Sutimlimab is an IgG4 antibody.

Blocking C1, the most upstream component of the classical pathway, is more promising in preventing samples from patients with cold agglutinin disease from inducing complement deposition on human erythrocytes

Cold agglutinins agglutinate erythrocytes and fix C1, triggering the classical complement cascade and leading to C3 split product opsonization of the red blood cell.

Upstream inhibition of the classical complement cascade is an effective treatment for patients with cold agglutinin disease.

In a trial using sutimlimab patients receiving a test dose of 10-mg/kg followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg.: Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL.

Seven of 10 patients with cold agglutinin disease responded to the anti-C1s antibody with a median 4-g/dL increase in hemoglobin levels.

All infusions were well tolerated without premedication.

No drug-related serious adverse events were observed.

Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL within 6 weeks.

Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week.

Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab.

Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia.

All 6 previously transfused patients became transfusion-free during treatment.

Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement–mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions.

The ensuing activation of the classical pathway of complement leads C1 esterase to activate C2 and C4, generating the C3 convertase, which cleaves C3 to C3a and C3b that opsonizes erythrocytes.

These are subsequently phagocytosed by the liver.

This extravascular hemolysis is considered to be the predominant mechanism of erythrocyte destruction in patients with cold agglutinin disease.

Intravascular hemolysis can occur by the cleavage of complement component 5 (C5) and formation of the membrane attack complex in some patients..

Cleavage of complement component 5 (C5) is largely curtailed by the presence of complement regulatory proteins CD55 and CD59 on the erythrocyte surface.

The C5 inhibitor eculizumab is associated with a limited hemoglobin increase (<1 g/dL) after treatment emphasizes the need to target upstream in the classical pathway to prevent complement opsonization in patients with cold agglutinin disease.

Complement-opsonized erythrocytes travel to the liver where they undergo phagocytosis, resulting in extravascular hemolysis.

Complement-mediated intravascular hemolysis can occur, which requires C5 cleavage and formation of the membrane attack complex, but it is generally prevented by complement regulatory proteins on the erythrocyte surface (CD55 and CD59).

C1 blockade prevents both extravascular and intravascular hemolysis.

Primary cold agglutinin disease is associated with a low-grade clonal B-cell lymphoproliferative disorder.

Secondary forms, ref2242ed to as secondary cold agglutinin syndrome, result from an underlying condition such as aggressive lymphoma in adults or Mycoplasma pneumoniae or Epstein-Barr virus infections.

Hemoglobin levels average hemoglobin range from 8.2 to 10.2 g/dL at presentation and 45% of patients have severe anemia with levels less than 8 g/dL.

Anemia can be life-threatening.

Can be complicated by thromboembolic events.

No drugs have been approved for the treatment of cold agglutinin disease (2019).

Corticosteroids are generally ineffective.

Corticosteroids dosage is unacceptably high in responding patients to maintain clinical benefit.

Rituximab depletes B cells and induces mainly partial responses in approximately one-half of patients after an average delay of 1.5 months, and relapses frequently occur within 1 year.

Rituximab with cytostatic agents increases the response rates and duration of responses, but they are often accompanied by severe toxicity.

Secondary cases of cold agglutinin disease may respond to antilymphoma therapy.

Transfusion clinical benefit may be fleeting owing to cold agglutinin–mediated complement attack on the donor erythrocytes in the circulation of the patient.

The use of chronic transfusions may be complicated by alloimmunization and iron overload.

In addition to blockade of C1s activity, the mechanism of action of sutimlimab also involves removal of C1s from the circulation.

In a study of 24 patients with cold agglutinin disease two received  sutimliab, upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue (Roth, A).

Sutimlimab significantly reduced total serum complement activity measured by CH50 from a median of 52% at baseline to 22%.

Circulating C3d-positive erythrocytes decreased from 40% to a nadir of 21% 5 weeks after the first dose.

Sutimlimab infusion reduces plasma levels of complement C1s, gradually reduces the percentage of C3d-positive (C3d+) erythrocytes, and increases plasma C4 concentrations, normalizes bilirubin levels and increases hemoglobin levels.

Sutimlimab infusions decreased median bilirubin levels by 61%, normalizing in most patients within 24 hours of the first infusion.

Sutimlimab did not change agglutination of erythrocytes on blood smears or symptoms of acrocyanosis.

Blockade of C1s by the mAb sutimlimab rapidly halted hemolysis, corrected anemia, and precluded the need for transfusions in patients with cold agglutinin disease.

Extravascular hemolysis was inhibited by sutimlimab as reflected by a normalization of bilirubin levels within 24 hours of treatment and recurred upon drug washout.

The inhibition of the classical complement pathway by sutimlimab stops extravascular-mediated hemolysis in patients with cold agglutinin disease.

Sutimlimab does not affect cold agglutinin titers or prevent their binding to erythrocytes.

The anemia in cold agglutinin disease is driven predominantly by the classical complement pathway and upstream C3 opsonin–mediated phagocytosis of erythrocytes.

It further highlights the critical need to block complement activation upstream of C5

To correct the anemia there is a need to block complement activation upstream of C5

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