Dosing regimen for Anti-BCMA agents

Abstract

To provide dosage and administration of anti-BCMA agents for the treatment of BCMA-positive neoplasms.SOLUTION: Provided is an antibody construct comprising a first domain which binds to BCMA, a second domain which binds to CD3 and a third domain which extends the half-life of the antibody construct, for use in the treatment or amelioration of a BCMA positive neoplasm, the antibody construct being administered at a minimum dose of 800 μg / day in at least one cycle, the one cycle comprising at least three individual administrations of the antibody construct.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to dosage and administration of anti-BCMA agents for the treatment of BCMA-positive neoplasms. More specifically, the present invention relates to an antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends or enhances the half-life of the antibody construct, for use in treating or ameliorating BCMA-positive neoplasms, wherein the antibody construct is administered at a specified dose for at least one cycle. Furthermore, the present invention relates to methods for treating BCMA-positive neoplasms comprising administering the specified dose of such an antibody construct, and to the use of such an antibody construct for the manufacture of a medicament for the treatment of BCMA-positive neoplasms. [Background technology]

[0002] Multiple myeloma (MM) is a malignant tumor of plasma cells that proliferates in the bone marrow and releases paraproteins. Observed clinical manifestations include infection, bone destruction, bone marrow failure, renal failure, and hypercalcemia. The age-adjusted annual incidence rate is increasing, at approximately 6 new cases per 100,000 people. The incidence rate is twice as high in the black population in the United States as in whites. The 5-year survival rate for MM rose from approximately 25% for newly diagnosed patients in 1975 to approximately 45% in 2006. This improvement is primarily due to new drugs, such as proteasome inhibitors and immunomodulators. However, MM is not considered curable with current approaches. Patients who are unresponsive to proteasome inhibitors and immunomodulators have a poor outcome, with a median overall survival of 9 months.

[0003] Outcomes are particularly poor in high-risk populations, such as the subgroup of del17p13-positive MM. Although many agents are in clinical development for MM, new treatment options remain needed. Patients presenting with symptomatic disease are initially treated with first-line induction therapy, followed by high-dose chemotherapy with autologous stem cell support in eligible patients. Patients eligible for intensive therapy are determined by age (upper limit 65–75 years), absence of comorbidities, and intact renal function. While this regimen has improved survival in young, healthy patients, the median duration of response did not exceed 3 years, and few patients remained disease-free for more than 10 years.

[0004] Consolidation and maintenance approaches have been tested to deepen and extend the duration of improvement. Because maintenance therapy is challenging due to lack of efficacy or tolerability, there remains the option to improve survival outcomes in the transplant setting by adding novel therapies to induction, consolidation, or maintenance regimens. Patients who are not candidates for high-dose therapy typically receive induction regimens similar to those of transplant candidates. These regimens include the proteasome inhibitor bortezomib or melphalan-based combinations with thalidomide. The median overall survival (OS) for melphalan-thalidomide-prednisone (MPT) in elderly patients is 40 months. Lenalidomide in combination with dexamethasone is the standard regimen for relapsed / refractory MM, but it can transition to the first-line setting in transplant-ineligible patients.

[0005] Other established regimens in the relapsed setting are repeated induction regimens or salvage combination therapy based on immunomodulators with bortezomib or alkylating agents. Improved outcomes (progression-free survival (PFS) and OS) are needed in patients with relapsed disease. Patients who do not respond to established therapies and progress on treatment have dismal outcomes, with OS of 9 months on treatment and 3 months off treatment. Unmet needs are greatest in these patients.

[0006] Bispecific molecules, such as BiTE® (bispecific T cell engager) antibody constructs, are recombinant protein constructs with (at least) one binding domain specific for a selected tumor-associated surface antigen on a target cell and a second binding domain specific for CD3, a subunit of the T cell receptor complex on T cells. Due to their special design, BiTE® antibody constructs are uniquely suited to transiently bind T cells to target cells while simultaneously potently activating the intrinsic cytolytic potential of T cells against the target cells. First-generation, so-called "canonical" (non-half-life extended) BiTE® antibody constructs (see WO 99 / 54440 and WO 2005 / 040220) have entered clinical use, including AMG103 (blinatumomab, anti-CD19xanti-CD3) and AMG110 (solitomab, anti-EpCAMxanti-CD3). Further development of the first-generation canonical BiTE® antibody constructs provided bispecific antibody constructs that bind to context-independent epitopes at the N-terminus of the CD3 epsilon chain of human and Callithrix jacchus, Saguinus oedipus, or Saimiri sciureus (WO 2008 / 119567). The first BiTE® molecule containing this novel CD3 epsilon-binding domain to be clinically tested was AMG330.

[0007] Antibody constructs such as those described in WO 2008 / 119567 are thought to undergo rapid clearance from the body; therefore, while they can rapidly reach most parts of the body, can be rapidly produced, and are easy to handle, their in vivo applications may be limited by their short persistence in vivo. Because of the short in vivo half-life of these relatively small molecules, continuous administration by continuous intravenous infusion has been used to achieve therapeutic efficacy. However, such continuous intravenous infusion is inconvenient for patients and may therefore hinder the selection of compounds that have proven more effective in treating the respective disease in the case of more convenient alternative therapeutic approaches. This has led to the development of bispecific therapeutic agents that retain similar therapeutic efficacy while at the same time possessing favorable pharmacokinetic properties, including a longer half-life. Therefore, an important further development of so-called canonical BiTE® molecules has been the addition of additional domains that extend or enhance the half-life of the antibody construct. The resulting molecules are also referred to as "HLE" (half-life extended) BiTE® molecules, see e.g., WO 2017 / 134140.

[0008] B-cell maturation antigen (BCMA, TNFRSF17, CD269) is a transmembrane protein belonging to the TNF receptor superfamily. BCMA expression is selectively induced during late plasma cell differentiation and is absent in naive and memory B cells. BCMA binding to its ligands (B-cell activating factor (BAFF) and proliferation-inducing ligand (APRIL)) promotes the survival of bone marrow plasma cells and plasmablasts. BCMA does not maintain normal B-cell homeostasis but is required for the survival of long-lived plasma cells. Studies in BCMA- / - mice have shown impaired survival of long-lived bone marrow plasma cells, yet B-cell development and early humoral immune responses are indistinguishable from those in wild-type mice. BCMA mRNA expression is highly elevated in malignant plasma cell disorders. In contrast, mRNA expression in normal tissues is very low and is restricted to lymphoid tissues, where normal long-lived plasma cells reside. BCMA protein expression has been reported to be restricted exclusively to plasma cells. BCMA expression is restricted to plasmablasts and long-lived plasma cells and is undetectable in other normal human tissues. BCMA is ubiquitously expressed on the cell surface of MM cells, and is expressed on malignant plasma cells at levels relatively higher than those observed on normal plasma cells. There is no correlation between BCMA expression and MM stage, response to last treatment, or time since diagnosis. Neither T cells, myeloid cells, nor CD34+ hematopoietic stem cells express BCMA. The selective expression of BCMA makes it a highly attractive target for antibody- and chimeric antigen receptor (CAR)-based therapies.

[0009] AMG420 (formerly BI836909) is a canonical bispecific T cell engager that binds BCMA on target cells and CD3-epsilon on T cells. It functions as a bridge between BCMA-positive target cells, such as MM cells, and cytotoxic T lymphocytes (CTLs) by directing the cytolytic activity of the CTLs to the target cells. AMG420 consists of two single-chain variable fragments (scFvs), one directed against BCMA and the other against CD3. Each scFv fragment consists of a VH and VL domain connected by a glycine / serine linker. The two scFv fragments are also connected by a glycine / serine linker. Half-life extended anti-BCMA x anti-CD3 antibody constructs, such as AMG 701, are described in detail in WO 2017 / 134134. There is an ongoing unmet medical need for the development of therapeutic agents for the treatment of BCMA-positive neoplasms, particularly using such half-life extended anti-BCMA x anti-CD3 molecules. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] WO 99 / 54440 [Patent Document 2] International Publication No. 2005 / 040220 [Patent Document 3] International Publication No. 2008 / 119567 [Patent Document 4] International Publication No. 2017 / 134140 [Patent Document 5] International Publication No. 2017 / 134134 Summary of the Invention [Means for solving the problem]

[0011] Given the description herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein, which equivalents are intended to be encompassed by the following clauses.

[0012] Item 1. An antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends the half-life of the antibody construct, for use in treating or ameliorating a BCMA-positive neoplasm, wherein the antibody construct is administered at a minimum dose of 800 μg / day for at least one cycle, wherein one cycle comprises at least three separate administrations of the antibody construct.

[0013] Item 2. The antibody construct of item 1, administered for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more cycles.

[0014] Item 3. The antibody construct according to item 1 or 2, wherein a cycle has a duration of about 25 to about 30 days, preferably about 26 or 27 to about 29 days and longer, preferably about 28 days.

[0015] Item 4. The antibody construct of any one of Items 1 to 3, administered at a dose of 800 μg / day to 12 mg / day, for example, 1000 μg, 1200 μg, 1500 μg, 1600 μg, 2000 μg, 2500 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 5500 μg, 6000 μg, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg, or 12 mg / day.

[0016] Item 5. The antibody construct of any one of Items 1 to 4, which is administered in one or two dose steps during an initial cycle.

[0017] Item 6. The antibody construct of Item 5, wherein the first dose is 800 μg / day to 1200 μg / day, the optional second dose is 2500 μg / day to 5000 μg / day, preferably about 3000 μg / day or about 4500 μg / day, and the final dose (target dose) is 6500 μg / day to 12 mg / day, for example, 6500 μg / day, 7000 μg / day, 7500 μg / day, 8000 μg / day, 8500 μg / day, 9000 μg / day, 9500 μg / day, 10 mg / day, 11 mg / day, or 12 mg / day.

[0018] Item 7. The antibody construct of any one of items 1 to 6, wherein the first cycle comprises or consists of 3 to 6 separate administrations, preferably 4 or 5 separate administrations, of the antibody construct.

[0019] Item 7a. The antibody construct of item 6 or 7, wherein the first dose of 800 μg / day is administered on day 1.

[0020] Item 7b. The antibody construct according to Item 7a, a) the target dose is administered on day 8 (+ / - 1 or 2 days), day 15 (+ / - 1 or 2 days), and day 22 (+ / - 1 or 2 days), and the target dose is 3000 μg / day to 12 mg / day, for example, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 5500 μg, 6000 μg, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg, or 12 mg / day; b) the target dose is administered on days 4 or 5 (+ / - 1 or 2 days), 12 (+ / - 1 or 2 days), and 19 (+ / - 1 or 2 days), wherein the target dose is defined as in a); c) the target dose is administered on days 3 or 4 (+ / - 1 or 2 days), 8 (+ / - 1 or 2 days), 15 (+ / - 1 or 2 days), and 22 (+ / - 1 or 2 days), wherein the target dose is defined as in a); or d) the second dose is administered on day 3 or 4 (+ / - 1 or 2 days), and the target dose is administered on day 8 (+ / - 1 or 2 days), day 15 (+ / - 1 or 2 days), and day 22 (+ / - 1 or 2 days), and the second dose is 2500 μg / day to 5000 μg / day, preferably about 3000 μg / day or about 4500 μg / day, and the target dose is higher than the second dose, as defined in a); Antibody constructs.

