Imlifidase for the treatment of anti-HLA antibody-mediated processes in kidney transplantation

Abstract

Allosensitization represents one of the most formidable obstacles in transplantation. Here, an immunologic barrier prohibits access to transplantation for the most highly-HLA sensitized individuals.In 2014, a revised kidney allocation system (KAS) in the United States dramatically improved transplant rates for sensitized patients. 1 However, longer term analysis revealed that transplant rates for the most highly-HLA sensitized (calculated panel reactive antibodies [cPRA] >99.9%) were not impacted by the revised KAS and these patients were more likely to die or be removed from the list than transplanted. 2 Even within the highly sensitized, there are marked differences in transplant rates where the post-KAS transplant rate for candidates with cPRA >99.9% is six times less than that for candidates with a cPRA 99.5%-99.9% despite both groups receiving similar priority under the revised KAS. 3 This information has led to a focus on development of clinical trials for desensitization therapies aimed at this group that has not benefited from the KAS.Several reports have documented the benefits of desensitization for improving access to transplantation and enhancing long-term patient survival compared to dialysis. 4,5 However, current therapies are often incomplete, especially for those in the highest cPRA categories. Therapeutic approaches that can rapidly and durably remove

Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS

“…Of the two immune evasion factors, IdeS is most advanced in clinical development 6 – 8 . S. pyogenes expresses two variants of this enzyme (often distinguished by naming the first and second variants IdeS/Mac-1 and Mac-2, respectively), which display less than 50 % sequence identity within the middle third of the protein 9 , but nonetheless exhibit largely indistinguishable endopeptidase activity 10 .…”

“…S. pyogenes expresses two variants of this enzyme (often distinguished by naming the first and second variants IdeS/Mac-1 and Mac-2, respectively), which display less than 50 % sequence identity within the middle third of the protein 9 , but nonetheless exhibit largely indistinguishable endopeptidase activity 10 . The enzyme targets IgG by cleaving within the lower hinge region, yielding F(ab′) 2 and Fc fragments 3 , 11 , 12 , an activity which has enabled its development (specifically, the Mac-1 enzyme variant) as a pre-treatment for transplantation in hypersensitised individuals with chronic kidney disease (Imlifidase, brand name Idefirix®) 6 – 8 . Along with EndoS, it has further potential use in the deactivation of pathogenic antibodies in autoimmune disorders 13 – 19 , deactivation of neutralising antibodies for in vivo gene therapy 20 , and for the potentiation of therapeutic antibodies by deactivation of competing serum IgG 21 , 22 .…”

Updated management for antibody-mediated rejection: opportunity to prolong kidney allograft survival

“…IdeS can effectively lower the total IgG to less than 1% of the pretreatment level within 48 h after intravenous infusion and the IgG remained low for 7 days [17]. Both CDC and antibody-mediated cellular cytotoxicity induced by DSA are also inhibited after treatment with IdeS [18 ▪ ]. The IdeS does not only cleave the IgG but also the B cell receptor of the memory B cell (CD19+/CD27+/IgG+) [19].…”

Extensive substrate recognition by the streptococcal antibody-degrading enzymes IdeS and EndoS

“…Of the two immune evasion factors, IdeS is most advanced in clinical development. The enzyme targets IgG by cleaving within the lower hinge region, yielding F(ab')2 and Fc fragments (3,6,7), an activity which has enabled its development, under the name Imlifidase, as a pre-treatment for kidney transplantation in hypersensitized patients with chronic kidney disease (8)(9)(10)(11)(12)(13)(14)(15)(16). Along with EndoS, it has further potential use in the deactivation of pathogenic antibodies in autoimmune disorders (11,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), deactivation of neutralising antibodies for in vivo gene therapy (27), and for the potentiation of therapeutic antibodies by deactivating competing serum IgG (28,29).…”

“…S. pyogenes expresses two variants of this enzyme (often distinguished by naming the first and second variants IdeS/Mac-1 and Mac-2, respectively), which display less than 50 % sequence identity within the middle third of the protein 6 , but nonetheless exhibit largely indistinguishable endopeptidase activity 7 . The enzyme targets IgG by cleaving within the lower hinge region, yielding F(ab¢)2 and Fc fragments 3,8,9 , an activity which has enabled its development as a pretreatment for transplantation in hypersensitized individuals with chronic kidney disease (Imlifidase, brand name Idefirix®) [10][11][12] . Along with EndoS, it has further potential use in the deactivation of pathogenic antibodies in autoimmune disorders [13][14][15][16][17][18][19] , deactivation of neutralising antibodies for in vivo gene therapy 20 , and for the potentiation of therapeutic antibodies by deactivation of competing serum IgG 21,22 .…”