IdeS: a new drug with great therapeutic potential
IdeS (Immunoglobulin G-degrading enzyme of Streptococcus pyogenes), is an enzyme that specifically cleaves IgG in the hinge region, generating one F(ab’)2 fragment and Fc fragment, thus leading to inhibition of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).
-Stanley Jordan at the ATC 2016 reported his initial evaluation of his FDA approved study using IdeS in the desensitization of kidney transplant recipients with donor-specific antibodies. 4 patients entered the trial. Three of 4 patients had numerous DSAs and +FCMX. All the patients received 0.24mg/Kg IdeS IV 4-6 hours prior to incompatible DD kidney transplant. IdeS treatment was well-tolerated. Assessment of DSAs beginning 6 hours’ post-transplant showed complete DSA elimination (>2M in one patient). Patients also received IVIG & rituximab ~ 10 days’ post-IdeS. Results of post-transplant biopsies showed evidence of ATN in 3/4 while one patient had Banff 1B CMR which responded well to pulse steroid treatment. No patient had evidence of ABMR. One patient had mild ABMR at 4M post-IdeS that responded to treatment (1)
-Another phase II clinical trial is ongoing in Sweden and report on this study was presented at the 26th international congress of the Transplantation Society. IdeS enabled kidney transplantation in all 10/10 included sensitized patients and resulted in a negative cross match in all patients. None of the patients had delayed graft function and all 10 transplantations resulted in a good renal function (2)
-A Phase II Pilot Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacodynamics and Pharmacokinetics of IdeS in Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients with Low ADAMTS13 Activity, is recruiting in London (3)
The following points were taken from the phase I clinical trial in 20 healthy volunteers who received ascending doses of IdeS (4):
1-The IdeS action on IgG is rapid and nearly complete: Minutes after IdeS administration, it cleaves one of the two heavy chains of the IgG generating a single cleaved IgG molecule (ScIgG). ScIgG has compromised effector functions with reduced binding to Fcγ receptors and reduced Fc mediated cytotoxicity. The conversion into F(ab’)2 and Fc fragments, was seen in all subjects who were dosed with 0.12 and 0.24 mg/kg body weight, six hours after administration only low concentrations of IgG could be detected in blood and IgG remained low for more than a week, until newly synthesized IgG appeared in plasma. This indicate that the entire extracellular IgG pool and not only the plasma pool, is cleaved by IdeS. The remarkable efficacy of the protease is greater than the efficacy of a single plasma volume exchange, which typically leaves 35% remaining IgG and 24 hours thereafter the level rises to 60%, mainly due to lymphatic drainage into the vascular space.
2-Since S. Pyogenes is a common human pathogen all subjects had pre-formed anti-IdeS IgG antibodies and reacted as expected with an IgG response peaking two to three weeks after the IdeS infusion. The amplitude of the anti-drug response varied substantially between individuals, although a dose-response pattern was noted. Six to twelve months after dosing all subjects were back to normal anti-IdeS antibody levels (i.e. <2–91 mg/L). Considering safety and potentially neutralizing antibodies it is anticipated that IdeS treatment could be repeated after six to twelve months in accordance with the experience from e.g. streptokinase treatment. These anti-IdeS antibodies might increase the risk of hypersensitivity/ infusion-like reactions against the drug IdeS. Before inclusion subjects were screened by IdeS-ImmunoCAP and those with elevated IgG antibody titers (>15 mg/L) were excluded from the study. A reference group (n = 130) were screened with the IdeS-ImmunoCAP prior to study start. Ten out of 130 subjects had IdeS Specific IgG below the cut-off (2.0 mg/L). The median level of anti-IdeS IgG was 6.1 mg/L (range: 2.0–78.0 mg/L; n = 130) with the 80% percentile at 15 mg/L. 78 healthy subjects were screened for this study and all had detectable IgG against IdeS. The median level of anti-IdeS IgG was 10.6 mg/L (range: 2.1–90.8 mg/L) and twenty-eight percent of the tested individuals had anti-IdeS IgG titers over 15.0 mg/L
3-In addition to total plasma IgG the authors investigated the effect of IdeS on antigen-specific IgG (diphtheria, tetanus, pertussis, polio and Hib). The results showed no significant difference in the cleavage and recovery of the IgG antibodies against these antigens compared to total IgG; all subjects had fully recovered their antigen-specific IgG at the time when the IgG pool was back to pre-dose levels.