[0021] Item 8. The antibody construct of any one of items 2 to 7, administered at a fixed dose during the second cycle and optionally during any subsequent cycles.

[0022] Item 8a. The antibody construct of Item 8, wherein the fixed dose is the maximum dose (target dose) administered during the first cycle.

[0023] Item 8b. The antibody construct of any one of items 2 to 8a, administered once weekly during the second cycle and optionally during any subsequent cycles.

[0024] Item 9. The antibody construct of any one of Items 1 to 8, which is administered parenterally, preferably intravenously, more preferably via intravenous bolus injection, bolus infusion or short-term intravenous infusion.

[0025] Item 10. The antibody construct of any one of Items 1 to 9, wherein the BCMA-positive neoplasm is selected from the group consisting of multiple myeloma, relapsed and / or refractory multiple myeloma, heavy-chain multiple myeloma, light-chain multiple myeloma, extramedullary myeloma, plasmacytoma, plasma cell leukemia, Waldenstrom's macroglobulinemia, and smoldering myeloma.

[0026] Item 10a. The antibody construct of item 10, wherein the BCMA-positive neoplasm is multiple myeloma.

[0027] Item 10b. The antibody construct of Item 10a, wherein the multiple myeloma is selected from the group consisting of relapsed and / or refractory multiple myeloma, heavy chain multiple myeloma, light chain multiple myeloma, extramedullary multiple myeloma, and smoldering multiple myeloma.

[0028] Item 11. The antibody construct according to any one of Items 1 to 9, a) the antibody construct is a single-chain polypeptide; b) the first domain is in the form of an scFv; c) the second domain is in the form of an scFv, and / or d) the first domain and the second domain are connected via a linker, preferably a peptide linker, more preferably a glycine / serine linker; Antibody constructs.

[0029] Item 12. The following: a) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172 and CDR-H3 as set forth in SEQ ID NO: 173, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 175 and CDR-L3 as set forth in SEQ ID NO: 176; b) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region as set forth in SEQ ID NO: 177 and a VL region as set forth in SEQ ID NO: 178; c) an antibody construct comprising a domain that binds to BCMA on the surface of a target cell, wherein said domain comprises an amino acid sequence as set forth in SEQ ID NO: 179; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; 12. The antibody construct of any one of items 1 to 11, which competes for binding to BCMA with or binds to the same epitope on BCMA as

[0030] Item 13. The following: a) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 633, CDR-L2 as set forth in SEQ ID NO: 634, and CDR-L3 as set forth in SEQ ID NO: 635; b) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region as set forth in SEQ ID NO: 639 and a VL region as set forth in SEQ ID NO: 641; c) an antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising the amino acid sequence as set forth in SEQ ID NO: 642; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; 13. The antibody construct according to any one of items 1 to 12, which competes for binding to CD3 with or binds to the same epitope on CD3 as

