A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury

Li, Changhai; Patel, Kunal; Tu, Zhengkun; Yang, Xiaofeng; Kulik, Liudmila; Alawieh, Ali; Allen, Patterson; Cheng, Qi; Wallace, Caroline; Kilkenny, Jane; Kwon, Jennie H.; Gibney, Barry C.; Cantu, Edward; Sharma, Ashish K.; Pipkin, M.; Machuca, Tiago; Emtiazjoo, A.; Goddard, Martin; Holers, V. Michael; Nadig, Satish N.; Christie, Jason D.; Tomlinson, Stephen; Atkinson, Carl

doi:10.1111/ajt.16404

Cited by 7 publications

(7 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our general approach has been to target and localize complement inhibition to sites of disease and injury, and we have previously described two targeting strategies. One involved a targeting moiety consisting of a fragment of complement receptor 2 (CR2) that recognizes C3d deposited at sites of complement activation ( 23 , 27 ), and the other an scFv that recognizes an injury specific neoepitope ( 13 , 28 ). We have shown that targeted complement inhibitors, in contrast to their untargeted counterparts, have minimal effect on levels of systemic complement activity due to their short circulatory half-life, do not increase host susceptibility to infection, and by increasing bioavailability enhance efficacy up to 20-fold ( 23 , 29 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation

et al. 2021

Self Cite

View full text Add to dashboard Cite

The complement system has long been recognized as a potential druggable target for a variety of inflammatory conditions. Very few complement inhibitors have been approved for clinical use, but a great number are in clinical development, nearly all of which systemically inhibit complement. There are benefits of targeting complement inhibition to sites of activation/disease in terms of efficacy and safety, and here we describe P-selectin targeted complement inhibitors, with and without a dual function of directly blocking P-selectin-mediated cell-adhesion. The constructs are characterized in vitro and in murine models of hindlimb ischemia/reperfusion injury and hindlimb transplantation. Both constructs specifically targeted to reperfused hindlimb and provided protection in the hindlimb ischemia/reperfusion injury model. The P-selectin blocking construct was the more efficacious, which correlated with less myeloid cell infiltration, but with similarly reduced levels of complement deposition. The blocking construct also improved tissue perfusion and, unlike the nonblocking construct, inhibited coagulation, raising the possibility of differential application of each construct, such as in thrombotic vs. hemorrhagic conditions. Similar outcomes were obtained with the blocking construct following vascularized composite graft transplantation, and treatment also significantly increased graft survival. This is outcome may be particularly pertinent in the context of vascularized composite allograft transplantation, since reduced ischemia reperfusion injury is linked to a less rigorous alloimmune response that may translate to the requirement of a less aggressive immunosuppressive regime for this normally nonlife-threatening procedure. In summary, we describe a new generation of targeted complement inhibitor with multi-functionality that includes targeting to vascular injury, P-selectin blockade, complement inhibition and anti-thrombotic activity. The constructs described also bound to both mouse and human P-selectin which may facilitate potential translation.

show abstract

Section: Discussionmentioning

confidence: 99%

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although a previous study has demonstrated an overall beneficial role of lipid-targeting natural IgM in atherosclerosis, the role of IgM in complement activation has not been determined in atherosclerosis. Whereas the C2 mAb can induce complement activation via an Fc fragment, as demonstrated in a lung transplant injury model ( 45 ), the C2scFv-Crry construct does not contain an Fc fragment and thus lacks the ability to activate complement. An area for future study will be the role of natural antibody in complement activation in driving atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…C2scFv-Crry was constructed and purified as previously described ( 45 ). The purity of C2scFv-Crry was determined by SDS-PAGE and complement inhibitory activity confirmed by zymosan assay.…”

Section: Methodsmentioning

confidence: 99%

“…The inhibitor, C2scFv-Crry, consists of single-chain variable fragment (scFv) derived from a natural IgM mAb (C2) linked to Crry, a murine inhibitor of C3 activation ( 43 ). C2scFv-Crry recognizes a subset of phospholipids exposed on injured cells post-ischemia injury ( 42 ), and it has been demonstrated that C2scFv-Crry is protective in arthritis ( 44 ) and lung transplantation ( 45 ) mouse models. Since C2scFv specifically recognizes phospholipids, which are components of oxLDL ( 46 ), we sought to determine the targeting and therapeutic effect of C2scFv-Crry in a model of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice

Dai

Liu

Ren

et al. 2021

Front. Cardiovasc. Med.

