-C1q antibodies and complement split products C3a and C4a and soluble C5b-9 in patients with NMO, multiple sclerosis and healthy controls. NMO patients had higher levels of C3a and anti-C1q antibodies than healthy controls. C3a levels correlated with disease activity, neurological disability and aquaporin-4 IgG in NMO patients suggesting a role of the alternative pathway of complement in the pathogenesis of NMO and supporting the strategy of therapeutic complement inhibition.

• Keywords
• Aquaporin-4 IgG, C1q antibodies, Complement, Neuromyelitis optica,
• MeSH
• Complement Activation immunology   MeSH
• Aquaporin 4 immunology   MeSH
• Autoantibodies blood   immunology   MeSH
• Adult MeSH
• Immunoglobulin G blood   immunology   MeSH
• Complement C1q immunology   metabolism   MeSH
• Complement C3a immunology   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Neuromyelitis Optica immunology   MeSH
• Prospective Studies MeSH
• Multiple Sclerosis, Relapsing-Remitting immunology   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aquaporin 4 MeSH
• AQP4 protein, human MeSH Browser
• Autoantibodies MeSH
• Immunoglobulin G MeSH
• Complement C1q MeSH
• Complement C3a MeSH

DNA aptamers were developed against lipopolysaccharide (LPS) from E. coli O111:B4 and shown to bind both LPS and E. coli by a colorimetric enzyme-based microplate assay. The polyclonal aptamers were coupled to human C1qrs protein either directly using a bifunctional linker or indirectly using biotinylated aptamers and a streptavidin-C1qrs complex. Both systems significantly reduced colony counts when applied to E. coli O111:B4 and K12 strains across a series of 10x dilutions of the bacteria in the presence of human serum; it was diluted 1: 10(3) in order to avoid significant bacterial lysis by the competing alternate pathway of complement activation. A number of candidate DNA aptamer sequences were cloned and sequenced from the anti-LPS aptamer library for future screening of antibacterial or "antibiotic" potential and to aid in eventual development of an alternative therapy for antibiotic-resistant bacterial infections.

• MeSH
• Anti-Bacterial Agents chemistry   immunology   pharmacology   MeSH
• SELEX Aptamer Technique MeSH
• Aptamers, Nucleotide chemistry   genetics   immunology   pharmacology   MeSH
• Escherichia coli drug effects   immunology   MeSH
• Escherichia coli Infections drug therapy   immunology   MeSH
• Complement C1 chemistry   immunology   MeSH
• Humans MeSH
• Lipopolysaccharides chemistry   immunology   MeSH
• Molecular Sequence Data MeSH
• Base Sequence MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Anti-Bacterial Agents MeSH
• Aptamers, Nucleotide MeSH
• Complement C1 MeSH
• Lipopolysaccharides MeSH

Autoantibodies against complement C1q (anti-C1q) have been well described in patients with systemic lupus erythematosus, where they correlate with the occurrence of severe lupus nephritis. However, data on anti-C1q in organ-specific autoimmune diseases are scarce. In order to determine the prevalence of anti-C1q in patients with autoimmune thyroid disorders (AITD) and a possible association with thyroid function, we measured prospectively anti-C1q in 23 patients with Graves' disease (GD) and 52 patients with Hashimoto's thyroiditis (HT). Anti-C1q levels were correlated with parameters of thyroid function and autoantibodies against thyroperoxidase, thyroglobulin and thyroid stimulating hormone (TSH) receptor. Twenty-one patients with multi-nodular goitre and 72 normal blood donors served as controls. We found elevated concentrations of anti-C1q more frequently in patients with AITD than in controls: seven of 23 (30%) patients with GD and 11 of 52 (21%) patients with HT, compared with one of 21 (5%) patients with multi-nodular goitre and six of 72 (8%) normal controls. Anti-C1q levels did not correlate with thyroid autoantibodies. However, in GD absolute levels of anti-C1q correlated negatively with TSH and positively with free thyroxine (FT4) and triiodothyronine (FT3). In contrast, in HT, anti-C1q correlated positively with TSH levels. No correlation between TSH and thyroid autoantibodies was found. In conclusion, we found an increased prevalence of anti-C1q in patients with AITD and their levels correlated with the thyroid function in both GD and HT. This correlation seems to be independent of thyroid autoantibodies. Therefore, anti-C1q might point to a pathogenic mechanism involved in the development of AITD that is independent of classical thyroid autoantibodies.

• MeSH
• Acute Disease MeSH
• Autoantibodies blood   MeSH
• Graves Disease immunology   physiopathology   MeSH
• Hashimoto Disease immunology   physiopathology   MeSH
• Complement C1q immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prospective Studies MeSH
• Chi-Square Distribution MeSH
• Aged MeSH
• Thyroid Gland physiopathology   MeSH
• Goiter immunology   MeSH
• Case-Control Studies MeSH
• Thyroid Function Tests MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Autoantibodies MeSH
• Complement C1q MeSH

The complement system is a major part of the innate immunity. The first component of the classical pathway of complement activation, C1q, plays a crucial role in the clearance of immune complexes and apoptotic bodies from the organism. Autoantibodies against C1q (anti-C1q) have been found in a number of autoimmune and infectious diseases. They have been best described in patients with systemic lupus erythematosus, where they are thought to play a pathogenic role in lupus nephritis (LN). Their high negative predictive value for the occurrence of active proliferative LN, as well as their possible ability to indicate a renal flare as soon as 6 months in advance, have rendered anti-C1q antibodies a novel non-invasive tool in the detection of active LN.

• MeSH
• Apoptosis immunology   MeSH
• Autoantibodies blood   MeSH
• Biomarkers blood   MeSH
• Antigen-Antibody Complex immunology   MeSH
• Complement Pathway, Classical MeSH
• Complement C1q immunology   MeSH
• Humans MeSH
• Lupus Nephritis diagnosis   immunology   MeSH
• Immunity, Innate MeSH
• Disease Progression MeSH
• Lupus Erythematosus, Systemic blood   immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Autoantibodies MeSH
• Biomarkers MeSH
• Antigen-Antibody Complex MeSH
• Complement C1q MeSH