[0031] Item 14. The first domain that binds to BCMA, (1) CDR-H1 as set forth in SEQ ID NO: 1, CDR-H2 as set forth in SEQ ID NO: 2, CDR-H3 as set forth in SEQ ID NO: 3, CDR-L1 as set forth in SEQ ID NO: 4, CDR-L2 as set forth in SEQ ID NO: 5, and CDR-L3 as set forth in SEQ ID NO: 6; (2) CDR-H1 as set forth in SEQ ID NO: 11, CDR-H2 as set forth in SEQ ID NO: 12, CDR-H3 as set forth in SEQ ID NO: 13, CDR-L1 as set forth in SEQ ID NO: 14, CDR-L2 as set forth in SEQ ID NO: 15, and CDR-L3 as set forth in SEQ ID NO: 16; (3) CDR-H1 as set forth in SEQ ID NO: 21, CDR-H2 as set forth in SEQ ID NO: 22, CDR-H3 as set forth in SEQ ID NO: 23, CDR-L1 as set forth in SEQ ID NO: 24, CDR-L2 as set forth in SEQ ID NO: 25, and CDR-L3 as set forth in SEQ ID NO: 26; (4) CDR-H1 as set forth in SEQ ID NO: 31, CDR-H2 as set forth in SEQ ID NO: 32, CDR-H3 as set forth in SEQ ID NO: 33, CDR-L1 as set forth in SEQ ID NO: 34, CDR-L2 as set forth in SEQ ID NO: 35, and CDR-L3 as set forth in SEQ ID NO: 36; (5) CDR-H1 as set forth in SEQ ID NO: 41, CDR-H2 as set forth in SEQ ID NO: 42, CDR-H3 as set forth in SEQ ID NO: 43, CDR-L1 as set forth in SEQ ID NO: 44, CDR-L2 as set forth in SEQ ID NO: 45, and CDR-L3 as set forth in SEQ ID NO: 46; (6) CDR-H1 as set forth in SEQ ID NO: 51, CDR-H2 as set forth in SEQ ID NO: 52, CDR-H3 as set forth in SEQ ID NO: 53, CDR-L1 as set forth in SEQ ID NO: 54, CDR-L2 as set forth in SEQ ID NO: 55, and CDR-L3 as set forth in SEQ ID NO: 56; (7) CDR-H1 as set forth in SEQ ID NO: 61, CDR-H2 as set forth in SEQ ID NO: 62, CDR-H3 as set forth in SEQ ID NO: 63, CDR-L1 as set forth in SEQ ID NO: 64, CDR-L2 as set forth in SEQ ID NO: 65, and CDR-L3 as set forth in SEQ ID NO: 66; (8) CDR-H1 as shown in SEQ ID NO: 71, CDR-H2 as shown in SEQ ID NO: 72, CDR-H3 as shown in SEQ ID NO: 73, CDR-L1 as shown in SEQ ID NO: 74, CDR-L2 as shown in SEQ ID NO: 75, and CDR-L3 as shown in SEQ ID NO: 76; (9) CDR-H1 as set forth in SEQ ID NO: 81, CDR-H2 as set forth in SEQ ID NO: 82, CDR-H3 as set forth in SEQ ID NO: 83, CDR-L1 as set forth in SEQ ID NO: 84, CDR-L2 as set forth in SEQ ID NO: 85, and CDR-L3 as set forth in SEQ ID NO: 86; (10) CDR-H1 as set forth in SEQ ID NO: 91, CDR-H2 as set forth in SEQ ID NO: 92, CDR-H3 as set forth in SEQ ID NO: 93, CDR-L1 as set forth in SEQ ID NO: 94, CDR-L2 as set forth in SEQ ID NO: 95, and CDR-L3 as set forth in SEQ ID NO: 96; (11) CDR-H1 as shown in SEQ ID NO: 101, CDR-H2 as shown in SEQ ID NO: 102, CDR-H3 as shown in SEQ ID NO: 103, CDR-L1 as shown in SEQ ID NO: 104, CDR-L2 as shown in SEQ ID NO: 105, and CDR-L3 as shown in SEQ ID NO: 106; (12) CDR-H1 as set forth in SEQ ID NO: 111, CDR-H2 as set forth in SEQ ID NO: 112, CDR-H3 as set forth in SEQ ID NO: 113, CDR-L1 as set forth in SEQ ID NO: 114, CDR-L2 as set forth in SEQ ID NO: 115, and CDR-L3 as set forth in SEQ ID NO: 116; (13) CDR-H1 as set forth in SEQ ID NO: 121, CDR-H2 as set forth in SEQ ID NO: 122, CDR-H3 as set forth in SEQ ID NO: 123, CDR-L1 as set forth in SEQ ID NO: 124, CDR-L2 as set forth in SEQ ID NO: 125, and CDR-L3 as set forth in SEQ ID NO: 126; (14) CDR-H1 as set forth in SEQ ID NO: 131, CDR-H2 as set forth in SEQ ID NO: 132, CDR-H3 as set forth in SEQ ID NO: 133, CDR-L1 as set forth in SEQ ID NO: 134, CDR-L2 as set forth in SEQ ID NO: 135, and CDR-L3 as set forth in SEQ ID NO: 136; (15) CDR-H1 as set forth in SEQ ID NO: 141, CDR-H2 as set forth in SEQ ID NO: 142, CDR-H3 as set forth in SEQ ID NO: 143, CDR-L1 as set forth in SEQ ID NO: 144, CDR-L2 as set forth in SEQ ID NO: 145, and CDR-L3 as set forth in SEQ ID NO: 146; (16) CDR-H1 as set forth in SEQ ID NO: 151, CDR-H2 as set forth in SEQ ID NO: 152, CDR-H3 as set forth in SEQ ID NO: 153, CDR-L1 as set forth in SEQ ID NO: 154, CDR-L2 as set forth in SEQ ID NO: 155, and CDR-L3 as set forth in SEQ ID NO: 156; (17) CDR-H1 as set forth in SEQ ID NO: 161, CDR-H2 as set forth in SEQ ID NO: 162, CDR-H3 as set forth in SEQ ID NO: 163, CDR-L1 as set forth in SEQ ID NO: 164, CDR-L2 as set forth in SEQ ID NO: 165, and CDR-L3 as set forth in SEQ ID NO: 166; (18) CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, CDR-H3 as set forth in SEQ ID NO: 173, CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 175, and CDR-L3 as set forth in SEQ ID NO: 176; (19) CDR-H1 as set forth in SEQ ID NO: 181, CDR-H2 as set forth in SEQ ID NO: 182, CDR-H3 as set forth in SEQ ID NO: 183, CDR-L1 as set forth in SEQ ID NO: 184, CDR-L2 as set forth in SEQ ID NO: 185, and CDR-L3 as set forth in SEQ ID NO: 186; (20) CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, CDR-H3 as set forth in SEQ ID NO: 193, CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196; (21) CDR-H1 as set forth in SEQ ID NO: 201, CDR-H2 as set forth in SEQ ID NO: 202, CDR-H3 as set forth in SEQ ID NO: 203, CDR-L1 as set forth in SEQ ID NO: 204, CDR-L2 as set forth in SEQ ID NO: 205, and CDR-L3 as set forth in SEQ ID NO: 206; (22) CDR-H1 as set forth in SEQ ID NO: 211, CDR-H2 as set forth in SEQ ID NO: 212, CDR-H3 as set forth in SEQ ID NO: 213, CDR-L1 as set forth in SEQ ID NO: 214, CDR-L2 as set forth in SEQ ID NO: 215, and CDR-L3 as set forth in SEQ ID NO: 216; (23) CDR-H1 as set forth in SEQ ID NO: 221, CDR-H2 as set forth in SEQ ID NO: 222, CDR-H3 as set forth in SEQ ID NO: 223, CDR-L1 as set forth in SEQ ID NO: 224, CDR-L2 as set forth in SEQ ID NO: 225, and CDR-L3 as set forth in SEQ ID NO: 226; (24) CDR-H1 as set forth in SEQ ID NO: 231, CDR-H2 as set forth in SEQ ID NO: 232, CDR-H3 as set forth in SEQ ID NO: 233, CDR-L1 as set forth in SEQ ID NO: 234, CDR-L2 as set forth in SEQ ID NO: 235, and CDR-L3 as set forth in SEQ ID NO: 236; (25) CDR-H1 as set forth in SEQ ID NO: 241, CDR-H2 as set forth in SEQ ID NO: 242, CDR-H3 as set forth in SEQ ID NO: 243, CDR-L1 as set forth in SEQ ID NO: 244, CDR-L2 as set forth in SEQ ID NO: 245, and CDR-L3 as set forth in SEQ ID NO: 246; (26) CDR-H1 as set forth in SEQ ID NO: 251, CDR-H2 as set forth in SEQ ID NO: 252, CDR-H3 as set forth in SEQ ID NO: 253, CDR-L1 as set forth in SEQ ID NO: 254, CDR-L2 as set forth in SEQ ID NO: 255, and CDR-L3 as set forth in SEQ ID NO: 256; (27) CDR-H1 as set forth in SEQ ID NO: 261, CDR-H2 as set forth in SEQ ID NO: 262, CDR-H3 as set forth in SEQ ID NO: 263, CDR-L1 as set forth in SEQ ID NO: 264, CDR-L2 as set forth in SEQ ID NO: 265, and CDR-L3 as set forth in SEQ ID NO: 266; (28) CDR-H1 as set forth in SEQ ID NO: 271, CDR-H2 as set forth in SEQ ID NO: 272, CDR-H3 as set forth in SEQ ID NO: 273, CDR-L1 as set forth in SEQ ID NO: 274, CDR-L2 as set forth in SEQ ID NO: 275, and CDR-L3 as set forth in SEQ ID NO: 276; (29) CDR-H1 as set forth in SEQ ID NO: 281, CDR-H2 as set forth in SEQ ID NO: 282, CDR-H3 as set forth in SEQ ID NO: 283, CDR-L1 as set forth in SEQ ID NO: 284, CDR-L2 as set forth in SEQ ID NO: 285, and CDR-L3 as set forth in SEQ ID NO: 286; (30) CDR-H1 as set forth in SEQ ID NO: 291, CDR-H2 as set forth in SEQ ID NO: 292, CDR-H3 as set forth in SEQ ID NO: 293, CDR-L1 as set forth in SEQ ID NO: 294, CDR-L2 as set forth in SEQ ID NO: 295, and CDR-L3 as set forth in SEQ ID NO: 296; (31) CDR-H1 as set forth in SEQ ID NO: 301, CDR-H2 as set forth in SEQ ID NO: 302, CDR-H3 as set forth in SEQ ID NO: 303, CDR-L1 as set forth in SEQ ID NO: 304, CDR-L2 as set forth in SEQ ID NO: 305, and CDR-L3 as set forth in SEQ ID NO: 306; (32) CDR-H1 as set forth in SEQ ID NO: 311, CDR-H2 as set forth in SEQ ID NO: 312, CDR-H3 as set forth in SEQ ID NO: 313, CDR-L1 as set forth in SEQ ID NO: 314, CDR-L2 as set forth in SEQ ID NO: 315, and CDR-L3 as set forth in SEQ ID NO: 316; (33) CDR-H1 as set forth in SEQ ID NO: 321, CDR-H2 as set forth in SEQ ID NO: 322, CDR-H3 as set forth in SEQ ID NO: 323, CDR-L1 as set forth in SEQ ID NO: 324, CDR-L2 as set forth in SEQ ID NO: 325, and CDR-L3 as set forth in SEQ ID NO: 326; (34) CDR-H1 as set forth in SEQ ID NO: 331, CDR-H2 as set forth in SEQ ID NO: 332, CDR-H3 as set forth in SEQ ID NO: 333, CDR-L1 as set forth in SEQ ID NO: 334, CDR-L2 as set forth in SEQ ID NO: 335, and CDR-L3 as set forth in SEQ ID NO: 336; (35) CDR-H1 as set forth in SEQ ID NO: 341, CDR-H2 as set forth in SEQ ID NO: 342, CDR-H3 as set forth in SEQ ID NO: 343, CDR-L1 as set forth in SEQ ID NO: 344, CDR-L2 as set forth in SEQ ID NO: 345, and CDR-L3 as set forth in SEQ ID NO: 346; (36) CDR-H1 as set forth in SEQ ID NO: 351, CDR-H2 as set forth in SEQ ID NO: 352, CDR-H3 as set forth in SEQ ID NO: 353, CDR-L1 as set forth in SEQ ID NO: 354, CDR-L2 as set forth in SEQ ID NO: 355, and CDR-L3 as set forth in SEQ ID NO: 356; (37) CDR-H1 as set forth in SEQ ID NO: 361, CDR-H2 as set forth in SEQ ID NO: 362, CDR-H3 as set forth in SEQ ID NO: 363, CDR-L1 as set forth in SEQ ID NO: 364, CDR-L2 as set forth in SEQ ID NO: 365, and CDR-L3 as set forth in SEQ ID NO: 366; (38) CDR-H1 as set forth in SEQ ID NO: 371, CDR-H2 as set forth in SEQ ID NO: 372, CDR-H3 as set forth in SEQ ID NO: 373, CDR-L1 as set forth in SEQ ID NO: 374, CDR-L2 as set forth in SEQ ID NO: 375, and CDR-L3 as set forth in SEQ ID NO: 376; (39) CDR-H1 as set forth in SEQ ID NO: 381, CDR-H2 as set forth in SEQ ID NO: 382, ​​CDR-H3 as set forth in SEQ ID NO: 383, CDR-L1 as set forth in SEQ ID NO: 384, CDR-L2 as set forth in SEQ ID NO: 385, and CDR-L3 as set forth in SEQ ID NO: 386; (40) CDR-H1 as set forth in SEQ ID NO: 391, CDR-H2 as set forth in SEQ ID NO: 392, CDR-H3 as set forth in SEQ ID NO: 393, CDR-L1 as set forth in SEQ ID NO: 394, CDR-L2 as set forth in SEQ ID NO: 395, and CDR-L3 as set forth in SEQ ID NO: 396; (41) CDR-H1 as set forth in SEQ ID NO: 401, CDR-H2 as set forth in SEQ ID NO: 402, CDR-H3 as set forth in SEQ ID NO: 403, CDR-L1 as set forth in SEQ ID NO: 404, CDR-L2 as set forth in SEQ ID NO: 405, and CDR-L3 as set forth in SEQ ID NO: 406; (42) CDR-H1 as set forth in SEQ ID NO: 411, CDR-H2 as set forth in SEQ ID NO: 412, CDR-H3 as set forth in SEQ ID NO: 413, CDR-L1 as set forth in SEQ ID NO: 414, CDR-L2 as set forth in SEQ ID NO: 415, and CDR-L3 as set forth in SEQ ID NO: 416; (43) CDR-H1 as set forth in SEQ ID NO: 421, CDR-H2 as set forth in SEQ ID NO: 422, CDR-H3 as set forth in SEQ ID NO: 423, CDR-L1 as set forth in SEQ ID NO: 424, CDR-L2 as set forth in SEQ ID NO: 425, and CDR-L3 as set forth in SEQ ID NO: 426; (44) CDR-H1 as set forth in SEQ ID NO: 431, CDR-H2 as set forth in SEQ ID NO: 432, CDR-H3 as set forth in SEQ ID NO: 433, CDR-L1 as set forth in SEQ ID NO: 434, CDR-L2 as set forth in SEQ ID NO: 435, and CDR-L3 as set forth in SEQ ID NO: 436; (45) CDR-H1 as set forth in SEQ ID NO: 441, CDR-H2 as set forth in SEQ ID NO: 442, CDR-H3 as set forth in SEQ ID NO: 443, CDR-L1 as set forth in SEQ ID NO: 444, CDR-L2 as set forth in SEQ ID NO: 445, and CDR-L3 as set forth in SEQ ID NO: 446; (46) CDR-H1 as set forth in SEQ ID NO: 451, CDR-H2 as set forth in SEQ ID NO: 452, CDR-H3 as set forth in SEQ ID NO: 453, CDR-L1 as set forth in SEQ ID NO: 454, CDR-L2 as set forth in SEQ ID NO: 455, and CDR-L3 as set forth in SEQ ID NO: 456; (47) CDR-H1 as set forth in SEQ ID NO: 461, CDR-H2 as set forth in SEQ ID NO: 462, CDR-H3 as set forth in SEQ ID NO: 463, CDR-L1 as set forth in SEQ ID NO: 464, CDR-L2 as set forth in SEQ ID NO: 465, and CDR-L3 as set forth in SEQ ID NO: 466; (48) CDR-H1 as set forth in SEQ ID NO: 471, CDR-H2 as set forth in SEQ ID NO: 472, CDR-H3 as set forth in SEQ ID NO: 473, CDR-L1 as set forth in SEQ ID NO: 474, CDR-L2 as set forth in SEQ ID NO: 475, and CDR-L3 as set forth in SEQ ID NO: 476; (49) CDR-H1 as set forth in SEQ ID NO: 481, CDR-H2 as set forth in SEQ ID NO: 482, CDR-H3 as set forth in SEQ ID NO: 483, CDR-L1 as set forth in SEQ ID NO: 484, CDR-L2 as set forth in SEQ ID NO: 485, and CDR-L3 as set forth in SEQ ID NO: 486; (50) CDR-H1 as set forth in SEQ ID NO: 491, CDR-H2 as set forth in SEQ ID NO: 492, CDR-H3 as set forth in SEQ ID NO: 493, CDR-L1 as set forth in SEQ ID NO: 494, CDR-L2 as set forth in SEQ ID NO: 495, and CDR-L3 as set forth in SEQ ID NO: 496; (51) CDR-H1 as set forth in SEQ ID NO: 501, CDR-H2 as set forth in SEQ ID NO: 502, CDR-H3 as set forth in SEQ ID NO: 503, CDR-L1 as set forth in SEQ ID NO: 504, CDR-L2 as set forth in SEQ ID NO: 505, and CDR-L3 as set forth in SEQ ID NO: 506; (52) CDR-H1 as set forth in SEQ ID NO: 511, CDR-H2 as set forth in SEQ ID NO: 512, CDR-H3 as set forth in SEQ ID NO: 513, CDR-L1 as set forth in SEQ ID NO: 514, CDR-L2 as set forth in SEQ ID NO: 515, and CDR-L3 as set forth in SEQ ID NO: 516; and (53) CDR-H1 as shown in SEQ ID NO: 521, CDR-H2 as shown in SEQ ID NO: 522, CDR-H3 as shown in SEQ ID NO: 523, CDR-L1 as shown in SEQ ID NO: 524, CDR-L2 as shown in SEQ ID NO: 525, and CDR-L3 as shown in SEQ ID NO: 526 14. The antibody construct according to any one of items 1 to 13, comprising a VH region comprising CDR-H1, CDR-H2, and CDR-H3, and a VL region comprising CDR-L1, CDR-L2, and CDR-L3, selected from:

[0032] Item 15. The first domain that binds to BCMA is selected from the group consisting of SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 307, 317, 327, 337, 347 15. The antibody construct of any one of Items 1 to 14, comprising a VH region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO: 177, 357, 367, 377, 387, 397, 407, 417, 427, 437, 447, 457, 467, 477, 487, 497, 507, 517 and 527, preferably SEQ ID NO: 177.

