monoclonal antibodies used as add-on therapy to Inhaled corticosteroids /LABAs in treatment of eosinophilic phenotype asthma

1. IMMUNE MODULATORY THERAPY
IN ASTHMA MANAGEMENT
GROUP 6
GLADYS J MWENDE BPHARM/2019/55345
MAKOKHA M SAMMY BPHARM/2019/55449
ELIZABETH OWITI BPHARM/2019/58674
DAVID S SASAKA BPHARM/2018/35465
REBECCA K SOI BPHARM/2019/55810
BPL 4101 RESPIRATORY AND CARDIOVASCULAR
PHARMACOLGY 4TH YEAR (1st SEM) BPHARM (MKU)

2. INTRODUCTION
ICS/B2 agonist combined therapy doesn’t prevent
disease progression /remodeling.
Are ineffective in 30-35% of patients
There's need for individualized precision therapy
as add-on to reduce dose, toxicities of ICS
mAbs exacerbations/ improve respiration function

3. ASTHMA PATHOPHYSIOLOGY

4. Allergen Dendritic (APC) Activated MHC II on APC
IL-4/IL-5 Th2 R APC-MHC II-Allergen complex
IL-4 Plasma cells B cell IgE Mast (Fc) Hist/LTC4/D4
( causes airway narrowing, mucus and fluid secretion)
IL-5 WBCs Eosinophils LTS/Proteases
(remodeling)

5. IMMUNOMODULATORY THERAPY
Treat chronic eosinophilic asthma that otherwise
require high dose(ICS/LABA) .Biologics reduce
Exacerbations ,improve respiratory function (> 10% FEV1)
GINA Guideline recommend use in step5 RX Type 2
asthma as add-on medicament to reduce ICS/LABA
Biologics offer individualized precision therapy

6. IMMUNOMODULATORY PHARMACOTHERAPY
mAbs – Monoclonal Antibody
•mAbs targeting IgE – Omalizumab
•mAbs targeting Th2 pathway IL-4/5 Mepolizumab
and Reslizumab
•mAbs targeting IL-4/3 Receptors - Dupilumab
•mAbs targeting IL-5 Receptor Benralizumab
• IL-5/4 synthesis inhibitors – Suplatast

7. ANTI-IgE mAbs – Omalizumab (Xolair)

8. Omalizumab 150-375mg admin SC over
30secs in deltoid region every 2-4wks
approved in 2005 for chronic asthma
In children >6ys and adults who don’t
Adequately respond to high doses ICS/LABAs
With +ve skin prick test or blood

9. For specific allergen, Xolair binds tightly
to IgE portion recognizing its receptor on
mast cells, basophils and monocytes
Omalizumab-IgE complex formed has no
affinity for Fc receptors.

10. xolair binds to circulating IgE decreasing;
Cell bound IgE, expression of high
affinity receptors, synthesis/release of mediators
Of inflammation, tissue infiltration and allergic
Inflammation, symptoms and asthma exacerbations
free IgE levels , expression of high affinity receptor

11. mAbs TARGETING Th2 PATHWAY CYTOKINES
ANTI-IL-5 mAbs
RESLIZUMAB (Cinqair) IV infusion once 4weekly
in 18yrs or more as add-on eosinophilic phenotype
asthma ,half-life of 24 days.
Binds alpha chain of IL-5R tightly on eosinophil
Surface inhibiting IL-5 bioactivity and signaling

12. IL-5 blockage reduces eosinophils production,
survival and Eos driven inflammation.
MEPOLIZUMAB (Nucala)
Binds tightly to IL-5R on Eosinophil surface
Inhibiting Eos proliferation reducing mean
Eosinophil count by 92% after 52wks Rx.

13. Admin SC 100mg with 80% bioavailability
With half life of 16-22 days allowing
4wks dosing schedule.

15. mAbs TARGETING IL-5 RECEPTOR
IL-5 Receptor ANTAGONIST
BENRALIZUMAB (12yrs and older)
Binds to IL-5R Inhibiting activation and
proliferation of eosinophils
inhibits B cells proliferation and activates
eosinophils apoptosis through Antibody-
dependent cell cytotoxicity (ADCC)
Has half life of 15-18 days.

16. IL-4 RECEPTOR ANTAGONIST
DUPILUMAB (Dupixent)
Recombinant human IgG4 mAbs that inhibits
1L-4 activation, reduces levels of type 2
inflammatory biomarkers IgE, Allergen specific
IgE, FENO. exacerbations & improves resp.
function. Inhibits IL-4/13 signaling down-
regulating type 2 activity .

17. HUMANISED MONOCLONAL IgG
DACLIZUMAB (ZENAPAX)
Increases pulmonary function (10% improvement)
In FEV1 values.
Results in two-thirds reduction in number
Of exacerbations in patients Rx with it
Versus placebo. Still in clinical trial for
Route of administration.

18. IL-4 & IL-5 SYNTHESIS INHIBITORS
SUPLATAST TOSILATE (PER ORAL)
Inhibits synthesis of IL-4/5,clinica trials
Indicates reduction in IgE and peripheral
Blood eosinophil counts, reduces also airway
Inflammation. Poses compliance challenge as
Its taken three times a day.

19. SUMMARY
mAbs show promising preclinical trials results,
but haven't shown significant benefits in human
trials indicating disparity between murine models
and human asthma. some are effective
to small sub-population of patients making
them commercially unviable.
.

20. search for better therapeutics is focused
on symptoms and improving quality of
life while preventing/altering disease course.
mAbs should have a favorable risk
benefit ratio, affordable leading to a
wider use.

21. REFERENCES
1. Laurence .L. Brunton. Ranal. Hilal-Dandan (2018). Goodman &
Gilman’s: The Pharmacological Basis of Therapeutics (13th .ed.)
‘pulmonary pharmacology’ (pg-733) Mc Graw Hill Education.
2. Bertram G. Katzung. Susan B. Masters. (2012). Basic and
Clinical Pharmacology (12th .ed.) ‘Drugs used in Asthma’ (pg-
355) Mc Graw Hill Company
3. K D. Tripathi (2019). Essentials of Medical Pharmacology (8th
.ed.) ‘Cardiac Glycosides and Drugs for Bronchial Asthma’ (pg-
258). Jaypee Brothers Medical Publishers.(P) Limited.
4. DR. Antony Yiaile (2022) ‘Pharmacology Of
Immunomodulatory Therapy in Asthma’ (class lecture notes
MKU University)