Bispecific antibody exhibiting increased alternative fviii-cofactor-function activity
a cofactor and antibody technology, applied in the field of bispecific antibodies with enhanced can solve the problem that bypassing formulations cannot sufficiently stop bleeding, and achieve the effect of enhancing fviii cofactor function substitution activity
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example 1
Screening of Variant Antibodies for Improvement of FVIII Cofactor Function-Substituting Activity
[0401]ACE910 is a humanized IgG4 antibody showing FVIII cofactor function-substituting activity and comprising anti-FIX(a) and anti-FX domains, the antibody being composed of two types of heavy chains (Q499 and J327) which recognize FIX(a) and FX, respectively, and commonly shared L chains (L404) (heavy chain SEQ ID NOs: 45 and 46, and light chain SEQ ID NO: 47). The present inventors comprehensively introduced amino acid modifications into L404 by methods known to those skilled in the art such as PCR for introducing mutations and performed a large-scale screening of FVIII cofactor function-substituting activity, thereby discovering L-chain amino acid substitutions that improve the FVIII cofactor function-substituting activity of ACE910.
[0402]Substitution variants were produced by modifying amino acids in all of the CDRs of L404 (SEQ ID NO: 47) in the L chain of the anti-FX antibody side ...
example 2
Obtaining Novel L Chains that are Compatible with Each H Chain of ACE910
[0405]As indicated in Example 1, FVIII cofactor function-substituting activity was able to be improved by comprehensively modifying amino acids in L404, which is the commonly shared L chain of ACE910. As another method of improving the FVIII cofactor function-substituting activity of ACE910, a conceivable method is that of obtaining from human antibody libraries novel L chains having sequences completely different from that of the commonly shared L chain, which are to be paired with the respective H chains of the anti-FIX(a) antibody and the anti-FX antibody (Q499 and J327).
[0406]With reference to methods known to those skilled in the art, specifically the method of Biochemical and Biophysical Research Communications, (2000), 275, 2: 553-557 and such, the present inventors newly produced a library of antibodies in which the L chain portion of the ACE910 antibody has been substituted with that from a human L chai...
example 3
Production of Variants of the Novel L Chain-Comprising Bispecific Antibodies
[0409]To improve the FVIII cofactor function-substituting activity of novel L chain-comprising bispecific antibodies obtained in Example 2, amino acid substitution modifications were introduced into QNK131 (light chain SEQ ID NO: 13) which is a novel L chain of an anti-FIX(a) antibody, to obtain QAL187 (light chain SEQ ID NO: 42) and QAL201 (light chain SEQ ID NO: 43). Similarly, amino acid substitution modifications were introduced into JNL095 (light chain SEQ ID NO: 31) which is a novel L chain of an anti-FX antibody, to obtain JYL280 (light chain SEQ ID NO: 44). In one example, a bispecific antibody (Q499 / QAL201 / J327 / JYL280) composed of an anti-FIX(a) antibody comprising heavy chain Q499 and light chain QAL201 and an anti-FX antibody comprising heavy chain J327 and light chain JYL280 was expressed and purified by a method known to those skilled in the art, and the result of measuring its FVIII cofactor fu...
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