[0033] Item 16. The first domain that binds to BCMA is selected from the group consisting of SEQ ID NOs: 8, 18, 28, 38, 48, 58, 68, 78, 88, 98, 108, 118, 128, 138, 148, 158, 168, 178, 188, 198, 208, 218, 228, 238, 248, 258, 268, 278, 288, 298, 308, 318, 328, 338, 348, 358, 368, 378, 388, 398, 408, 418, 428, 438, 448, 458, 468, 478, 488, 498, 508, 518, 528, 538, 548, 558, 568, 578, 588, 598, 608, 618, 628, 638, 648, 658, 668, 678, 688, 698, 708, 718, 728, 738, 748, 758, 768, 778, 788, 798, 808, 818, 828, 838, 848, 858, 868, 878, 888, 898, 908, 918, 928, 938, 948, 958, 968, 978, 98 16. The antibody construct of any one of items 1 to 15, comprising a VL region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO: 48, 358, 368, 378, 388, 398, 408, 418, 428, 438, 448, 458, 468, 478, 488, 498, 508, 518 and 528, preferably SEQ ID NO: 178.

[0034] Item 17. The first domain that binds to BCMA, (1) a VH region as set forth in SEQ ID NO: 7 and a VL region as set forth in SEQ ID NO: 8; (2) a VH region as set forth in SEQ ID NO: 17 and a VL region as set forth in SEQ ID NO: 18; (3) a VH region as set forth in SEQ ID NO: 27 and a VL region as set forth in SEQ ID NO: 28; (4) a VH region as set forth in SEQ ID NO: 37 and a VL region as set forth in SEQ ID NO: 38; (5) a VH region as set forth in SEQ ID NO: 47 and a VL region as set forth in SEQ ID NO: 48; (6) a VH region as set forth in SEQ ID NO: 57 and a VL region as set forth in SEQ ID NO: 58; (7) a VH region as set forth in SEQ ID NO: 67 and a VL region as set forth in SEQ ID NO: 68; (8) a VH region as set forth in SEQ ID NO: 77 and a VL region as set forth in SEQ ID NO: 78; (9) a VH region as set forth in SEQ ID NO: 87 and a VL region as set forth in SEQ ID NO: 88; (10) a VH region as set forth in SEQ ID NO: 97 and a VL region as set forth in SEQ ID NO: 98; (11) a VH region as set forth in SEQ ID NO: 107 and a VL region as set forth in SEQ ID NO: 108; (12) a VH region as set forth in SEQ ID NO: 117 and a VL region as set forth in SEQ ID NO: 118; (13) a VH region as set forth in SEQ ID NO: 127 and a VL region as set forth in SEQ ID NO: 128; (14) a VH region as set forth in SEQ ID NO: 137 and a VL region as set forth in SEQ ID NO: 138; (15) a VH region as set forth in SEQ ID NO: 147 and a VL region as set forth in SEQ ID NO: 148; (16) a VH region as set forth in SEQ ID NO: 157 and a VL region as set forth in SEQ ID NO: 158; (17) A VH region as set forth in SEQ ID NO: 167 and a VL region as set forth in SEQ ID NO: 168; (18) A VH region as set forth in SEQ ID NO: 177 and a VL region as set forth in SEQ ID NO: 178; (19) A VH region as set forth in SEQ ID NO: 187 and a VL region as set forth in SEQ ID NO: 188; (20) a VH region as set forth in SEQ ID NO: 197 and a VL region as set forth in SEQ ID NO: 198; (21) a VH region as set forth in SEQ ID NO: 207 and a VL region as set forth in SEQ ID NO: 208; (22) a VH region as set forth in SEQ ID NO: 217 and a VL region as set forth in SEQ ID NO: 218; (23) a VH region as set forth in SEQ ID NO: 227 and a VL region as set forth in SEQ ID NO: 228; (24) a VH region as set forth in SEQ ID NO: 237 and a VL region as set forth in SEQ ID NO: 238; (25) a VH region as set forth in SEQ ID NO: 247 and a VL region as set forth in SEQ ID NO: 248; (26) a VH region as set forth in SEQ ID NO: 257 and a VL region as set forth in SEQ ID NO: 258; (27) A VH region as set forth in SEQ ID NO: 267 and a VL region as set forth in SEQ ID NO: 268; (28) a VH region as set forth in SEQ ID NO: 277 and a VL region as set forth in SEQ ID NO: 278; (29) a VH region as set forth in SEQ ID NO: 287 and a VL region as set forth in SEQ ID NO: 288; (30) a VH region as set forth in SEQ ID NO: 297 and a VL region as set forth in SEQ ID NO: 298; (31) A VH region as set forth in SEQ ID NO: 307 and a VL region as set forth in SEQ ID NO: 308; (32) a VH region as set forth in SEQ ID NO: 317 and a VL region as set forth in SEQ ID NO: 318; (33) a VH region as set forth in SEQ ID NO: 327 and a VL region as set forth in SEQ ID NO: 328; (34) a VH region as set forth in SEQ ID NO: 337 and a VL region as set forth in SEQ ID NO: 338; (35) a VH region as set forth in SEQ ID NO: 347 and a VL region as set forth in SEQ ID NO: 348; (36) a VH region as set forth in SEQ ID NO: 357 and a VL region as set forth in SEQ ID NO: 358; (37) A VH region as set forth in SEQ ID NO: 367 and a VL region as set forth in SEQ ID NO: 368; (38) a VH region as set forth in SEQ ID NO: 377 and a VL region as set forth in SEQ ID NO: 378; (39) a VH region as set forth in SEQ ID NO: 387 and a VL region as set forth in SEQ ID NO: 388; (40) a VH region as set forth in SEQ ID NO: 397 and a VL region as set forth in SEQ ID NO: 398; (41) A VH region as set forth in SEQ ID NO: 407 and a VL region as set forth in SEQ ID NO: 408; (42) a VH region as set forth in SEQ ID NO: 417 and a VL region as set forth in SEQ ID NO: 418; (43) a VH region as set forth in SEQ ID NO: 427 and a VL region as set forth in SEQ ID NO: 428; (44) a VH region as set forth in SEQ ID NO: 437 and a VL region as set forth in SEQ ID NO: 438; (45) a VH region as set forth in SEQ ID NO: 447 and a VL region as set forth in SEQ ID NO: 448; (46) A VH region as set forth in SEQ ID NO: 457 and a VL region as set forth in SEQ ID NO: 458; (47) A VH region as set forth in SEQ ID NO: 467 and a VL region as set forth in SEQ ID NO: 468; (48) a VH region as set forth in SEQ ID NO: 477 and a VL region as set forth in SEQ ID NO: 478; (49) A VH region as set forth in SEQ ID NO: 487 and a VL region as set forth in SEQ ID NO: 488; (50) a VH region as set forth in SEQ ID NO: 497 and a VL region as set forth in SEQ ID NO: 498; (51) A VH region as set forth in SEQ ID NO: 507 and a VL region as set forth in SEQ ID NO: 508; (52) a VH region as set forth in SEQ ID NO: 517 and a VL region as set forth in SEQ ID NO: 518; and (53) A VH region as shown in SEQ ID NO: 527 and a VL region as shown in SEQ ID NO: 528 17. The antibody construct according to any one of items 1 to 16, comprising a VH domain and a VL domain selected from the group consisting of:

[0035] Item 18. The antibody construct of any one of items 1 to 17, wherein the first domain that binds to BCMA comprises or consists of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 19, 29, 39, 49, 59, 69, 79, 89, 109, 129, 139, 149, 159, 169, 179, 189, 199, 209, 219, 229, 239, 249, 259, 269, 279, 289, 299, 309, 319, 329, 339, 349, 359, 369, 379, 389, 399, 409, 419, 429, 439, 449, 459, 469, 479, 489, 499, 519 and 529, preferably SEQ ID NO: 179.

[0036] Item 19. The second domain that binds to CD3 is (a) CDR-L1 as set forth in SEQ ID NO: 542, CDR-L2 as set forth in SEQ ID NO: 543, and CDR-L3 as set forth in SEQ ID NO: 544; (b) CDR-L1 as set forth in SEQ ID NO: 599, CDR-L2 as set forth in SEQ ID NO: 600, and CDR-L3 as set forth in SEQ ID NO: 601; and (c) CDR-L1 as set forth in SEQ ID NO: 621, CDR-L2 as set forth in SEQ ID NO: 622, and CDR-L3 as set forth in SEQ ID NO: 623 19. The antibody construct according to any one of items 1 to 18, comprising a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from the group consisting of:

[0037] Item 20. The second domain that binds to CD3, (a) CDR-H1 as set forth in SEQ ID NO: 534, CDR-H2 as set forth in SEQ ID NO: 535, and CDR-H3 as set forth in SEQ ID NO: 536; (b) CDR-H1 as set forth in SEQ ID NO: 545, CDR-H2 as set forth in SEQ ID NO: 546, and CDR-H3 as set forth in SEQ ID NO: 547; (c) CDR-H1 as set forth in SEQ ID NO: 557, CDR-H2 as set forth in SEQ ID NO: 558, and CDR-H3 as set forth in SEQ ID NO: 559; (d) CDR-H1 as set forth in SEQ ID NO: 568, CDR-H2 as set forth in SEQ ID NO: 569, and CDR-H3 as set forth in SEQ ID NO: 570; (e) CDR-H1 as set forth in SEQ ID NO: 579, CDR-H2 as set forth in SEQ ID NO: 580, and CDR-H3 as set forth in SEQ ID NO: 581; (f) CDR-H1 as set forth in SEQ ID NO: 591, CDR-H2 as set forth in SEQ ID NO: 592, and CDR-H3 as set forth in SEQ ID NO: 593; (g) CDR-H1 as set forth in SEQ ID NO: 602, CDR-H2 as set forth in SEQ ID NO: 603, and CDR-H3 as set forth in SEQ ID NO: 604; (h) CDR-H1 as set forth in SEQ ID NO: 613, CDR-H2 as set forth in SEQ ID NO: 614, and CDR-H3 as set forth in SEQ ID NO: 615; (i) CDR-H1 as set forth in SEQ ID NO: 624, CDR-H2 as set forth in SEQ ID NO: 625, and CDR-H3 as set forth in SEQ ID NO: 626; and (j) CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638 20. The antibody construct according to any one of items 1 to 19, comprising a VH region comprising CDR-H1, CDR-H2, and CDR-H3 selected from the group consisting of:

[0038] Item 21. The second domain that binds to CD3, (a) CDR-L1 as set forth in SEQ ID NO: 531, CDR-L2 as set forth in SEQ ID NO: 532, CDR-L3 as set forth in SEQ ID NO: 533, CDR-H1 as set forth in SEQ ID NO: 534, CDR-H2 as set forth in SEQ ID NO: 535, and CDR-H3 as set forth in SEQ ID NO: 536; (b) CDR-L1 as set forth in SEQ ID NO: 542, CDR-L2 as set forth in SEQ ID NO: 543, CDR-L3 as set forth in SEQ ID NO: 544, CDR-H1 as set forth in SEQ ID NO: 545, CDR-H2 as set forth in SEQ ID NO: 546, and CDR-H3 as set forth in SEQ ID NO: 547; (c) CDR-L1 as set forth in SEQ ID NO: 554, CDR-L2 as set forth in SEQ ID NO: 555, CDR-L3 as set forth in SEQ ID NO: 556, CDR-H1 as set forth in SEQ ID NO: 557, CDR-H2 as set forth in SEQ ID NO: 558, and CDR-H3 as set forth in SEQ ID NO: 559; (d) CDR-L1 as set forth in SEQ ID NO: 565, CDR-L2 as set forth in SEQ ID NO: 566, CDR-L3 as set forth in SEQ ID NO: 567, CDR-H1 as set forth in SEQ ID NO: 568, CDR-H2 as set forth in SEQ ID NO: 569, and CDR-H3 as set forth in SEQ ID NO: 570; (e) CDR-L1 as set forth in SEQ ID NO: 576, CDR-L2 as set forth in SEQ ID NO: 577, CDR-L3 as set forth in SEQ ID NO: 578, CDR-H1 as set forth in SEQ ID NO: 579, CDR-H2 as set forth in SEQ ID NO: 580, and CDR-H3 as set forth in SEQ ID NO: 581; (f) CDR-L1 as set forth in SEQ ID NO: 588, CDR-L2 as set forth in SEQ ID NO: 589, CDR-L3 as set forth in SEQ ID NO: 590, CDR-H1 as set forth in SEQ ID NO: 591, CDR-H2 as set forth in SEQ ID NO: 592, and CDR-H3 as set forth in SEQ ID NO: 593; (g) CDR-L1 as set forth in SEQ ID NO: 599, CDR-L2 as set forth in SEQ ID NO: 600, CDR-L3 as set forth in SEQ ID NO: 601, CDR-H1 as set forth in SEQ ID NO: 602, CDR-H2 as set forth in SEQ ID NO: 603, and CDR-H3 as set forth in SEQ ID NO: 604; (h) CDR-L1 as set forth in SEQ ID NO: 610, CDR-L2 as set forth in SEQ ID NO: 611, CDR-L3 as set forth in SEQ ID NO: 612, CDR-H1 as set forth in SEQ ID NO: 613, CDR-H2 as set forth in SEQ ID NO: 614, and CDR-H3 as set forth in SEQ ID NO: 615; (i) CDR-L1 as set forth in SEQ ID NO: 621, CDR-L2 as set forth in SEQ ID NO: 622, CDR-L3 as set forth in SEQ ID NO: 623, CDR-H1 as set forth in SEQ ID NO: 624, CDR-H2 as set forth in SEQ ID NO: 625, and CDR-H3 as set forth in SEQ ID NO: 626; and (j) CDR-L1 as set forth in SEQ ID NO: 633, CDR-L2 as set forth in SEQ ID NO: 634, CDR-L3 as set forth in SEQ ID NO: 635, CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638 21. The antibody construct according to any one of items 1 to 20, comprising a VL region comprising CDR-L1, CDR-L2, and CDR-L3, and a VH region comprising CDR-H1, CDR-H2, and CDR-H3, selected from the group consisting of:

[0039] Item 22. The antibody construct according to any one of Items 1 to 21, wherein the second domain that binds to CD3 comprises a VL region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO: 550, SEQ ID NO: 551, SEQ ID NO: 584, SEQ ID NO: 585, SEQ ID NO: 629 and SEQ ID NO: 630, preferably SEQ ID NO: 629.

[0040] Item 23. The antibody construct according to any one of Items 1 to 22, wherein the second domain that binds to CD3 comprises a VH region having an amino acid sequence selected from the group consisting of SEQ ID NO: 537, SEQ ID NO: 538, SEQ ID NO: 548, SEQ ID NO: 549, SEQ ID NO: 560, SEQ ID NO: 561, SEQ ID NO: 571, SEQ ID NO: 572, SEQ ID NO: 582, SEQ ID NO: 583, SEQ ID NO: 594, SEQ ID NO: 595, SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 616, SEQ ID NO: 617, SEQ ID NO: 627, SEQ ID NO: 628, SEQ ID NO: 639, SEQ ID NO: 640, and SEQ ID NO: 644, preferably SEQ ID NO: 639.

[0041] Item 24. The second domain that binds to CD3, (a) a VL region as set forth in SEQ ID NO: 539 or 521 and a VH region as set forth in SEQ ID NO: 537 or 538; (b) a VL region as set forth in SEQ ID NO: 550 or 521 and a VH region as set forth in SEQ ID NO: 548 or 549; (c) a VL region as set forth in SEQ ID NO: 562 or 521 and a VH region as set forth in SEQ ID NO: 560 or 561; (d) a VL region as set forth in SEQ ID NO: 573 or 521 and a VH region as set forth in SEQ ID NO: 571 or 572; (e) a VL region as set forth in SEQ ID NO: 584 or 585 and a VH region as set forth in SEQ ID NO: 582 or 583; (f) a VL region as set forth in SEQ ID NO: 596 or 521 and a VH region as set forth in SEQ ID NO: 594 or 595; (g) a VL region as set forth in SEQ ID NO: 607 or 585 and a VH region as set forth in SEQ ID NO: 605 or 606; (h) a VL region as set forth in SEQ ID NO: 618 or 521 and a VH region as set forth in SEQ ID NO: 616 or 617; (i) a VL region as set forth in SEQ ID NO: 629 or 630 and a VH region as set forth in SEQ ID NO: 627 or 628; (j) a VL region as set forth in SEQ ID NO: 641 or 630 and a VH region as set forth in SEQ ID NO: 639 or 640; and (k) a VL region as set forth in SEQ ID NO: 645 and a VH region as set forth in SEQ ID NO: 644 24. The antibody construct according to any one of items 1 to 23, comprising a VL domain and a VH domain selected from the group consisting of:

[0042] Item 25. The antibody construct according to any one of Items 1 to 24, wherein the second domain that binds to CD3 comprises or consists of a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 540, 541, 552, 553, 563, 564, 574, 575, 586, 587, 597, 598, 608, 609, 619, 620, 631, 632, 642, 643 and 646, preferably SEQ ID NO: 642.

[0043] Item 26. The antibody construct according to any one of Items 1 to 25, comprising a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, and 530.

[0044] Item 27. From the N-terminus to the C-terminus, (a) First domain; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 687, 693, and 694; (c) second domain; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 686, 687, 688, 689, 690, 691, 692, 693, or 694; (e) a first polypeptide monomer (comprising a hinge, CH2 and CH3 domain); (f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 695, 696, 697, 698, or 699; and (g) a second polypeptide monomer (comprising a hinge, CH2, and CH3 domain) 27. The antibody construct according to any one of items 1 to 26, comprising:

[0045] Item 28. From the N-terminus to the C-terminus, (a) SEQ ID NOs: 9, 19, 29, 39, 49, 59, 69, 79, 89, 109, 129, 139, 149, 159, 169, 179, 189, 199, 209, 219, 229, 239, 249, 259, 269, 279, 289, 299, 309, 319, 329, 339, 349, 359, 369, 379, 389, 399, 409, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 10 a first domain having an amino acid sequence selected from the group consisting of 19, 429, 439, 449, 459, 469, 479, 489, 499, 519 and 529, wherein the peptide linker having SEQ ID NO: 694 contained within these sequences may be replaced with any one of SEQ ID NOs: 686-693 and 695-699; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 687, 693, and 694; (c) a second domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 540, 541, 552, 553, 563, 564, 574, 575, 586, 587, 597, 598, 608, 609, 619, 620, 631, 632, 642, 643, and 646, wherein the peptide linker having SEQ ID NO: 694 within these sequences can be replaced by any one of SEQ ID NOs: 686-693 and 695-699; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 686, 687, 688, 689, 690, 691, 692, 693, and 694; and (e) a third domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 700 to 707; 28. The antibody construct according to any one of items 1 to 27, comprising:

[0046] Item 29. From N-terminus to C-terminus, (a) a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, and 530; (b) a linker having an amino acid sequence as set forth in SEQ ID NO: 686; (c) a polypeptide having an amino acid sequence as set forth in SEQ ID NO: 700 29. The antibody construct according to any one of items 1 to 28, comprising:

[0047] Item 30. The antibody construct according to any one of Items 1 to 29, having a molecular weight of about 75 to about 200 kDa, about 80 to about 175 kDa, about 85 to about 150 kDa, about 90 to about 130 kDa, about 95 to about 120 kDa, preferably about 100 to about 115 kDa, or about 105 to about 110 kDa.

[0048] Item 31. Excretion half-life (T 1 / 2 31. The antibody construct according to any one of items 1 to 30, wherein the incubation time is about 3 to about 14 days, about 4 to about 12 days, about 3 or 4 to about 10 days, about 3 or 4 to about 8 days, or about 5 to about 7 days. [Brief explanation of the drawings]

[0049] [Figure 1] FIG. 1 shows a representative dose finding for AMG 701. [Figure 2] FIG. 2 shows the Week 1 phase dosing optimization protocol. DETAILED DESCRIPTION OF THE INVENTION

[0050] It is therefore an object of the present invention to provide a dosing scheme for extended half-life anti-BCMAx anti-CD3 antibody constructs that results in a favorable safety and tolerability profile while generating positive efficacy signals in BCMA-positive neoplasms.

[0051] Accordingly, the present invention relates to an antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends the half-life of the antibody construct, for use in treating or ameliorating a BCMA-positive neoplasm, wherein the antibody construct is administered at a minimum dose of 800 μg / day in at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct.

[0052] Furthermore, the present invention relates to a method for treating or ameliorating a BCMA-positive neoplasm comprising administering to a subject in need thereof an antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends the half-life of the antibody construct, wherein the antibody construct is administered at a minimum dose of 800 μg / day for at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct.

[0053] The present invention further relates to the use of an antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends the half-life of the antibody construct, for the manufacture of a medicament for the treatment of a BCMA-positive neoplasm, wherein the antibody construct is administered at a minimum dose of 800 μg / day for at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct.

[0054] The present invention also relates to the use of an antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends the half-life of the antibody construct, for the treatment or amelioration of a BCMA-positive neoplasm, wherein the antibody construct is administered at a minimum dose of 800 μg / day for at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct.

[0055] A "neoplasm" is an abnormal growth of tissue, usually, although not necessarily, forming a mass. When a mass forms, it is commonly referred to as a "tumor." In brain tumors, uncontrolled cell division means that the neoplastic mass expands in size, which in enclosed spaces such as the intracranial cavity quickly becomes problematic as the mass invades the brain space and displaces the brain, leading to compression of brain tissue and increased intracranial pressure and parenchymal destruction. In accordance with the present invention, the terms "neoplasm" or "tumor" also refer to conditions that would benefit from treatment with the antibody constructs described herein. This includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the condition (neoplasm or tumor) of interest.

[0056] Neoplasms or tumors can be benign, potentially malignant (precancerous), or malignant (cancerous). Malignant neoplasms / tumors are commonly called cancers. They usually invade and destroy surrounding tissues and may form metastases, i.e., spread to other parts, tissues, or organs of the body. A "primary tumor" is a tumor that grows at the anatomical site where tumor progression begins and progresses to produce a cancerous mass. For example, a brain tumor occurs when abnormal cells form in the brain. Most cancers develop at their primary site but then form metastases or spread to other parts (e.g., tissues and organs) of the body. These additional tumors are secondary tumors. Most cancers continue to be called after their primary site even after they have spread to other parts of the body.

