M281 for Autoimmune Hemolytic Anemia
(ENERGY Trial)
Recruiting in Palo Alto (17 mi)
+160 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
Sponsor: Janssen Research & Development, LLC
Disqualifiers: Pregnancy, Breastfeeding, Cold AIHA, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial is testing a medication called nipocalimab to see if it can help people with a blood disorder called warm autoimmune hemolytic anemia. The medication works by stopping the immune system from destroying red blood cells, which can help reduce anemia symptoms.
Do I have to stop taking my current medications for the trial?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.
How does the drug M281 differ from other treatments for autoimmune hemolytic anemia?
M281, also known as Nipocalimab, is unique because it targets the neonatal Fc receptor, which plays a role in recycling antibodies in the body. This mechanism is different from other treatments that may focus on different pathways or receptors involved in autoimmune hemolytic anemia.
12345Eligibility Criteria
Adults over 18 with warm autoimmune hemolytic anemia (wAIHA) who are currently or previously treated for wAIHA can join. Those with cold antibody AIHA, mixed type AIHA, or paroxysmal cold hemoglobinuria cannot participate. Pregnant or breastfeeding individuals and those with other significant health issues are also excluded.Inclusion Criteria
I am 18 years old or older.
I have been treated for warm autoimmune hemolytic anemia for over 3 months.
Participants must be able to understand and voluntarily provide written informed consent to participate in the study and comply with all study procedures
Exclusion Criteria
Participants must not have other clinically relevant abnormalities currently or in their history that the Investigator would deem them ineligible to participate
I have been diagnosed with a type of anemia caused by cold-reacting antibodies.
Participants must not be pregnant or breastfeeding
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Double-blind Treatment
Participants receive M281 or placebo every 2 or 4 weeks during the double-blind period
24 weeks
Bi-weekly or monthly visits
Open-label Extension
Participants receive M281 every 2 or 4 weeks during the open-label extension period
144 weeks
Bi-weekly or monthly visits
Follow-up
Participants are monitored for safety and effectiveness after treatment
8 weeks
Participant Groups
The trial is testing the effectiveness and safety of a medication called M281 in adults with wAIHA compared to a placebo. Participants will either receive M281 or a placebo to determine if M281 improves their condition.
5Treatment groups
Experimental Treatment
Group I: Placebo administered every 2 weeks (double-blind period)Experimental Treatment1 Intervention
Participants will receive M281 matching placebo administered every 2 weeks during the 24 weeks double-blind period.
Group II: M281 administered every 4 weeks (open-label extension period)Experimental Treatment1 Intervention
Participants will receive M281 administered every 4 weeks during the 144 weeks open-label extension period.
Group III: M281 administered every 4 weeks (double-blind period)Experimental Treatment2 Interventions
Participants will receive M281 administered every 4 weeks alternating with placebo every 4 weeks during the 24 weeks double-blind period.
Group IV: M281 administered every 2 weeks (open-label extension period)Experimental Treatment1 Intervention
Participants will receive M281 administered every 2 weeks during the 144 weeks open-label extension period.
Group V: M281 administered every 2 weeks (double-blind period)Experimental Treatment1 Intervention
Participants will receive M281 administered every 2 weeks during the 24 weeks double-blind period.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Florida Health Jacksonville - RheumatologyGainesville, FL
Alliance for Multispeciality ResearchKansas City, MO
University of FloridaGainesville, FL
East Carolina UniversityGreenville, NC
More Trial Locations
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Who Is Running the Clinical Trial?
Janssen Research & Development, LLCLead Sponsor
References
Galactosylation of IgG1 modulates FcγRIIB-mediated inhibition of murine autoimmune hemolytic anemia. [2013]Murine immune effector cells express three different stimulatory FcγRs (FcγRI, FcγRIII and FcγRIV) and one inhibitory receptor, FcγRIIB. Competitive engagement of stimulatory and inhibitory FcγRs has been shown to be critical for the development of immune complex-mediated inflammatory disorders. Because of the previous demonstration that FcγRIIB was unable to inhibit FcγRIII-mediated autoimmune hemolytic anemia induced by 105-2H IgG1 anti-RBC mAb, we reevaluated the regulatory role of FcγRIIB on the development of anemia using two additional IgG1 anti-RBC mAbs (34-3C and 3H5G1) and different 34-3C IgG subclass-switch variants. We were able to induce a more severe anemia in FcγRIIB-deficient mice than in FcγRIIB-sufficient mice after injection of 34-3C and 3H5G1 IgG1, but not 105-2H IgG1. Structural analysis of N-linked oligosaccharides attached to the CH2 domain revealed that 105-2H was poorly galactosylated as compared with the other mAbs, while the extent of sialylation was comparable between all mAbs. In addition, we observed that a more galactosylated 105-2H variant provoked more severe anemia in FcγRIIB-deficient mice than FcγRIIB-sufficient mice. In contrast, the development of anemia induced by three non-IgG1 subclass variants of the 34-3C mAb was not down-regulated by FcγRIIB, although they were more galactosylated than its IgG1 variant. These data indicate that FcγRIIB-mediated inhibition of autoimmune hemolytic anemia is restricted to the IgG1 subclass and that galactosylation, but not sialylation, of IgG1 (but not other IgG subclasses) is critical for the interaction with FcγR, thereby determining the pathogenic potential of IgG1 autoantibodies.
