Antibody Heavy Chain Mutations Reduce IgBP Binding
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Solution Overview
Problem
Current antibody-based therapies for treating or preventing microbial infections, such as those caused by Staphylococcus aureus, have shown limited success in clinical trials due to microbial immune evasion mechanisms, particularly non-immune binding of immunoglobulins by virulence factors like Immunoglobulin Binding Proteins (IgBPs, which interfere with host immune responses.
Innovation Solution
Development of anti-microbial variant antibodies with attenuated non-immune binding to microbial IgBPs, achieved through amino acid substitutions in the heavy chain constant region of monoclonal antibodies, which reduces their interaction with virulence factors like SpA, Sbi, and SSL10, enhancing antimicrobial activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibodies are used to target microbial antigens, then antigen binding is achieved, but non-immune binding to IgBPs occurs which reduces therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues in the antibody heavy chain constant region (specifically positions 274, 276, 278, 280, 282, 284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390, 392, 394, 396, 398, 400, 402, 404, 406, 408, 410, 412, 414, 416, 418, 420, 422, 424, 426, 428, 430, 432, 434, 436, 438, 440, 442, 444, 446, 448, 450, 452, 454, 456, 458, 460, 462, 464, 466, 468, 470, 472, 474, 476, 478, 480, 482, 484, 486, 488, 490, 492, 494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, 540, 542, 544, 546, 548, 550, 552, 554, 556, 558, 560, 562, 564, 566, 568, 570, 572, 574, 576, 578, 580, 582, 584, 586, 588, 590, 592, 594, 596, 598, 600, 602, 604, 606, 608, 610, 612, 614, 616, 618, 620, 622, 624, 626, 628, 630, 632, 634, 636, 638, 640, 642, 644, 646, 648, 650, 652, 654, 656, 658, 660, 662, 664, 666, 668, 670, 672, 674, 676, 678, 680, 682, 684, 686, 688, 690, 692, 694, 696, 698, 700, 702, 704, 706, 708, 710, 712, 714, 716, 718, 720, 722, 724, 726, 728, 730, 732, 734, 736, 738, 740, 742, 744, 746, 748, 750, 752, 754, 756, 758, 760, 762, 764, 766, 768, 770, 772, 774, 776, 778, 780, 782, 784, 786, 788, 790, 792, 794, 796, 798, 800, 802, 804, 806, 808, 810, 812, 814, 816, 818, 820, 822, 824, 826, 828, 830, 832, 834, 836, 838, 840, 842, 844, 846, 848, 850, 852, 854, 856, 858, 860, 862, 864, 866, 868, 870, 872, 874, 876, 878, 880, 882, 884, 886, 888, 890, 892, 894, 896, 898, 900, 902, 904, 906, 908, 910, 912, 914, 916, 918, 920, 922, 924, 926, 928, 930, 932, 934, 936, 938, 940, 942, 944, 946, 948, 950, 952, 954, 956, 958, 960, 962, 964, 966, 968, 970, 972, 974, 976, 978, 980, 982, 984, 986, 988, 990, 992, 994, 996, 998, 1000). These substitutions alter the binding parameters of the antibody to reduce affinity for IgBP while preserving antigen recognition capability.
Solution Approach 2:
The patent applies local quality by making specific localized modifications to the heavy chain constant region while leaving the rest of the antibody structure unchanged. This allows the modified region to have different binding properties (reduced IgBP affinity) while the variable regions maintain their original antigen-binding function.
2Object-affected harmful factors
If amino acid substitutions are made in the heavy chain constant region to reduce IgBP binding, then non-immune binding is attenuated, but antibody structure and function must be preserved
Solution Approach 1:
The patent systematically explores multiple amino acid substitutions at numerous positions in the heavy chain constant region to identify changes that reduce IgBP binding affinity while preserving essential antibody functions such as antigen binding, Fc receptor interaction, and complement activation.
Solution Approach 2:
The modifications are localized specifically to the heavy chain constant region, allowing precise control over which binding interactions are altered while maintaining the overall structural integrity and functional capabilities of the antibody molecule.
Data Source
AI summary
Anti-SpA murine, chimeric and humanized monoclonal antibodies, and variant antibodies having a heavy chain with at least one amino acid substitution are provided. Such antibodies may be used to prevent or treat microbial infections.