Self Cite

View full text Add to dashboard Cite

Rationale: Previous studies have indicated an important role for complement in atherosclerosis, a lipid-driven chronic inflammatory disease associated to oxidative stress in the vessel wall. However, it remains unclear how complement is activated in the process of atherogenesis. An accepted general model for complement activation in the context of ischemia reperfusion injury is that ischemia induces the exposure of neoepitopes that are recognized by natural self-reactive IgM antibodies, and that in turn activate complement.Objective: We investigated whether a similar phenomenon may be involved in the pathogenesis of atherosclerosis, and whether interfering with this activation event, together with inhibition of subsequent amplification of the cascade at the C3 activation step, can provide protection against atherogenesis.Methods and Results: We utilized C2scFv-Crry, a novel construct consisting of a single chain antibody (scFv) linked to Crry, a complement inhibitor that functions at C3 activation. The scFv moiety was derived from C2 IgM mAb that specifically recognizes phospholipid neoepitopes known to be expressed after ischemia. C2scFv-Crry targeted to the atherosclerotic plaque of Apoe−/− mice, demonstrating expression of the C2 neoepitope. C2scFv-Crry administered twice per week significantly attenuated atherosclerotic plaque in the aorta and aortic root of Apoe−/− mice fed with a high-fat diet (HFD) for either 2 or 4 months, and treatment reduced C3 deposition and membrane attack complex formation as compared to vehicle treated mice. C2scFv-Crry also inhibited the uptake of oxidized low-density-lipoprotein (oxLDL) by peritoneal macrophages, which has been shown to play a role in pathogenesis, and C2scFv-Crry-treated mice had decreased lipid content in the lesion with reduced oxLDL levels in serum compared to vehicle-treated mice. Furthermore, C2scFv-Crry reduced the deposition of endogenous total IgM in the plaque, although it did not alter serum IgM levels, further indicating a role for natural IgM in initiating complement activation.Conclusion: Neoepitope targeted complement inhibitors represent a novel therapeutic approach for atherosclerosis.

show abstract

“…Complement activation and deposition during reperfusion plays a role in IRI after acute MI, as well as in acute peripheral artery occlusion and in allografts, particularly kidney and liver (82)(83)(84). Accordingly, inhibiting complement activation has shown therapeutic benefit in animal models of each of these conditions (82)(83)(84)(85)(86)(87)(88). Clinical translation, however, has been slow and remains in preclinical and early-stage clinical trials (89)(90)(91).…”

Section: Complementmentioning

confidence: 99%

Minimizing Ischemia Reperfusion Injury in Xenotransplantation

et al. 2021

View full text Add to dashboard Cite

The recent dramatic advances in preventing “initial xenograft dysfunction” in pig-to-non-human primate heart transplantation achieved by minimizing ischemia suggests that ischemia reperfusion injury (IRI) plays an important role in cardiac xenotransplantation. Here we review the molecular, cellular, and immune mechanisms that characterize IRI and associated “primary graft dysfunction” in allotransplantation and consider how they correspond with “xeno-associated” injury mechanisms. Based on this analysis, we describe potential genetic modifications as well as novel technical strategies that may minimize IRI for heart and other organ xenografts and which could facilitate safe and effective clinical xenotransplantation.

show abstract

A novel injury site-natural antibody targeted complement inhibitor protects against lung transplant injury

Cited by 7 publications

References 37 publications

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation

Characterization of Novel P-Selectin Targeted Complement Inhibitors in Murine Models of Hindlimb Injury and Transplantation

Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice

Minimizing Ischemia Reperfusion Injury in Xenotransplantation

Contact Info

Product

Resources

About