[0057] Lymphomas and leukemias are hematopoietic or lymphoid neoplasms. Multiple myeloma (MM), also known as plasma cell myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. For purposes of this invention, lymphomas and leukemias as well as MM are encompassed by the terms "tumor," "cancer," or "neoplasm." Lymphomas are a group of blood cancers that develop from lymphocytes (a type of white blood cell). Leukemias are a group of cancers that usually begin in the bone marrow and result in large numbers of abnormal white blood cells. These white blood cells are not fully developed and are called blasts or leukemic cells. Lymphomas and leukemias are part of a broader group of tumors of the hematopoietic and lymphatic tissues.

[0058] For purposes of the present invention, the terms "neoplasm," "tumor," and "cancer" may be used interchangeably and include both primary and secondary tumors / cancers (or "metastases") as well as mass-forming neoplasms (tumors) and lymphoid neoplasms (e.g., lymphomas and leukemias), including MRD.

[0059] The term "minimal residual disease" (MRD) refers to evidence of the presence of a small number of residual cancer cells remaining in a patient after cancer treatment, for example, when the patient is in a state of remission (the patient has no symptoms or signs of disease). The extremely small number of residual cancer cells typically cannot be detected by conventional means because standard tests used to evaluate or detect cancer are insufficiently sensitive to detect MRD. Recently, highly sensitive molecular biological MRD tests, such as flow cytometry, PCR, and next-generation sequencing, have become available. These tests can measure minimal levels of cancer cells in tissue samples, sometimes as few as one cancer cell per million normal cells. In the context of the present invention, the terms "prevention," "treatment," or "amelioration" of a neoplasm are also intended to encompass "prevention, treatment, or amelioration of MRD," regardless of whether MRD is detected.

[0060] BCMA-positive neoplasms are presumed to be B-cell or plasma cell neoplasms. B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. B cells function in the humoral immune component of the adaptive immune system by secreting antibodies. In addition, B cells present antigens (they are also classified as professional antigen-presenting cells) and secrete cytokines. In mammals, B cells mature in the bone marrow, located in the center of most bones. B cells differ from the other two classes of lymphocytes (T cells and natural killer (NK) cells) in that they express a B-cell receptor (BCR) on their cell membrane. The BCR enables B cells to bind to specific antigens and initiate antibody responses against them. Plasma cells, also called plasma B cells, plasma cells, or effector B cells, are white blood cells that secrete large amounts of antibodies. Plasma cells are normally transported by the plasma and lymphatic system. Plasma cells originate from the bone marrow. B cells differentiate into plasma cells that produce antibody molecules closely modeled on receptors on precursor B cells. Once released into the blood and lymph, these antibody molecules bind to target antigens and begin their neutralization or destruction.

[0061] The expression level of BCMA on the cell surface can be determined, for example, by flow cytometry analysis. Cell subpopulations selected for BCMA expression analysis (e.g., B cells, plasma cells, MM cells, CD138+ cells) can be stained with, for example, an anti-BCMA antibody followed by a secondary antibody and then analyzed by FACS assay. BCMA-negative cell lines (K562, A549, TC71, CCRF-CEM, etc.) can be used as controls. A shift in the FACS assay (BCMA-negative cell lines defining 0% BCMA expression) indicates that the analyzed cells are BCMA-positive. Different levels of BCMA expression, such as low, moderate, or high expression, can be present on surface cells. See also Quinn et al., Blood (2011) 117:890-901 and Sanchez et al., Br J Heamatol 2012 Jul 18.

[0062] A "BCMA-positive neoplasm" or "(BCMA-positive) B-cell or plasma cell neoplasm" may be selected from the group including, but not limited to, multiple myeloma, relapsed and / or refractory multiple myeloma, heavy-chain multiple myeloma, light-chain multiple myeloma, extramedullary myeloma (extramedullary plasmacytoma, extramedullary multiple myeloma), plasmacytoma, plasma cell leukemia, Waldenstrom's macroglobulinemia (lymphoplasmacytic lymphoma), and smoldering myeloma (smoldering multiple myeloma). Accordingly, the present disclosure also relates to the antibody constructs described herein for use in the treatment or amelioration of multiple myeloma (MM), plasmacytoma, plasma cell leukemia, and Waldenstrom's macroglobulinemia. The MM may be selected from the group consisting of or including relapsed and / or refractory multiple myeloma, heavy chain multiple myeloma, light chain multiple myeloma, extramedullary multiple myeloma, and smoldering multiple myeloma.

[0063] The antibody constructs of the present invention (and pharmaceutical compositions comprising such antibody constructs) are useful in the treatment, amelioration, and / or prevention of a BCMA-positive neoplasm as described herein in a subject in need thereof. The term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Treatment includes administration of the antibody construct (or pharmaceutical composition comprising such antibody construct) to the body of a patient or to tissues or cells removed from a patient or subject in need thereof, having a BCMA-positive neoplasm as described herein, a symptom of such a neoplasm, or a predisposition to such a neoplasm, with the aim of eradicating, curing, ameliorating, alleviating, altering, repairing, ameliorating, improving, or otherwise affecting one or more symptoms of or predisposition to a BCMA-positive neoplasm.

[0064] The terms "subject in need," "patient," or "in need of treatment" include those who already have a BCMA-positive neoplasm as well as those in a state of MRD and those in whom a neoplasm is to be prevented. These terms also include human and other mammalian subjects receiving either prophylactic or therapeutic treatment.

[0065] The term "amelioration," as used herein, refers to any improvement in a patient's disease state (disease being a BCMA-positive neoplasm) due to administration of an antibody construct according to the present invention to such a patient or subject in need thereof. Such improvement may be seen as a slowing or halting of the progression of the patient's disease, and / or as a reduction in the severity of disease symptoms, an increase in the frequency or duration of disease-free symptom-free periods, or prevention of functional impairment or disability due to the disease.

[0066] The term "prevention", as used herein, means avoiding the occurrence or recurrence of a disease as specified herein by administration of an antibody construct according to the present invention to a subject in need thereof.

[0067] With multiple myeloma, symptoms and signs vary widely, as many organs can be affected by the disease. Common symptoms of multiple myeloma include high calcium levels, kidney failure, anemia, and bone lesions (both hallmarks of "CRAB"). In advanced MM, bone pain, bleeding, and frequent infections can occur. Complications also include amyloidosis. The International Myeloma Working Group (IMWG) has established diagnostic criteria for MM that outline three "myeloma diagnostic events" (MDEs) in addition to the typical CRAB features: Bone marrow test shows 60% or more clonal plasma cells A tumor-to-non-tumor serum free light chain ratio of 100 or greater, with absolute tumor light chain levels of at least 100 mg / L (the patient's "tumor-derived" free light chains—either kappa or lambda—are above the normal reference range; "non-tumor-derived" free light chains are typically in the normal range or below). Multiple focal lesions on MRI (magnetic resonance imaging) that are at least 5 mm in size

[0068] The presence of at least one of these markers is considered sufficient for the diagnosis of multiple myeloma, regardless of the presence or absence of symptoms or CRAB features. See also Palumbo AJ Clin Oncol. 2014 Feb 20;32(6):587-600.

[0069] Bone pain affects nearly 70% of patients and is the most common symptom. It usually involves the spine and ribs. Vertebral involvement can lead to spinal cord compression or kyphosis. Myeloma bone disease is due to overexpression of receptor activator of nuclear factor-κB ligand (RANKL) by the bone marrow stroma. RANKL activates osteoclasts, which resorb bone. The resulting bone lesions are lytic in nature (i.e., they cause destruction) and are best seen on plain radiographs. Bone destruction also leads to the release of calcium into the blood, causing hypercalcemia and its associated symptoms.

[0070] The anemia seen in myeloma is usually normocytic and normochromic, resulting from replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.

[0071] A bone marrow biopsy can be performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for MM. MM patients usually have ≥ 10% clonal bone marrow plasma cells. Immunohistochemistry (using antibodies against surface proteins to stain specific cell types) can detect plasma cells that express immunoglobulins in the cytoplasm and sometimes on the cell surface; for example, myeloma cells are typically positive for the markers CD56, CD38, CD138, and CD319, although other markers may also be included to define or identify MM.

[0072] So-called "paraproteins" (also called myeloma proteins, monoclonal proteins, or M proteins) are abnormal immunoglobulin fragments typically produced in excess by the abnormal monoclonal proliferation of plasma cells in MM. While MM patients can theoretically produce all classes of immunoglobulins, IgG paraproteins are the most common, followed by IgA and IgM, while IgD and IgE myelomas are extremely rare. Additionally, antibody light and / or heavy chains can be secreted singly: kappa or lambda light chains, or any of the five types of heavy chains (alpha, gamma, delta, epsilon, or mu (μ) heavy chains). This proliferation of paraproteins has several deleterious effects on the body, including impaired immune function, abnormally high blood viscosity, and kidney damage. Patients without evidence of paraproteins may have "nonsecretory" myeloma (which does not produce immunoglobulins); these account for approximately 3% of all MM patients. Except for patients with true nonsecretory MM, the presence of paraproteins in serum and / or urine is indicative of MM. Quantitative measurement of paraproteins in a patient's urine and / or serum can be used to establish a diagnosis and / or monitor the disease.

[0073] Renal failure can occur both acutely and chronically. The most common cause of renal failure in MM is due to proteins secreted by malignant cells. Myeloma cells produce various types of monoclonal proteins, most commonly immunoglobulins (antibodies) and free light chains, resulting in abnormally high levels of these proteins (paraproteins) in the blood. Depending on the size of these proteins, they can be excreted by the kidneys, but the kidneys can also be damaged by their effects. Furthermore, increased bone resorption leads to hypercalcemia and nephrocalcinosis, thereby contributing to renal failure.

[0074] The most common infections occurring in MM are pneumonia and pyelonephritis. The increased risk of infection is due to immunodeficiency. Total immunoglobulin levels are typically elevated in MM, but the majority of antibodies are ineffective monoclonal antibodies from clonal plasma cells.

[0075] Administration of an antibody construct in the treatment or amelioration of a BCMA-positive neoplasm according to the present invention comprises: a reduction in the level of paraprotein or free light chain in urine and / or serum by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, respectively, compared to the level of paraprotein or free light chain in urine and / or serum before the start of treatment, i.e., before the first administration of the antibody construct (in this particular context, "before" means within 1, 2, 4, 6, 8, or 12 hours, within 1, 2, 3, 4, 5, or 6 days, within 1, 2, 3, or 4 weeks, or within 1, 2, 3, or 4 months); - reduce the percentage of plasma cells in the bone marrow by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to the percentage of plasma cells in the bone marrow before the start of treatment, i.e., before the first administration of the antibody construct (in this particular context, "before" means within 1, 2, 4, 6, 8, or 12 hours, within 1, 2, 3, 4, 5, or 6 days, within 1, 2, 3, or 4 weeks, or within 1, 2, 3, or 4 months); induces a reduction in any of the above symptoms by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to the symptoms before the start of treatment, i.e., before the first administration of the antibody construct (in this particular context, "before" means within 1, 2, 4, 6, 8, or 12 hours, within 1, 2, 3, 4, 5, or 6 days, within 1, 2, 3, or 4 weeks, or within 1, 2, 3, or 4 months, depending on the symptom); inhibits tumor growth or tumor cell proliferation by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% compared to untreated patients or untreated cells; and / or It is envisioned that the therapy will induce lysis of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% of cells of the BCMA-positive neoplasm compared to untreated patients or untreated cells.

