Low-viscosity antigen binding proteins and methods of making them

An antigen binding protein that specific for PCSK9, which comprises one or more sequence modifications selected from:

• a. a VH1|1-18 germline subfamily sequence comprising one or more substitutions selected from 82X1, 94X2, and 95X3, wherein X1 is selected from R, K and H, X2 is selected from S, T, N and Q and X3 is selected from R, K, and H;
• b. a VH3|3-33 germline subfamily sequence comprising one or more substitutions selected from 1X4, 17X5, and 85X6, wherein X4 is selected from D and E, X5 is selected from G, A, V, I, L, and M, and X6 is selected from G.A, V, I, L, and M;
• c. a VK3|L16 germline subfamily sequence comprising one or more substitutions selected from 4X10, 13X11, 76X12, 95X13, 97X14, and 98P, wherein X10 is selected from G, A, V, I, L, and M, X11 is selected from G, A, V, I, L, and M, X12 is selected from D and E, X13 is selected from R, K and H, and X14 is selected from D and E, wherein the antigen binding protein does not comprise only substitution 78F;
• d. a VK3|L6 germline subfamily sequence comprising one or more substitutions selected from 76X12 and 95X13;
• e. an Fc domain sequence comprising one or more substitutions selected from 253X15, 440X16, and 439X17, wherein X15 is selected from G, A, V, I, L, and M, X16 is selected from R, K, and H, and X17 is selected from D and E, wherein the Fc domain sequence comprises only one of 440X16 and 439X17 and wherein the antigen binding protein comprises at least one of 253X15 or modifications selected from subparagraphs a, b, c, d and f when X16 is K or X17 is E and the antigen binding protein specifically binds CD20;
• and
• f. an Fc domain sequence comprising X18X19 at its C-terminus wherein X18 is one to four amino acids selected from D and E or from H, K, and R, and X19 is selected from P, M, G, A, V, I, L, S, T, N, Q, F, Y and W and is absent when X18 comprises D or E, is present when X18 comprises K or R at its C-terminal end, and is present or absent when X18 comprises H at its C-terminal end, and wherein the antigen binding protein comprises at least one of 253X15 or substitutions selected from subparagraphs a through e when PGKP, PGKKP, PGKKKP, or PGE appears at the C-terminus of the Fc domain and the antigen binding protein specifically binds CD20 or CD38;
• wherein the amino acids in subparagraphs a, b, c, and d are numbered according to the Aho numbering system and the amino acids in subparagraph e are numbered according to the EU numbering system.

An antigen binding protein that specifically binds PCSK9 comprising the heavy and light chain sequences of a PCSK-9 binding polypeptide except that said antigen binding protein comprises a set of substitutions selected from FIG. 10:

• a. T82R, R94S, and S95R in the heavy chain,
• b. S59K, T82R, R94S, and S95R in the heavy chain,
• c. T82R, R94S, and S95R in the heavy chain and G13L in the light chain, and
• d. S59K, T82R, R94S, and S95R in the heavy chain and G13L in the light chain;
• wherein the amino acids are numbered according to the Aho numbering system.