Variant Immunoglobulins with Improved Manufacturability
AssigneeLonza Biologics PLC
InventorsAndreas Arnell, Jose Jimenez, Rebecca Michael, Yvette Stallwood, Jesus Zurdo
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Abstract
This invention relates to the modification of the amino acid sequence of an immunoglobulin molecule at certain key positions within regions of the VH and VL FR and CDR3 domains and/or the CH1 domain which are prone to aggregation. Immunoglobulins modified as described may display improved manufacturability, for example, reduced aggregation propensity and/or increased production levels.
Claims58
A method of improving the manufacturability of an immunoglobulin, comprising;
- identifying a parent immunoglobulin having a VL domain and a VH domain,
- introducing a substitution into a framework aggregation-prone segment and/or a CDR3 aggregation-prone segment in the VL domain of the parent immunoglobulin, and/or
- introducing a substitution into a framework region aggregation-prone segment and/or a CDR3 aggregation-prone segment in the VH domain of the parent immunoglobulin, and/or;
- introducing a substitution into a constant region aggregation-prone segment in the CH1 domain of the parent immunoglobulin,
- thereby producing a variant immunoglobulin having a VL domain and a VH domain which displays improved manufacturability relative to the parent immunoglobulin.
A variant immunoglobulin comprising;
- a light chain variable (VL) domain which comprises a substitution at framework (FR) aggregation-prone segment and/or a complementary determining region 3 (CDR3) aggregation-prone segment;
- a heavy chain variable (VH) domain which comprises a substitution at a framework region aggregation-prone segment and/or a CDR3 aggregation-prone segment;
- and/or,
- a heavy chain constant region 1 (CH1) domain which comprises a substitution at a CH1 aggregation-prone segment.
A variant immunoglobulin or a method according to any one of the preceding claims wherein the variant immunoglobulin is humanised.
A variant immunoglobulin or a method according to any one of the preceding claims wherein the variant immunoglobulin is expressed in a recombinant system.
A variant immunoglobulin or a method according to any one of the preceding claims wherein the variant immunoglobulin is isolated and/or purified following expression.
A variant immunoglobulin or a method according to any one of the preceding claims wherein the variant immunoglobulin is formulated with a pharmaceutically acceptable excipient.
A method of assessing the manufacturability of an immunoglobulin comprising;
- identifying the amino acid residue at one or more positions selected from the group consisting of positions 37, 45 and 46 in the VL domain of the immunoglobulin, positions 1, 17, 94, 95, 96, 100, 100d and 102, in the VH domain,
- wherein the presence of a residue other than Q at position 37;
- E, K, R, Q or V, preferably K or R, at position 45, L or Y, preferably L, at position 46, in the VL domain of the immunoglobulin and/or;
- the presence of a residue other than A, D, E, Q or V at position 1, R at position 17, Rat position 94, A at position 96, F, G, L, M or P, preferably F or M at position 100d, A, F, H, I, L, V or Y, preferably V or Y, at position 102, in the VH domain of the immunoglobulin,
- is indicative that the manufacturability of the immunoglobulin are sub-optimal.
Dependencies are inferred from the claim text.