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Inhibition of plasma kallikrein by a highly specific active site blocking antibody.

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Kenniston JA, Faucette RR, Martik D, Comeau SR, Lindberg AP, Kopacz KJ, Conley GP, Chen J, Viswanathan M, Kastrapeli N, Cosic J, Mason S, DiLeo M, Abendroth J, Kuzmic P, Ladner RC, Edwards TE, TenHoor C, Adelman BA, Nixon AE, Sexton DJ
OpenAccess logo J Biol Chem 289 23596-608 (2014)
Related entries: 4ogx, 4ogy

Cited: 73 times
EuropePMC logo PMID: 24970892

Abstract

Plasma kallikrein (pKal) proteolytically cleaves high molecular weight kininogen to generate the potent vasodilator and the pro-inflammatory peptide, bradykinin. pKal activity is tightly regulated in healthy individuals by the serpin C1-inhibitor, but individuals with hereditary angioedema (HAE) are deficient in C1-inhibitor and consequently exhibit excessive bradykinin generation that in turn causes debilitating and potentially fatal swelling attacks. To develop a potential therapeutic agent for HAE and other pKal-mediated disorders, we used phage display to discover a fully human IgG1 monoclonal antibody (DX-2930) against pKal. In vitro experiments demonstrated that DX-2930 potently inhibits active pKal (Ki = 0.120 ± 0.005 nM) but does not target either the zymogen (prekallikrein) or any other serine protease tested. These findings are supported by a 2.1-Å resolution crystal structure of pKal complexed to a DX-2930 Fab construct, which establishes that the pKal active site is fully occluded by the antibody. DX-2930 injected subcutaneously into cynomolgus monkeys exhibited a long half-life (t½ ∼ 12.5 days) and blocked high molecular weight kininogen proteolysis in activated plasma in a dose- and time-dependent manner. Furthermore, subcutaneous DX-2930 reduced carrageenan-induced paw edema in rats. A potent and long acting inhibitor of pKal activity could be an effective treatment option for pKal-mediated diseases, such as HAE.

Articles - 4pub mentioned but not cited (2)

  1. Inhibition of plasma kallikrein by a highly specific active site blocking antibody. Kenniston JA, Faucette RR, Martik D, Comeau SR, Lindberg AP, Kopacz KJ, Conley GP, Chen J, Viswanathan M, Kastrapeli N, Cosic J, Mason S, DiLeo M, Abendroth J, Kuzmic P, Ladner RC, Edwards TE, TenHoor C, Adelman BA, Nixon AE, Sexton DJ, Sexton DJ. J Biol Chem 289 23596-23608 (2014)
  2. Structural insights into antigen recognition of an anti-β-(1,6)-β-(1,3)-D-glucan antibody. Sung KH, Josewski J, Dübel S, Blankenfeldt W, Rau U. Sci Rep 8 13652 (2018)


Reviews citing this publication (24)

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Articles citing this publication (47)

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  4. Factor XI Deficiency Alters the Cytokine Response and Activation of Contact Proteases during Polymicrobial Sepsis in Mice. Bane CE, Ivanov I, Matafonov A, Boyd KL, Cheng Q, Sherwood ER, Tucker EI, Smiley ST, McCarty OJ, Gruber A, Gailani D. PLoS One 11 e0152968 (2016)
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  9. Lanadelumab demonstrates rapid and sustained prevention of hereditary angioedema attacks. Riedl MA, Maurer M, Bernstein JA, Banerji A, Longhurst HJ, Li HH, Lu P, Hao J, Juethner S, Lumry WR, HELP Investigators. Allergy 75 2879-2887 (2020)
  10. Long-term prevention of hereditary angioedema attacks with lanadelumab: The HELP OLE Study. Banerji A, Bernstein JA, Johnston DT, Lumry WR, Magerl M, Maurer M, Martinez-Saguer I, Zanichelli A, Hao J, Inhaber N, Yu M, Riedl MA, HELP OLE Investigators. Allergy 77 979-990 (2022)
  11. An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension. Riedl MA, Bernstein JA, Craig T, Banerji A, Magerl M, Cicardi M, Longhurst HJ, Shennak MM, Yang WH, Schranz J, Baptista J, Busse PJ. Clin Transl Allergy 7 36 (2017)
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  28. Protease Inhibition Mechanism of Camelid-like Synthetic Human Antibodies. Nam DH, Lee KB, Kruchowy E, Pham H, Ge X. Biochemistry 59 3802-3812 (2020)
  29. Simple Approach to Accurately Predict Pharmacokinetics of Therapeutic Monoclonal Antibodies after Subcutaneous Injection in Humans. Haraya K, Tachibana T. Clin Pharmacokinet 60 111-120 (2021)
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  31. Bradykinin 1 Receptor Antagonist BI1026706 Does Not Reduce Central Retinal Thickness in Center-Involved Diabetic Macular Edema. Lang GE, Tadayoni R, Tang W, Barth C, Weiss-Haljiti C, Chong V, BI 1026706 Study Group. Transl Vis Sci Technol 9 25 (2020)
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  33. Structural Basis for Activity and Specificity of an Anticoagulant Anti-FXIa Monoclonal Antibody and a Reversal Agent. Ely LK, Lolicato M, David T, Lowe K, Kim YC, Samuel D, Bessette P, Garcia JL, Mikita T, Minor DL, Coughlin SR. Structure 26 187-198.e4 (2018)
  34. C1 inhibitor and prolylcarboxypeptidase modulate prekallikrein activation on endothelial cells. Merkulova AA, Abdalian S, Silbak S, Pinheiro A, Schmaier AH. J Allergy Clin Immunol 152 961-971.e7 (2023)
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  36. Generation of highly selective monoclonal antibodies inhibiting a recalcitrant protease using decoy designs. Lee KB, Dunn ZS, Lopez T, Mustafa Z, Ge X. Biotechnol Bioeng 117 3664-3676 (2020)
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