Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model

Anwar, Imran J.; Ezekian, Brian; DeLaura, Isabel; Manook, Miriam; Schroder, Paul M.; Yoon, Janghoon; Curfman, Verna; Branum, Evelyn; Messina, Julia A.; Harnois, Melissa J; Permar, Sallie R.; Farris, Alton B.; Kwun, Jean; Knechtle, Stuart J.

doi:10.1111/ajt.17208

Cited by 8 publications

(5 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prevention of cognate T-B cell interactions through costimulatory blockade inhibits GC reactions and prevents repopulation of PCs from alloreactive memory B cell (Bmem) reservoirs. Similar combination regimens such as carfilzomib with lulizumab or tocilizumab, and daratumumab and plerixafor have similarly blunted the post-transplant humoral response (21,22,30). Given similarities in desensitization and AMR treatments, we applied this dual targeting strategy to AMR.…”

Section: Discussionmentioning

confidence: 99%

“…Many biologics are available to target different components of the humoral response (16). These agents target initial B cell help from T cells (costimulation blockade) (17,18), B cell survival (BAFF) (19), plasma cells (proteasome inhibitor, anti-CD38mAb) (17,18,(20)(21)(22), antibodies (i.e., Imlifidase or anti-FcRn mAb) (23)(24)(25) and complement activation or split products (i.e., Eculizumab, C1-INH) (26-28), and have been tested in the clinic or in pre-clinical models for a variety of indications. However, optimal outcomes may not be achieved by just targeting a single component of the humoral response, due to compensatory pathways and mechanisms (20).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model

Schmitz,

Manook,

Fitch

et al. 2023

Front. Transplant.

Self Cite

View full text Add to dashboard Cite

IntroductionOne-third of HLA-incompatible kidney transplant recipients experience antibody mediated rejection (AMR) with limited treatment options. This study describes a novel treatment strategy for AMR consisting of proteasome inhibition and costimulation blockade with or without complement inhibition in a nonhuman primate model of kidney transplantation.MethodsAll rhesus macaques in the present study were sensitized to maximally MHC-mismatched donors by two sequential skin transplants prior to kidney transplant from the same donor. All primates received induction therapy with rhesus-specific ATG (rhATG) and were maintained on various immunosuppressive regimens. Primates were monitored postoperatively for signs of acute AMR, which was defined as worsening kidney function resistant to high dose steroid rescue therapy, and a rise in serum donor-specific antibody (DSA) levels. Kidney biopsies were performed to confirm AMR using Banff criteria. AMR treatment consisted of carfilzomib and belatacept for a maximum of four weeks with or without complement inhibitor.ResultsTreatment with carfilzomib and belatacept was well tolerated and no treatment-specific side effects were observed. After initiation of treatment, we observed a reduction of class I and class II DSA in all primates. Most importantly, primates had improved kidney function evident by reduced serum creatinine and BUN as well as increased urine output. A four-week treatment was able to extend graft survival by up to two months.DiscussionIn summary, combined carfilzomib and belatacept effectively treated AMR in our highly sensitized nonhuman primate model, resulting in normalization of renal function and prolonged allograft survival. This regimen may translate into clinical practice to improve outcomes of patients experiencing AMR.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model

Schmitz,

Manook,

Fitch

et al. 2023

Front. Transplant.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Rhesus glycoprotein B (gB)‐specific IgG were quantified using ELISA as previously reported 22,31 . 384‐well plates were coated with 2 mg/mL RhCMV gB, diluted in 0.1 M sodium bicarbonate buffer.…”

Section: Methodsmentioning

confidence: 99%

The impact of IdeS (imlifidase) on allo‐specific, xeno‐reactive, and protective antibodies in a sensitized rhesus macaque model

DeLaura,

Zikos,

Anwar

et al. 2023

Xenotransplantation

Self Cite

View full text Add to dashboard Cite

BackgroundHighly sensitized patients face many barriers to kidney transplantation, including higher rates of antibody‐mediated rejection after HLA‐incompatible transplant. IdeS, an endopeptidase that cleaves IgG nonspecifically, has been trialed as desensitization prior to kidney transplant, and successfully cleaves donor‐specific antibody (DSA), albeit with rebound.MethodsIdeS was generated and tested (2 mg/kg, IV) in two naïve and four allosensitized nonhuman primates (NHP). Peripheral blood samples were collected at regular intervals following IdeS administration. Total IgG, total IgM, and anti‐CMV antibodies were quantified with ELISA, and donor‐specific antibody (DSA) and anti‐pig antibodies were evaluated using flow cytometric crossmatch. B cell populations were assessed using flow cytometry.ResultsIdeS successfully cleaved rhesus IgG in vitro. In allosensitized NHP, robust reduction of total, DSA, anti‐pig, and anti‐CMV IgG was observed within one day following IdeS administration. Rapid rebound of all IgG antibody populations was observed, with antibody levels returning to baseline around day 14 post‐infusion. Total IgM level was not affected by IdeS. Interestingly, a comparable reduction in antibody populations was observed after the second dose of IdeS. However, we have not observed any significant modulation of B cell subpopulations after IdeS.ConclusionsThis study evaluated efficacy of IdeS in the allosensitized NHP in IgG with various specificities, mirroring antibody kinetics in human patients. The efficacy of IdeS on preexisting anti‐pig antibodies may be useful in clinical xenotransplantation. However, given the limitation of IdeS on its durability as a monotherapy, optimization of IdeS with other agents targeting the humoral response is further needed.

show abstract

“…286 Based on its mechanisms of action, we presume that preventive or prophylactic anti-IL-6-directed treatment is more likely to be effective than its administration in response to established or even early-onset AMR. The combination of IL-6R blockade and carfilzomib-based therapy prolonged allograft survival in highly-sensitized NHPs 287 and may be worth exploring in xenotransplantation.…”

Section: Anti-il-6r Mabsmentioning

confidence: 99%

Antibody‐mediated rejection in xenotransplantation: Can it be prevented or reversed?

Habibabady,

McGrath,

Kinoshita

et al. 2023

Xenotransplantation

View full text Add to dashboard Cite

Antibody‐mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti‐donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti‐inflammatory therapy. Depletion or neutralization of anti‐pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG‐degrading enzymes do not deplete IgM. Despite the expression of human complement‐regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti‐C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell‐targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti‐inflammatory agents, anti‐IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti‐inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ‐source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD‐L1, HLA E, and/or HLA‐G.

show abstract

Addition of interleukin-6 receptor blockade to carfilzomib-based desensitization in a highly sensitized nonhuman primate model

Cited by 8 publications

References 49 publications

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model

The impact of IdeS (imlifidase) on allo‐specific, xeno‐reactive, and protective antibodies in a sensitized rhesus macaque model

Antibody‐mediated rejection in xenotransplantation: Can it be prevented or reversed?

Contact Info

Product

Resources

About