Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.

Safety evaluation of biological drugs: what are toxicology studies in primates telling us?

A total of 26 toxicology studies performed with biological drugs (monoclonal antibodies and related immunoglobulins as well as recombinant human proteins) in the primate have been evaluated to give an insight into the types of study designs used and results. The evaluation involved examination of pivotal repeat dose studies which ranged from 2 to 13 weeks in duration, used to support early clinical investigation. Either no findings were seen or restricted to those which could largely be explained by the drug's pharmacology. Based on these results and supporting findings from a literature review of other similar drugs in development or approved for marketed use, a case has been made to revisit aspects of the standard design approach of toxicology studies for biological drugs. Thus, consideration should be given to a move away from the use of three drug-treated and numerous non-dose recovery groups currently used to support initial clinical entry to a robust toxicological assessment that could be achieved in many cases with one control and one or two drug-treated groups and with non-dose recovery groups only for the control and highest level used. An argument for not routinely measuring for anti-drug antibodies unless there is a specific drug-related reason is also made.

An autoantibody in narcolepsy disrupts colonic migrating motor complexes.

Despite strong circumstantial evidence for the autoimmune hypothesis of narcolepsy, conventional immunological methods have failed to detect an autoantibody. This study investigated the real-time effects of narcoleptic immunoglobulins on a spontaneous colonic migrating motor complex (CMMC) preparation. IgG from patients with narcolepsy with cataplexy or healthy controls was added directly to isolated mouse colons undergoing CMMC activity to test for autoantibodies that disrupt colonic motility. The effect of immunoglobulins prepared for clinical intravenous treatment (IVIg) on autoantibody-mediated colonic disruption was also assessed. Narcoleptic IgGs markedly reduced the frequency of CMMCs or irreversibly abolished them. Abrogation of CMMCs was followed by an increase in the resting tension of the colon preparation and appearance of atropine-sensitive phasic smooth muscle contractions. IVIg partially neutralized the inhibitory effect of narcoleptic IgG on the CMMCs. The dramatic effect of narcoleptic IgG on CMMC generation is consistent with an autoantibody-mediated disruption of enteric neural pathways. The ex vivo whole-organ approach allows real-time examination of the physiological effects of the narcoleptic autoantibody and offers a new avenue for exploring the autoimmune basis of narcolepsy. The neutralizing effect of IVIg on the autoantibody provides a rationale for the reported clinical improvement in cataplexy when IVIg are given at disease onset.

Type I transmembrane receptor with inhibitory function in mouse mast cells and NK cells.

The MHC class I-specific inhibitory receptors on human and mouse NK cells have surprisingly different structures. The mouse receptors (Ly-49) are type II transmembrane glycoproteins of the C-type lectin family, whereas the human receptors (killer cell inhibitory receptors (KIR)) belong to the Ig superfamily. This difference prompted a search for Ig-like inhibitory receptors in mice. Here we show that gp49, a mouse mast cell protein of unknown function but with sequence similarity to KIR, is expressed in NK cells. The gp49 cytoplasmic tail, containing a sequence related to an inhibitory motif shared by KIR and Ly-49, delivered a strong inhibitory signal in both human and mouse NK cells when substituted for a KIR cytoplasmic tail. These data show that Ig-like receptors with inhibitory properties exist in both species and that mouse mast and NK cells may recognize common inhibitory ligands.

The immunological impairment of arcuate neuropeptide Y neurons by ricin A chain produces persistent decrease of food intake and body weight.

