Humanized BCMA-CAR-T Cells for Low-Immunogenic Myeloma Targeting
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Solution Overview
Problem
Current therapies for multiple myeloma, such as monoclonal antibodies and CAR-T cell therapies targeting BCMA, face challenges in specificity and immunogenicity, limiting their effectiveness in treating BCMA-positive cancer cells.
Innovation Solution
Development of humanized BCMA antibodies and BCMA-CAR-T cells with specific co-stimulatory domains, such as CD28 and 4-1BB, to enhance cytolytic activity and persistence, thereby targeting BCMA-positive cancer cells with high specificity and reduced immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mouse monoclonal antibodies or non-humanized CAR-T cells are used to target BCMA, then cytotoxic activity against multiple myeloma cells is achieved, but immunogenicity increases leading to reduced persistence and effectiveness
Solution Approach 1:
The patent applies humanization to modify the antibody sequence parameters, changing it from mouse-derived to human-derived amino acid sequence. This parameter change reduces immunogenicity while preserving BCMA binding affinity and cytotoxic activity, directly resolving the contradiction between therapeutic effectiveness and immunogenicity
Solution Approach 2:
The patent creates a humanized version by copying and adapting the functional structure of mouse monoclonal antibodies (ganzomab, ophd1) into a human antibody framework. This copying approach maintains the antigen-binding capability while replacing the immunogenic mouse protein structure with a human-compatible structure
2Reliability
If first generation CARs are used, then simple structure is maintained, but cytolytic activity and persistence are insufficient
Solution Approach 1:
The patent merges multiple functional domains into a single chimeric antigen receptor construct: the BCMA-specific scFv domain for antigen recognition, the CD28 or 4-1BB domain for costimulatory signaling, and the CD3ζ domain for activation signaling. This merging of multiple functions into one receptor enhances cytolytic activity and persistence compared to first-generation CARs
Solution Approach 2:
The CAR construct functions as a composite molecular structure combining different protein domains with distinct functions: the antibody-derived scFv portion provides specificity, the costimulatory domain (CD28/4-1BB) provides enhanced signaling, and the CD3ζ tail provides activation. This composite structure achieves superior antitumor activity
3Object-affected harmful factors
If humanized BCMA antibodies are developed, then immunogenicity is reduced, but binding specificity and affinity must be maintained
Solution Approach 1:
The patent carefully modifies the antibody sequence parameters through humanization, changing amino acid residues at specific positions (such as positions 31, 52, 88, 98, 100, 102, 104, 106, 108, 110, 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) to reduce immunogenicity while preserving critical binding residues. This selective parameter modification resolves the contradiction between reducing immunogenicity and maintaining binding specificity
Solution Approach 2:
The patent applies local quality by making specific positions in the antibody sequence human-like while keeping other positions mouse-derived. Critical complementarity-determining region (CDR) positions are preserved for BCMA binding, while framework regions are humanized to reduce immunogenicity. This localized differentiation resolves the contradiction between binding specificity and immunogenicity
Data Source
AI summary
The present invention is directed to a humanized BCMA single-chain variable fragment (scFv), comprising VH having the amino acid sequence of SEQ ID NO: 4 and VL having the amino acid sequence of SEQ ID NO: 5. The present invention is also directed to a BCMA chimeric antigen receptor fusion protein comprising from N-terminus to C-terminus: (i) a single-chain variable fragment (scFv) of the present invention, (ii) a transmembrane domain, (iii) at least one co-stimulatory domains, and (iv) an activating domain. A preferred co-stimulatory domain is CD28 or 41-BB. The humanized BCMA-CAR-T cells have specific killing activity with secretion of cytokine IFN-gamma in CAR-T cells in vitro and in vivo.