Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity.
Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Nathaniel
N
Washburn
Institute of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
Inessa
I
Schwab
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Daniel
D
Ortiz
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Naveen
N
Bhatnagar
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Jonathan C
JC
Lansing
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Amy
A
Medeiros
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Steven
S
Tyler
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Divya
D
Mekala
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Edward
E
Cochran
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Hetal
H
Sarvaiya
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Kevin
K
Garofalo
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Robin
R
Meccariello
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
James W
JW
Meador
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Laura
L
Rutitzky
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Birgit C
BC
Schultes
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Leona
L
Ling
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
William
W
Avery
Institute of Genetics, Department of Biology, University of Erlangen-Nürnberg, 91058 Erlangen, Germany.
Falk
F
Nimmerjahn
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Anthony M
AM
Manning
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and.
Ganesh V
GV
Kaundinya
Research Department, Momenta Pharmaceuticals, Cambridge, MA 02142; and cbosques@momentapharma.com.
Carlos J
CJ
Bosques
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001768:Blister / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D015195:Drug Design; D016107:Epidermolysis Bullosa Acquisita / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D016756:Immunoglobulins, Intravenous / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy / Q000473:pathology; D011961:Receptors, Fc / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D007140:Immunoglobulin Fab Fragments; D016756:Immunoglobulins, Intravenous; D011961:Receptors, Fc; D019158:N-Acetylneuraminic Acid
IVIg; antibody; autoimmune disease; inflammation; sialylation