[0076] The ability of the antibody constructs of the present invention to inhibit tumor growth / tumor cell proliferation or induce cytolysis can be evaluated in animal models predictive of efficacy in human tumors or in in vitro or ex vivo studies (e.g., antibody construct-induced depletion of BCMA-positive cells by autologous T cells from BM aspirates of multiple myeloma patients). Evaluation of the efficacy of the antibody construct can be further performed as follows: Tumor evaluation can be performed by myeloma involvement analysis, FISH (fluorescence in situ hybridization), and bone marrow (BM) karyotyping. Data for BM karyotyping and FISH can be obtained from BM samples. Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) allow for measurement of serum / urine M proteins. Immunofixation is another means of detecting serum and / or urinary M proteins. It is also envisioned that serum free light chain assays and ratio analyses can be performed. Free light chain (FLC) In the case of multiple myeloma, FLC may be analyzed in serum and urine (sFLC and uFLC). The levels of tumor-derived / non-tumor-derived FLC, the ratio of monoclonal lambda-FLC / kappa-FLC, and the ratio of monoclonal kappa-FLC / lambda-FLC may be determined. Furthermore, quantitative and qualitative immunoglobulin (Ig) analysis may be performed, and serum beta-2 microglobulin may be assessed. It is also contemplated that skeletal surveys and evaluation for plasmacytoma may be performed. Screening imaging analysis to assess extramedullary recurrence using whole-body MRI or PET / CT may be performed. Suitable imaging for assessing bone lesions includes, but is not limited to, CT scans, MRI, PET, PET-CT, or other standard of care. It is also contemplated that minimal residual disease may be measured by next-generation sequencing (NGS)-based assays. For this purpose, bone marrow aspirates may be collected from subjects believed to be complete responders. At the same time that BM MRD samples are collected, plasma samples may also be collected from the subject to assess the feasibility of detecting MRD in ctDNA (circulating tumor DNA). MRD response is assessed by detecting <1 tumor cell / 10 in bone marrow per FACS using antibodies against cytIgλ, cytIgκ, CD19, CD56, or CD138, CD38, and CD45, as appropriate. 4In one embodiment of the present invention, these markers are sufficient to define a tumor cell in the context of the present invention.

[0077] It is envisaged that the response of a patient or subject to administration of an antibody construct according to the invention will be measured in one of the following ways: Quantitative measurement of paraprotein (M protein) or free light chains in urine and / or crystals; Determination of the percentage of plasma cells in the bone marrow; and / or Imaging of extramedullary symptoms (CT, MRI).

[0078] The present invention provides an antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends the half-life of the antibody construct, for use in treating or ameliorating a BCMA-positive neoplasm, wherein the antibody construct is administered at a minimum dose of 800 μg / day in at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct.

[0079] The antibody construct of the present invention is administered in at least one cycle, although more administration cycles, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more cycles, are also contemplated. The term "at least one cycle" refers to "one or more cycles." According to the present invention, "one cycle" corresponds to a period of about 25 to about 30 or 31 days, about 26 or 27 to about 29 days, and preferably about 28 days or 4 weeks. A cycle begins with the first administration of the antibody construct of the present invention on "Day 1." A cycle can be immediately followed by a subsequent cycle, although a period without administration between two cycles is also contemplated. Different administration cycles need not be completely identical. In particular, it is contemplated that the first cycle may differ from subsequent cycles, particularly with regard to the dose of the antibody construct.

[0080] The term "minimum dose of" means "a dose of at least." The dose of the antibody construct is 800 μg / day to 12 mg / day. This can be 1000 μg, 1200 μg, 1500 μg, 1600 μg, 2000 μg, 2500 μg, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 5500 μg, 6000 μg, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg, or 12 mg / day.

[0081] The dose (daily dose) of the antibody construct to be administered in the first cycle may be stable throughout the cycle or may be increased in one or two steps. In this context, "stable" or "stable throughout the cycle" means that the dose (e.g., 800 μg) to be administered daily is the same / constant for each administration within the cycle. In contrast, "step" or "dose step" means that there is an increase in the dose (daily dose) to be administered from one administration to the next. One dose step within a cycle means that a first dose is administered on one day, followed by a second (higher) dose on the following day. Thus, two dose steps within a cycle means that a first dose is followed by a second dose that is higher than the first dose, and this second dose is followed by a third dose that is higher than the second dose. If there are one or two steps, the final dose to be administered in (at least) the first cycle is the so-called "target dose." The target dose is expected to be 6500 μg / day to 12 mg / day. The target dose may be, for example, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg, or 12 mg / day. The target dose is expected to be achieved on day 3, 4, 5, 6, 7, 8, 9, or 10 of the initial cycle. If the initial cycle has one or two stages, the first dose to be administered on day 1 is expected to be 800 μg to 1200 μg / day. If the initial cycle has two stages, the second dose to be administered is expected to be 2500 μg to 5000 μg / day, preferably about 3000 μg or about 4500 μg / day. If the initial cycle has two phases, it is envisioned that the second dose will be administered on the third, fourth or fifth day.

[0082] One cycle comprises at least three individual administrations of the antibody construct, preferably four individual administrations. This means that a subject in need thereof receives the antibody construct of the present invention at least three times, preferably four times, during a cycle. For example, if a cycle consists of four weeks, the subject in need thereof may be administered the antibody construct once a week. "Individual administration" therefore means administration of a specified dose as defined above on a single day. Within a cycle, such individual administration is followed by a period (usually at least one day) during which the antibody construct is not administered. It is also envisioned that a first cycle comprises or consists of three to six individual administrations of the antibody construct, preferably four or five individual administrations. It is envisioned that at least two or three administrations within the first cycle are at the target dose.

[0083] It is envisaged that in the first cycle, the antibody construct will be administered on day 1 (d1). It is envisaged that a further or subsequent administration day in the first cycle will be d3 or d4 or d5. It is envisaged that a further administration day will be d7 or d8 or d9. It is envisaged that a further administration day will be d11 or d12 or d13. It is envisaged that a further administration day will be d14 or d15 or d16. It is envisaged that a further administration day will be d18 or d19 or d20. It is envisaged that a further administration day will be d21 or d22 or d23.

[0084] According to one embodiment, the first cycle begins with administration of 800 μg of the antibody construct on day 1. According to a further embodiment, administration of the antibody construct in the first cycle continues as follows: e) administration of a target dose on day 8 (+ / - 1 or 2 days), day 15 (+ / - 1 or 2 days), and day 22 (+ / - 1 or 2 days), where the target dose can be, for example, 3000 μg, 3500 μg, 4000 μg, 4500 μg, 5000 μg, 5500 μg, 6000 μg, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg, or 12 mg per day; f) administering the target dose on days 4 or 5 (+ / - 1 or 2 days), 12 (+ / - 1 or 2 days), and 19 (+ / - 1 or 2 days), where the target dose may be as defined in a); g) administering the target dose on days 3 or 4 (+ / - 1 or 2 days), 8 (+ / - 1 or 2 days), 15 (+ / - 1 or 2 days), and 22 (+ / - 1 or 2 days), where the target dose may be as defined in a); or h) Administration of a second dose (higher than 800 μg / day) on day 3 or 4 (+ / - 1 or 2 days) and target doses on days 8 (+ / - 1 or 2 days), 15 (+ / - 1 or 2 days) and 22 (+ / - 1 or 2 days). It is envisaged that the second dose is 2500 μg to 5000 μg / day, preferably about 3000 μg or about 4500 μg / day, and the target dose may be as defined in a) and must be higher than the second dose.

[0085] It is contemplated that the antibody construct will be administered at a fixed dose (constant daily dose) during the second cycle, and optionally during any subsequent cycles. No dose staging is contemplated for the second cycle, and optionally any subsequent cycles. Starting with the second cycle, it is contemplated that the antibody construct will be administered at a target dose. The target dose is contemplated to be between 6500 μg and 12 mg / day. The target dose can be, for example, 6500 μg, 7000 μg, 7500 μg, 8000 μg, 8500 μg, 9000 μg, 9500 μg, 10 mg, 11 mg, or 12 mg / day. It is contemplated that starting with the second cycle, the antibody construct will be administered at weekly intervals. For example, administration in the second cycle and any subsequent cycles is on d1, d8 (+ / - 1 or 2 days), d15 (+ / - 1 or 2 days) and d22 (+ / - 1 or 2 days).

[0086] A preferred administration scheme is shown in FIGS.

[0087] The antibody construct of the present invention is expected to have a molecular weight of about 75 to about 200 kDa, about 80 to about 175 kDa, about 85 to about 150 kDa, about 90 to about 130 kDa, about 95 to about 120 kDa, preferably about 100 to about 115 kDa or about 105 to about 110 kDa.

[0088] The antibody constructs of the invention comprise a domain (a "third domain") that extends or enhances the half-life or excretion half-life of the construct. The terms "extend" or "enhance" may be defined with respect to or relative to an antibody construct that does not comprise such a domain (an "HLE domain"). It is envisaged that the half-life or excretion half-life of the antibody constructs of the invention will be at least 2-fold longer, or at least 5-fold longer, or at least 10-fold longer, or at least 20-fold longer than the half-life or excretion half-life of an antibody construct that does not comprise the third domain.

[0089] Alternatively, the third domain may have a "half-life" or "terminal half-life" or "elimination half-life" (T) of about 3 to about 14 days, about 4 to about 12 days, about 3 or 4 to about 10 days, about 3 or 4 to about 8 days, or about 5 to about 7 days. 1 / 2 ) that provides the antibody construct of the present invention with a "half-life". "Half-life" is the time required for a quantity to decrease to half of its initial value. Medical science refers to the half-life of a substance or drug (here, an antibody construct) in the human body, for example, in serum or plasma. Thus, "half-life" is sometimes referred to as "serum half-life" or "plasma half-life". This can be determined by measuring the concentration of an administered antibody construct in the serum / plasma of a subject. Typically, the elimination or removal of an administered substance / drug refers to the body's clearance through biological processes such as metabolism, excretion, and also involving kidney and liver function. "Excretion half-life" can be defined as the time required for the concentration of a drug (here, an antibody construct of the present invention) to reach half of its original value.

[0090] The antibody constructs of the present invention are generally designed for a particular route and method of administration. In pharmacology, a route of administration is the way a substance is taken into the body. Routes of administration are generally classified according to where the substance is applied, and these can be topical (local), enteral (system-wide effect of the substance, but delivered through the digestive tract), or parenteral (systemic action of the substance, but delivered by a route other than the digestive tract). In the context of the present invention, routes of administration include topical, enteral, and parenteral routes. The reasons for choosing a drug administration route depend on various factors, such as: Physical and chemical properties of the drug. Physical properties include solid, liquid, and gas. Chemical properties include solubility, stability, pH, and irritancy. Desired site of action: action may be local and accessible or systemic and inaccessible. The proportion of the degree of absorption of the drug from different routes. Patient condition.

