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The complement system is well known for its role in innate immunity and in maintenance of tissue homeostasis, providing a first line of defence against infection and playing a key role in flagging apoptotic cells and debris for disposal. Unfortunately, complement also contributes to pathogenesis of many diseases, in some cases driving pathology, and in others amplifying or exacerbating the inflammatory and damaging impact of non-complement disease triggers. The driving role of complement in a single disease, paroxysmal nocturnal hemoglobinuria (PNH), provoked the development and eventual FDA (US Food and Drug Administration) approval of eculizumab (Soliris™), an anti-C5 antibody, for therapy. Although PNH is very rare, eculizumab provided clinical validation and demonstrated that inhibiting the complement system was not only well-tolerated, but also provided rapid therapy and saved lives. This clinical validation, together with advances in genetic analyses that demonstrated strong associations between complement and common diseases, drove new drug discovery programmes in both academic laboratories and large pharmaceutical companies. Numerous drugs have entered clinical development and several are in phase 3 trials; however, many have fallen by the wayside. Despite this high attrition rate, crucial lessons have been learnt and hurdles to development have become clear. These insights have driven development of next generation anti-complement drugs designed to avoid pitfalls and facilitate patient access. In this article, we do not set out to provide a text-heavy review of complement therapeutics but instead will simply highlight the targets, modalities and current status of the plethora of drugs approved or in clinical development. With such a fast-moving drug development landscape, such a compendium will inevitably become out-dated; however, we provide a snapshot of the current field and illustrate the increased choice that clinicians might enjoy in the future in selecting the best drug for their application, decisions based not only on efficacy but also cost, mechanistic target, modality and route of delivery.

The human complement system constitutes a Janus-faced part of our immune machinery, which confers rapid protection against microbial intruders but can quickly turn against the host and contribute to inflammatory, immune-, age- and foreign body-related clinical complications1.The defence-offence profile often tilts unfavourably during ageing, traumatic insults or genetic dysregulation of the cascade. The list of disorders with known complement contribution is growing constantly, and with it the incentive to control complement activation therapeutically1-3. Since the introduction of complement-specific drugs in 2007, and the generally positive experience in the clinic, the interest in developing new therapeutic inhibitors has been growing constantly and has led to a cornucopious pipeline2,3. While the clinically available arsenal is currently limited to a few targets and mostly orphan and rare indications, it is expected that the recently sparked confidence and commercial interest will soon lead to a significant broadening of treatment options and, consequently, clinical conditions in which complement-targeted drugs will be applied2 New frontiers, such as applications in the therapy of cancer or neurological diseases are already on the horizon4,5

Iscalimab is a fully-human, CD40 pathway blocking, non-depleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n=56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1 or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n=20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and non-linear pharmacokinetics. Complete (≥ 90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 μg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 co-stimulatory pathway with potential use in transplantation and other autoimmune diseases. Abbreviations: n, number of patients

The CD40-CD154 costimulatory pathway is essential for T cell–dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ533 was unable to mediate depletion of human CD40 expressing B cells. In vivo, CFZ533 blocked primary and recall T cell-dependent antibody responses in nonhuman primates and abrogated germinal formation without depleting peripheral blood B cells. We also established a relationship between plasma concentrations of CFZ533 and CD40 pathway-relevant pharmacodynamic effects in tissue.Collectively these data support the scientific rationale and posology for clinical utility of this antibody in select autoimmune diseases and solid organ transplantation.

CFZ533 is a pathway blocking, nondepleting anti-CD40 antibody that is in clinical development for inhibition of transplant organ rejection and therapy for autoimmune diseases. A 26-week GLP toxicity study in sexuallymature Cynomolgus monkeys was conducted in order to support chronic application of CFZ533. CFZ533 was subcutaneously administered at doses up to 150mg/kg/week and was safe and generally well tolerated. CFZ533 showed no adverse effects for cardiovascular, respiratory, and neurobehavioral endpoints, and no changes were observed for blood lymphocyte and platelet counts or blood coagulation markers. In line with the nondepleting nature of CFZ533, CD20þ B cells in the blood were onlymarginally reduced. A complete suppression of germinal center (GC) development in lymph nodes and spleen was themost prominent result of post-mortem histological investigations. This was corroborated by an abrogated T-dependent antibody response (TDAR) to the antigen Keyhole Limpet Hemocyanin (KLH) as well as an absence of anti-drug antibodies (ADAs) in the absence of B cell depletion as seen with immunophenotyping and histology.When serumlevels of CFZ533 in recovery animals dropped levels necessary for full CD40 occupancy on B cells, all animals were able tomount a TDAR to KLH. All histological changes also reverted to normal appearance after recovery. In summary, CFZ533 was shown to be well tolerated and safe in the 26-week toxicity study with a distinct pharmacodynamic profile in histology and immune function. Abbreviations: GLP, Good Laboratory Practices

CD40–CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98–100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection. Abbreviations: MHC, major histocompatibility complex; NHP, nonhuman primate

The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors.Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Longterm survival of porcine islets has been achieved using CD154-specific antibodies to interrupt the CD40/CD154 costimulation pathway; however, CD154-specific antibodies seem unlikely candidates for clinical translation. An alternative strategy for CD40/CD154 pathway interruption is use of CD40-specific antibodies. Herein, we evaluate the ability of a chimeric CD40-specific monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (∼50 000 IEQ/kg) were transplanted intraportally into pancreatectomized diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and the IL-2 receptor-specific antibody basiliximab, and maintenance therapy with sirolimus and the B7-specific fusion protein belatacept. Chi220 effectively promoted xenoislet engraftment and survival, with five of six treated recipients achieving insulin-independent normoglycemia (median rejection-free survival 59 days; mean 90.8 days, maximum 203 days). No thromboembolic phenomena were observed. CD40 represents a promising alternative to CD154 as a therapeutic target, and the efficacy of CD40-specific antibodies in islet xenotransplantation warrants further investigation. Abbreviations: IL-2, interleukin-2