Mutated Fc Region Polypeptide Enhancing Receptor Binding
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Solution Overview
Problem
Current therapeutic antibodies and Fc fusion proteins face challenges in optimizing the Fc fragment's activity for enhanced effectiveness and reduced side effects, particularly in antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis.
Innovation Solution
Development of a polypeptide with a mutated Fc region incorporating specific mutations such as G316D, K326E, N315D, P396L, and others, which enhance the functional activity of the Fc region by increasing affinity for Fc receptors or modifying receptor interactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If the Fc fragment activity is optimized to enhance therapeutic effectiveness, then the functional activity (ADCC, CDC, ADCP) is improved, but the complexity of protein structure increases due to multiple mutations
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (G316D, K326E, N315D, P396L, etc.) at predetermined positions in the Fc region to modify its functional properties. These point mutations change local chemical parameters (charge, hydrophobicity, steric properties) to enhance binding affinity for Fc receptors and improve effector functions like ADCC and CDC without requiring extensive structural redesign
Solution Approach 2:
The invention implements local quality by targeting specific residues in the Fc region (such as positions 316, 326, 315, 396, 421, 402, 294, 248) with mutations that locally modify interaction properties. Each mutation is strategically placed to affect specific receptor binding interfaces or glycosylation sites, thereby enhancing functional activity at localized regions while preserving the overall Fc structure
2Strength
If multiple mutations are introduced to enhance Fc receptor binding affinity, then the binding strength is improved, but the manufacturing precision required increases
Solution Approach 1:
The patent applies preliminary action by pre-identifying and selecting specific mutation positions (G316D, K326E, N315D, P396L, etc.) based on structural and functional analysis of the Fc region. These positions are predetermined to optimize receptor binding, allowing manufacturers to directly implement the designed mutations without requiring extensive screening or optimization during production, thereby reducing the actual manufacturing complexity despite the multiple mutations
Data Source
AI summary
The present invention relates to a polypeptide comprising a mutated Fc region and exhibiting a functional activity mediated by the Fc region that has been modified compared with that of a parent polypeptide, characterized in that said Fc region comprises at least one combination of 2 mutations, wherein said combination is chosen from: (i) a mutation chosen from 326E, 326T, 352L, 378V, 378T, 396L, 397M, 421T, 334N, 334R, 307N and 394P; and (ii) at least one mutation chosen from 226Y, 227S, 230S, 231V, 234P, 2431, 243L, 246R, 246E, 247T, 248E, 253F, 254F 255W, 259A, 261R, 262A, 263A, 266M, 267N, 267G, 274E, 274R, 276S, 278H, 379A, 282A, 283G, 284L, 2861, 286Y, 287T, 288E, 288R, 290E, 298N, 302A, 305 A, 307P, 308A, 3081, 308G, 309P, 312G, 315D, 316D, 319H, 320T, 320R, 320M, 322E, 3231, 333G, 339T, 349S, 325S, 334N, 334R, 336T, 340E, 343S, 345G, 349H, 350A 352S, 359A, 361H, 362R, 3631, 366A, 373D, 375R, 377T, 378V, 378T, 380G, 383R, 385R, 389S, 389T, 392R, 393A, 3931, 394P, 396L, 3971, 397M, 398P, 405V, 405L, 410R, 412M, 414R, 421T, 423L, 423Y, 423S, 423P, 428T, 431V, 431T, 434K, 434S, 435R, 436H, 439R, 440G, 440N, 442F, 442P and 447N, the numbering being that of the EU index or equivalent in Kabat and with the condition that the mutation (i) does not take place on the same amino acid as the mutation (ii). The present invention also relates to the use of such a polypeptide, to compositions comprising same, and to methods for preparing such a polypeptide.