4- A large inter-individual variation in the rate of IgG recovery was observed and there was no indication of differences between the dose-groups. The F(ab’)2 as well as the Fc fragments reached lowest levels
between one and seven days’ post dosing. The elimination of Fc fragments was somewhat faster than the elimination of F(ab’)2 fragments.
5-No clinically significant changes in hematology, clinical chemistry or coagulation were identified.
However, a transient proteinuria was observed after 24–48 hours in subjects administered an IdeS dose resulting in significant cleavage of IgG compared to placebo treatment. This probably reflected the clearance of IgG cleavage products from the circulation since there was a correlation between subjects with elevated proteinuria and subjects where IdeS had an effect.
6- Subjects were excluded from the study if they had, or had a history of, any clinically significant immunodeficiency including but not limited to immunoglobulin A deficiency, had elevated levels of anti-IdeS IgG (>15 mg/L), tested positive for serum hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus (HIV), ongoing tuberculosis, ongoing syphilis, active herpes simplex or herpes zoster infection during screening.
Another human in vitro and ex vivo study showed that IdeS cleaves the IgG present in the BCR complex and very efficiently blocks Ag binding to the BCR. As a consequence of IdeS cleaving the BCR, signaling cascades downstream of the BCR are blocked, and memory B cells are temporarily silenced, preventing them from responding to antigenic stimulation and their transition into Ab-producing cells (5).
Comments and discussion
-In my opinion, this is a very promising drug in the management of patients with antibody-mediated rejection, in the desensitization of transplant recipients with donor-specific antibodies and in many autoimmune diseases, where autoantibodies play a major role in the pathogenesis of the disease. The depletion of IgG pool is near complete, however, the antibodies may reappear few weeks after. Repeat dosing is possible, however, all healthy volunteers studied developed rise in the anti-IdeS titers and it took 6-12 months for titers to drop. In kidney transplant recipients receiving several immunosuppressive medications, the response likely to be different and this may allow sooner and more frequent dosing if needed. However, no published data are available yet on this point and measurement of anti-IdeS level will be essential.
-IdeS appears to cleave IgG in the plasma, interstitium and cell-membrane bound IgG. The data about cleavage of BCR is interesting and will likely prevent an immediate memory response, which should help protect the graft from AMR in the immediate post-transplant period, however, the B cell will recover and replace the BCR at some point, in addition, other BCRs (IgA and, IgM) are not cleaved.
-The very low level of IgG after the treatment with IdeS will expose patients to infection. In the phase I trial in healthy volunteers, all received Augmentin or Doxycycline until their IgG level was >450 ng/dl. A similar strategy should be used in kidney transplant patients. Another option in transplant recipient is give them IVIG until they recover their own pool.
1-2016 American Transplant Congress. Abstract 3019.
2-Press release by Hansa Medical AB
4-Complete Removal of Extracellular IgG Antibodies in a Randomized Dose-Escalation Phase I Study with the Bacterial Enzyme IdeS– A Novel Therapeutic Opportunity. PLOS ONEDOI: 10.1371/journal. Pone. 0132011 July 15, 2015.
5- The Bacterial Enzyme IdeS Cleaves the BCR- IgG-Type of B Cell Receptor (BCR), Abolishes BCR-Mediated Cell Signaling, and Inhibits Memory B Cell Activation. J Immunol published online 9 November 2015.