Anti-PD1 Antibody CDR Optimization for Specific Binding
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Solution Overview
Problem
Existing anti-PD1 antibodies for cancer treatment have suboptimal specificity and affinity due to limitations in their development systems.
Innovation Solution
Development of anti-PD1 antibodies utilizing natural affinity maturation processes to enhance specificity and binding affinity, featuring specific heavy and light chain complementarity determining regions (CDRs) with defined amino acid sequences or conservative substitutions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anti-PD1 antibodies are used for cancer treatment, then therapeutic function is provided, but specificity and affinity are suboptimal
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequences of complementarity-determining regions (CDRs) in the antibody variable regions. Specific substitutions in VH CDRs (e.g., positions 32, 38, 52, 56, 98, 100, 102, 104, 106, 108, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260, 262, 264, 266, 268, 270, 272, 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) and VL CDRs improve both specificity and binding affinity simultaneously. This direct sequence optimization approach resolves the contradiction by changing the fundamental parameters of the antibody structure to achieve superior performance in both measured aspects.
2Reliability
If existing anti-PD1 antibodies are used, then cancer treatment is enabled, but cross-reactivity with related proteins occurs
Solution Approach 1:
The patent applies local quality by making specific amino acid substitutions in the CDR regions of the antibody variable domains. These localized changes in the binding interface (VH CDRs and VL CDRs) enhance specificity for PD1 while reducing cross-reactivity with related proteins such as CTLA-4 and PD-L1. The substitutions are concentrated in the complementarity-determining regions that directly contact the antigen, allowing precise control of binding selectivity without affecting the overall antibody structure.
3Reliability
If natural affinity maturation processes are utilized, then binding affinity and specificity are improved, but development complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-selecting parent antibodies with appropriate binding characteristics before undergoing affinity maturation. The process begins with established anti-PD1 antibodies (such as 17D8, 319-8-2, 319-9-x, 397-27-x) that already possess baseline binding activity, and then applies targeted mutagenesis and selection procedures to enhance affinity and specificity. This preliminary selection step reduces the complexity of the overall development process by starting from a known functional baseline rather than de novo antibody generation.
Data Source
AI summary
Described herein are novel anti-PD1 antibody reagents (e.g., antibodies, antigen-binding fragments thereof, and/or chimeric antigen receptors). Also described herein antibody-drug conjugates or kits comprising the disclosed antibody reagents, as well as methods of treating cancer by administering the disclosed antibody reagents.