COMPLEMENT THERAPY

Introduction

v  The complement system is a part of the immune system that helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism.

v  Consist of more than 30 protein present in human serum →  synthesize mainly in liver    

v  Complement was identified in the late 1800s as a heat-labile, bactericidal component in serum by Bordet whereas the word “complement” was introduced by Paul Ehrlich.

v  Important component of innate host defense, however, it can be recruited and brought into action by the adaptive immune system.

Functions

The following are the basic functions of complement:

v  Opsonization. 

v  Activation of Inflammatory Response.

v  Cell Lysis.

v  Clearance of Immune Complex.

Activation of complement occurs via one of these three pathways:

v  Classical pathway---- activated by Ag/Ab complex.

v  Alternative pathway--- triggered when the C3b protein directly binds the microbe.

v  Lectin pathway--- starts with mannose binding lectins.

The complement system off balance

v  An imbalance in complement, either by insufficient or excessive complement activity, can have important pathological consequences.

v  Antibody-based treatments can be employed to restore the balance in the complement network in order to achieve therapeutic effects.

v  Complement inhibition can be beneficial in pathologies where the system is hyper activate

E.g. sepsis, trans-plant rejection, ischemia and reperfusion (I/R) injury.

v   Antibody-mediated activation of complement, in contrast, can be a valuable approach in the treatment of infectious diseases and cancer.

Antibody mediated complement inhibition

Autoimmune and inflammatory disease

v  Increased complement activation play an important role in autoimmune disorders because of the change in function of complement or dysregulation of CRP’s that leads to chronic infection or tissue damage.

v  AHUS and PNH.

v  Anti-c5 antibody Eculizamb.

Age-related Degenerative Diseases

Age-related Macular Degeneration (AMD):

v  Vision loss results from a gradual deterioration of light-sensing cells due to chronic low-grade complement activation resulting in inflammation.

v  In this association of complement and AMD ,many factors are involved like complement Factor H, C2, C3, C7, Factor B, Factor D, Factor I, CFHR1/CFHR3.

v  Lead to different therapeutic approaches which includes:

·         Anti-Factor D antibody lampalizumab

·         Systemic eculizumab

·         Other complement inhibiting antibodies for AMD are administered as direct intravitreal injections to achieve adequate drug levels in the retina.

v  These trials will indicate whether local complement inhibition is a feasible therapeutic approach in late stage AMD.

Clinical Complications of Allo-Transplantation Include

Graft-versus-host disease (GvHD):

v  Mediated by donor T-cells that attack host cells, leading to epithelial tissue injury in skin, intestine, and liver.

Complement Therapy:

v  Complement plays an important role in such ischemic tissue infarction by anaphylatoxin-mediated immune responses and through MAC-directed lysis of parenchymal cells. It is believed that both the classical and the lectin pathways are part of the injurious processes upon I/R.

1. Combination therapies.

v  Targeting multiple proteins by the use of antibody cocktails or bispecific antibodies is a promising strategy to dampen or recruit complement and to counter immune evasion molecules on pathogens and on cancer cells.

v  The interaction between various animal toxins and the human complement system and its inhibition may provide leads for potential therapeutic intervention.

v  Therapies based on the combination of two existing antibodies have progressed up to approval for human use e.g. trastuzumab and pertuzumab.

v  Bispecific IgG antibodies that combine two distinct antibody binding sites, offering the ability to address two distinct targets with a single antibody.

v  Combination therapies, by dual or multispecific targeting approaches, may allow the combined inhibition of complement activation pathways to treat complex pathologies, such as discussed for sepsis.

v   These approaches may be employed to maximize the effects of complement activation, such as aimed for in therapies for infectious disease or cancer.

v  Combination therapies of complement activating antibodies with antibodies that inhibit the activity of host or pathogen.

CONCLUSION

v  Complement is recognized as a key player in a wide range of normal as well as disease-related immune, developmental and homeostatic processes.

v  Knowledge of complement components, structures, interactions leads to novel treatments for cancer, infectious, autoimmune- or age-related diseases as well as for preventing transplantation rejection. 

v  Complement is recognized as a key player in a wide range of normal as well as disease-related immune, developmental and homeostatic processes.

v  Knowledge of complement components, structures, interactions leads to novel treatments for cancer, infectious, autoimmune- or age-related diseases as well as for preventing transplantation rejection.