Humanized and stabilized fc5 variants for enhancement of blood brain barrier transport
AssigneesBiogen MA Inc., National Research Council of Canada
InventorsBenjamin A. Smith, Andreas Lehmann, Thomas O. Cameron, R. Blake Pepinsky, Dingyi Wen, Graham K. Farrington, Gopalan Raghunathan, Nels E. Pederson, Danica Stanimirovic, Traian Sulea, Arsalan S. Haqqani
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Abstract
Featured are compositions comprising humanized and engineered variants of an antibody variable domain (e.g., FC5), chimeric molecules comprising same, compositions comprising same, and uses thereof.
Claims53
An antibody variable domain that transmigrates across the blood brain barrier, wherein the antibody variable domain comprises an amino acid sequence that is at least 85% identical to the sequence set forth in SEQ ID NO:1, wherein the amino acid sequence comprises:
- (a) complementarity determining region (CDR)1, CDR2, and CDR3, wherein CDR2 comprises the sequence set forth in SEQ ID NO:50, and wherein:
- (i) CDR1 comprises the sequence set forth in SEQ ID NO:47, CDR3 comprises the sequence set forth in SEQ ID NO:51, and the amino acid sequence comprises cysteines at the positions corresponding to positions 49 and 70 of SEQ ID NO:1;
- (ii) CDR1 comprises the sequence set forth in SEQ ID NO:48, CDR3 comprises the sequence set forth in SEQ ID NO:51, and the amino acid sequence comprises cysteine at the position corresponding to position 79 of SEQ ID NO:1;
- (iii) CDR1 comprises the sequence set forth in SEQ ID NO:49, and CDR3 comprises the sequence set forth in SEQ ID NO:52;
- (iv) CDR1 comprises the sequence set forth in SEQ ID NO:58, and CDR3 comprises the sequence set forth in SEQ ID NO:52;
- (v) CDR1 comprises the sequence set forth in SEQ ID NO:49, and CDR3 comprises the sequence set forth in SEQ ID NO:53;
- (vi) CDR1 comprises the sequence set forth in SEQ ID NO:58, and CDR3 comprises the sequence set forth in SEQ ID NO:53;
- (vii) CDR1 comprises the sequence set forth in SEQ ID NO:49, and CDR3 comprises the sequence set forth in SEQ ID NO:54;
- (viii) CDR1 comprises the sequence set forth in SEQ ID NO:58, and CDR3 comprises the sequence set forth in SEQ ID NO:54;
- (ix) CDR1 comprises the sequence set forth in SEQ ID NO:49, and CDR3 comprises the sequence set forth in SEQ ID NO:55;
- or
- (x) CDR1 comprises the sequence set forth in SEQ ID NO:58, and CDR3 comprises the sequence set forth in SEQ ID NO:55;
- or
- (b) (i) amino acid substitutions, as compared to SEQ ID NO:1, at one or more of the positions corresponding to positions 5, 6, 14, 75, 87, 88, 93, 114, and 117 of the sequence set forth in SEQ ID NO:1;
- and (ii) CDR1 comprising the sequence set forth in SEQ ID NO:47 or 57, CDR2 comprising the sequence set forth in SEQ ID NO:50, and CDR3 comprising the sequence set forth in SEQ ID NO:51.
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A method of assessing the lability of an antibody variable domain, the method comprising
- providing an antibody variable domain;
- adding the antibody variable domain to a serum sample to create a mixture;
- incubating the mixture;
- purifying the antibody variable domain;
- and
- performing peptide mapping.
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A method of screening for a stabilized form of FCS, the method comprising:
- providing an antibody variable domain comprising a FC5 variant that differs from SEQ ID NO:1 at one or more amino acids;
- adding the antibody variable domain to a serum sample to create a mixture;
- incubating the mixture;
- purifying the antibody variable domain;
- performing peptide mapping;
- and
- selecting an antibody variable domain that exhibits increased peptide recovery.
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Dependencies are inferred from the claim text.