Neuropeptide Y is demonstrated as a potent orexigenic peptide when injected into the rat hypothalamic paraventricular nuclei. The neuropeptide Y innervation of paraventricular nuclei originates from both hypothalamic arcuate nuclei and brainstem neurons, whose specific role in the control of food intake is still under discussion. To assess the role of the arcuate neuropeptide Y in the regulation of food intake, we propose a new method for immunologically impairing the neuronal secretion of neuropeptide Y from a unique brain site. The monoclonal antibody to the neuropeptide Y precursor epitope, the C-flanking peptide, was microinjected with two cellular toxins (the ricin A chain and the monensin) into the hypothalamic arcuate nuclei or paraventricular nuclei. One microinjection into the arcuate nuclei reduced the food intake and body weight gain for 10 days. It prevented the food intake stimulation usually induced by a 12 h food deprivation. This decrease of food intake was not due to the aversive properties of monoclonal antibody or cellular toxins, or the immunoneutralization of the biologically active neuropeptide Y, because (i) the acute effect of the microinjection into the arcuate nuclei promoted a transient increase of the food intake likely induced by a strong release of neuropeptide Y from the arcuate neurons which were immunologically damaged, and (ii) the C-flanking peptide monoclonal antibody binds neither neuropeptide Y nor its receptors. The microinjection was inefficient when C-flanking peptide monoclonal antibody was replaced by non-specific rat immunoglobulins or when the C-flanking peptide monoclonal antibody/toxins mixture was injected into the paraventricular nuclei. The data bring further arguments in two domains.(ABSTRACT TRUNCATED AT 250 WORDS)

[The nephrotoxic effects of single duck immunoglobulins in the triggering of Masugi nephritis]. / Der nephrotoxische Effekt der einzelnen Entenimmunglobuline bei der Ausläosung der Masugi-Nephritis.

Studies were conducted into the roles played by various duck immunoglobulins in the anti-basal membrane of nephrotoxic nephritis in rabbit. The 7.8S and 5.7S immunoglobulins which originated from nephrotoxic duck serum were found to be responsible for the development of nephritis in rabbit. No pathogenetic role was played by any other proteins of duck serum. The affinity for the glomerulus basal membrane of 7.8S immunoglobulin was found to be higher than that of 5.7S globulin. As to trigger dosage, nephritis was safely inducted by 10 mg/kg body weight (BW) in the context of 7.8S immunoglobulins and by 15 mg/kg BW in the case of 5.7S immunoglobulins. One and the same morphological nature was recorded from nephritis, no matter by which of the above immunoglobulins it had been caused. Nephrotoxic duck immunoglobulins proved to be highly suitable for induction of experimental glomerulonephritis due to absence from this model of the heterologous phase of nephritis. Hence, the autologous phase is unambiguous and can be examined with higher accuracy.

[Evaluation of the toxic action of prophylactic and therapeutic preparations on cell cultures. III. The detection of toxic properties in medical biological preparations by the degree of cell damage in the L132 continuous cell line]. / Otsenka toksicheskogo deistviia profilakticheskikh i lechebnykh preparatov na kul'turakh kletok. Soobshchenie III. Vyiavlenie toksicheskikh svoistv v meditsinskikh biologicheskikh preparatakh po stepeni povrezhrdeniia kletk v perebvivaemoi linii L132.

The methods of the quality control of medical biological preparations, including tests on animals, do not ensure the complete absence of toxicity in a final product. The use of the method of "subcultures with the introduced preparation" makes it possible to determine the toxicity of both specific and nonspecific components of vaccines and sera from the number of dead and damaged cells. The toxic action of preparations kills and damages the cells at the site of injection, thus inducing the formation of autoantigens whose effect on the body cannot be predicted. Thus thimerosal, commonly used as preservative, has been found not only to render its primary toxic effect, but also capable of changing the properties of cells. This fact suggests that the use of thimerosal for the preservation of medical biological preparations, especially those intended for children, is inadmissible.

Comparative pyrogen reactivity of rabbit and man to human albumin and immunoglobulin solutions.

According to the prescriptions of the Hungarian Pharmacopoeia regarding the pyrogenicity of human albumin and immunoglobulin solutions, the temperature increase should not exceed 0.5 degrees C in rabbits. If the average rise in temperature of rabbits is between 0.6 to 1.1 degrees C, the preparation--in other respects meeting the requirements--can be tested in man (generally 20 persons per preparation). Products causing an average rise in temperature less than 0.6 degrees C and provoking individual rises of temperature below 1 degrees C in man, can be issued. On the basis of these data going back for many years, no reliable correlation could be found between the pyrogen test in rabbits and temperature rise in man. The same preparation which failed to pass the rabbit pyrogen test proved to be apyrogenic in man.