A novel human CD32 mAb blocks experimental immune haemolytic anaemia in FcgammaRIIA transgenic mice. [2007]A fully human IgG1 kappa antibody (MDE-8) was generated, which recognised Fc-gamma receptor IIa (FcgammaRIIa) molecules on CD32 transfectants, peripheral blood monocytes, polymorphonuclear cells and platelets. This antibody blocked FcgammaRIIa ligand-binding via its F(ab')(2) fragment. Overnight incubation of monocytes with F(ab')(2) fragments of MDE-8 leads to a c. 60% decrease in cell surface expression of FcgammaRIIa. MDE-8 whole antibody induced a concomitant c. 30% decrease of FcgammaRI on THP-1 cells and monocytes. In humans FcgammaRIIa plays an important role in the clearance of antibody-coated red blood cells in vivo. As an equivalent of FcgammaRIIa does not exist in mice, the in vivo effect of MDE-8 was studied in an FcgammaRIIa transgenic mouse model. In these mice, antibody-induced anaemia could readily be blocked by MDE-8. These data document a new human antibody that effectively blocks FcgammaRIIa, induces modulation of both FcgammaRIIa and FcgammaRI from phagocytic cells, and ameliorates antibody-induced anaemia in vivo.
High pathogenic potential of low-affinity autoantibodies in experimental autoimmune hemolytic anemia. [2019]To assess the potency of low-affinity anti-red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti-mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a-injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity IgM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia.
Interleukin 3 perfusion prevents death due to acute anemia induced by monoclonal antierythrocyte autoantibody. [2019]We have evaluated the therapeutic activity of rIL-3, in comparison with recombinant granulocyte-macrophage CSF (rGM-CSF) and recombinant erythropoietin (rEpo), on a lethal form of acute anemia induced by a single injection of a monoclonal IgG1 anti-mouse RBC (MRBC) autoantibody. Continuous perfusion of rIL-3 before the administration of anti-MRBC mAb prevented animals from the death due to anemia with a rapid recovery in greater than 90% of the cases, while only partial protection (one third of the cases) was obtained by rEpo perfusion, and no protection by rGM-CSF. Since the anti-MRBC mAb induced a marked agglutination of RBC in spleens and livers, and subsequent hemodynamic failure may be an additional contributing factor to the animals' death, the activation of Fc gamma receptor-dependent phagocytosis by rIL-3, as well as the increased number of monocytes/macrophages resulting from rIL-3 perfusion, may also facilitate rapid elimination of these agglutinated RBC, resulting in the further amelioration of the animals' survival. Our results suggest that the therapeutic effect of rIL-3 on anti-MRBC autoantibody-induced anemia is achieved by: (a) its activity to promote the growth and differentiation of erythroid progenitors responsive to Epo and of monocyte/macrophage lineage; and (b) its activity to enhance the phagocytic activity of macrophages to efficiently eliminate agglutinated RBC in spleens and livers.
Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fc gamma receptor. [2019]In the present study 3-iodo-4-hydroxy-5-nitrophenacetyl (NIP)-specific antibodies were compared for induction of antibody dependent lysis of NIP-derivatised red blood cells effected by pre-stimulated U937 or HL-60 cells and by K cells. The chimaeric antibodies have heavy chains corresponding to human IgG subclasses 1-4, and include site-directed mutants of IgG3 as well as the aglycosylated form of IgG3; a mouse IgG2b antibody and a site-directed mutant IgG2b were also examined. rIFN stimulated U937 or HL-60 cells express increased levels of Fc gamma R1 compared to unstimulated cells; PMA stimulated HL-60 and U937 cells express an increased level of Fc gamma R11 compared to unstimulated cells; K cells express Fc gamma R111. Using these effector cell populations and the target cells mentioned above, we have compared anti-NIP antibodies with different heavy chain constant domains for their ability to induce ADCC through human Fc gamma R1, Fc gamma R11 and Fc gamma R111. The results suggest that all three human Fc gamma receptors appear to recognise a binding site on IgG within the lower hinge (residues 234-237) and trigger ADCC via this site, but that each receptor sees this common site in a different way. The possibility that other amino acid residues also participate in the binding/triggering site(s) cannot be excluded.