[0091] The antibody constructs of the present invention (and pharmaceutical compositions comprising the antibody constructs) are particularly useful for parenteral administration. Parenteral administration is generally more rapid acting than topical or enteral administration and often results in very high bioavailability, up to 100%, particularly with IV administration. In general, parenteral administration includes, but is not limited to, intravenous (IV), intracerebral, intraarterial, intraperitoneal, intraosseous, and intravesical delivery.

[0092] Administration according to the present invention is preferably intravenous. Parenteral or intravenous administration can be performed by injection (e.g., using a needle and syringe) or infusion (e.g., via a catheter and pump system). Therefore, administration according to the present invention is contemplated to be by intravenous injection or infusion. Typically, IV infusion is administered through a line, port, or catheter (a small, flexible tube), such as a central venous access or central venous catheter (CVC), which is a catheter placed in a large vein, or a peripheral venous catheter (PVC), which is a catheter placed in a peripheral vein. Generally, catheters or lines can be placed in a vein in the neck (internal jugular vein), a vein in the chest (subclavian vein or axillary vein), a vein in the groin (femoral vein), or through a vein in the arm (also known as a PICC line or peripherally inserted central catheter). A central IV line has a catheter advanced through a vein and drains into a large central vein, usually the superior vena cava, the inferior vena cava, or even the right atrium of the heart. A peripheral intravenous (PIV) line is used in peripheral veins (veins in the arms, hands, legs, and feet). A port is a central venous line with no external connector; instead, it has a small reservoir that is covered with silicone rubber and implanted under the skin. Medication is administered intermittently by inserting a small needle into the skin, piercing the silicone, and entering the reservoir. When the needle is withdrawn, the reservoir cover reseals itself. The cover can tolerate hundreds of needle sticks during its lifetime.

[0093] The present invention provides bolus administration of the antibody constructs of the present invention. A bolus is the administration of a discrete amount of a drug, agent, or other compound within a specific, negligible time period, typically within 1-30 minutes. Often, the bolus administration is intravenous. A bolus is typically administered by injection (e.g., intravenous bolus injection), although a bolus infusion (e.g., intravenous bolus injection) is also possible. A short-term infusion is an infusion (usually an IV infusion) of a relatively small volume (e.g., 50 mL-500 mL or 100 mL-250 mL) administered over a period of up to 3 hours, typically 30-60 minutes or 60 minutes. Short-term (short-term IV) infusion of the antibody constructs is contemplated by the present invention.

[0094] An intravenous "intermittent infusion" is the infusion of a fixed amount of medication over a set period, such as 20-120 minutes or 30-60 minutes, at predetermined intervals, such as every 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours. The goal is to administer small amounts of medication on a regular basis. Intermittent medication, like any other form of infusion, can be administered by gravity or via an electronic infusion device (EID), also known as an infusion pump.

[0095] For infusion, an infusion pump can be used to infuse a drug (antibody construct) into a patient's circulatory system. Pumps are typically used intravenously, but arterial and epidural infusions are also possible. Solutions for infusion can be prepared in IV infusion bags and delivered via an infusion line. Infusion pumps can administer liquids in an unreliable manner when performed manually. For example, they can administer as little as 0.1 mL per hour, minute-by-minute injections, repeated bolus injections up to a maximum number per hour, or volumes that vary depending on the time of day. It is also possible to administer an infusion using only gravity-induced pressure. Different types of infusions according to the present invention include, but are not limited to, bolus injections, short-term infusions, and intermittent infusions. Thus, the antibody constructs of the present invention can be administered, for example, as a bolus administration (bolus injection or bolus infusion), as an injection, or as a short-term infusion, for example, over a period of about 30 to about 90 minutes or about 60 minutes.

[0096] Pharmaceutical compositions can be administered using medical equipment.The example of medical equipment for administering pharmaceutical compositions is described in United States Patent (USP) 4,475,196;4,439,196;4,447,224;4,447,233;4,486,194;4,487,603;4,596,556;4,790,824;4,941,880;5,064,413;5,312,335;5,312,335;5,383,851; and 5,399,163.

[0097] In the context of the present invention, it is contemplated that premedication will be administered prior to each administration (or "individual administration") of the antibody construct, particularly during the first cycle. In this particular context, "prior to" is contemplated to mean within 24, 18, 12, 6, 5, 4, or 3 hours, and preferably within 120, 90, 60, or 30 minutes, of administration of the antibody construct. Premedication may be administered 30 to 120 minutes or 30 to 60 minutes before administration of the antibody construct. It is also contemplated that concurrent medications will be administered simultaneously with or after initiation of administration of the antibody construct in the first cycle, and, optionally, simultaneously with or after initiation of administration of the antibody construct in one or more subsequent cycles, if required by the patient. In this particular context, "after" is intended to mean within 24 hours, 18 hours, 12 hours, 6 hours, 5 hours, 4 hours, or 3 hours after the start of administration of the antibody construct, and preferably within 120, 90, 60, 30, 20, 15, or 10 minutes after the start of administration of the antibody construct. Co-administration can be, for example, 10 to 120 minutes, 10 to 60 minutes, 10 to 30 minutes, or 15 to 20 minutes after the start of administration of the antibody construct. The purpose of pre-medication or co-administration can be, for example, to prevent or reduce the severity of an infusion-related reaction. Pre-medication is preferred over co-administration.

[0098] Premedication or co-medication may include any one or combination of the following: Paracetamol (acetaminophen, APAP) or equivalent; preferably administered orally (po) or intravenously; preferably administered po in a dose of 100-4000 mg, preferably 200-3000 mg or 300-2500 mg or 400-2000 mg or 500-1500 mg, preferably 600-1400 mg, 700-1300 mg, 800-1200 mg, 900-1100 mg or about 1000 mg paracetamol (or equivalent dosages and / or equivalent doses for another route of administration). A person skilled in the art will know how to identify paracetamol equivalents. These include, but are not limited to, ibuprofen (e.g., administered in a dose of 100 to 3200 mg, preferably 200 to 3000 mg or 300 to 2500 mg or 400 to 2000 mg, preferably 500 to 1500 mg, 600 to 1200 mg, 700 to 1000 mg, 750 to 900 mg or about 800 mg) and metamizol (e.g., administered in a dose of 100 to 4000 mg, preferably 200 to 3000 mg or 300 to 2500 mg or 400 to 2000 mg or about 500 to 1000 mg). one or more analgesics selected from meperidine, dipyrone, hydromorphone, fentanyl, and tramadol An antihistamine, preferably administered orally or intravenously, preferably at a dose equivalent to 50 mg of diphenhydramine administered intravenously. Those skilled in the art know how to identify antihistamines. These include, but are not limited to, oral, parenteral or rectal antihistamines such as azatadine (maximum dose, e.g., 4 mg / day), brompheniramine (maximum dose, e.g., 30 mg / day), cetirizine (maximum dose, e.g., 15 mg / day), chlorpheniramine (maximum dose, e.g., 30 mg / day), clemastine (maximum dose, e.g., 10 mg / day), cyproheptadine (maximum dose, e.g., 15 mg / day), desloratadine (maximum dose, e.g., 7 mg / day), dexchlorpheniramine (maximum dose, e.g., 15 mg / day), diphenhydramine (maximum dose, e.g., 350 mg / day), doxylamine (maximum dose, e.g., 180 mg / day), fexofenadine (maximum dose, e.g., 200 mg / day), loratadine (maximum dose, e.g., 15 mg / day), phenindamine (maximum dose, e.g., 180 mg / day). Glucocorticoids, preferably administered orally or intravenously, preferably in a dose equivalent to 2-20 mg or 4-16 mg or 6-12 mg or 8 mg of dexamethasone iv (equivalent dose based on the potency of the glucocorticoid).

[0099] All four substances or groups of substances listed above may be administered as premedication or co-medication, or as a combination of only two substances, or a combination of three substances, or as only one of the four substances. It is contemplated that the glucocorticoid (GC) dose administered before the start of the second cycle may be the same as the GC dose administered before the start of the first cycle, or may be reduced to about 50% of the dose administered before the start of the first cycle, or may be omitted for the second (and / or any potential subsequent) cycle. For example, if the antibody construct according to the present invention is well tolerated during the first cycle without significant signs of infusion-related reactions, a GC dose reduction may be applied. It is further contemplated that the dose may be further reduced before the start of the third and any subsequent cycles. Alternatively, the GC may be administered as premedication (and potentially co-medication) before the start of the first cycle, but no GC premedication or co-medication is administered in the second, third, fourth, and / or fifth cycles. Generally, the dosage of pre-medication or co-medication used in accordance with embodiments of the present invention will depend on the circumstances of the individual patient.

[0100] Glucocorticoids are a class of steroid hormones, the corticosteroids. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor. A less common synonym is glucocorticosteroid. Cortisol (known as hydrocortisone when used pharmaceutical-wise) is the most important human glucocorticoid. Various synthetic glucocorticoids, much more potent than cortisol, have been produced for therapeutic use. They differ in both pharmacokinetics (e.g., absorption coefficient, half-life, volume of distribution, clearance) and pharmacodynamics (e.g., glucocorticoid potency or mineralocorticoid potency). Cortisol is the standard of comparison for glucocorticoid potency. An example of a commonly prescribed alternative steroid equivalent would be prednisone (5 mg) = cortisone (25 mg) = dexamethasone (0.75 mg) = hydrocortisone (20 mg) = methylprednisolone (4 mg). These doses represent pharmacological equivalents to systemic administration of glucocorticoids. Another corticosteroid comparison chart showing the half-lives of various substances can be found, for example, at www.nadf.us / downloads / adrenalhormone.pdf. Corticosteroid conversion calculators or equivalent tables are available on the internet.

[0101] Examples of GCs that may be used as premedication or co-medication in this embodiment include, but are not limited to, cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, beclomethasone, budesonide, triamcinolone, cloprednol, deflazacort, fluocortolone, cortivazol, paramethasone, fluticasone, fluticasone propionate, triamcinolone acetonide, and combinations and / or pharmaceutically acceptable derivatives thereof. Different GCs may be used alone or in combination in the context of the present invention. Dexamethasone, prednisone, and prednisolone are preferred embodiments of GCs.

[0102] It is envisioned that all substances already classified or to be classified as "glucocorticoids" may similarly be used in connection with the present invention. Such future glucocorticoids include compounds that specifically bind to and activate the glucocorticoid receptor. The term "specifically binds to the GC receptor" means, according to the present invention, that a GC (or a compound assumed to act like a GC) associates (e.g., interacts) with the GC receptor (also known as NR3C1) to a statistically significant degree compared to association with proteins / receptors in general (i.e., non-specific binding). When the GC receptor binds to glucocorticoids, its primary mechanism of action is the regulation of gene transcription. In the absence of GCs, the glucocorticoid receptor (GR) is present in the cytosol complexed with various proteins, including heat shock protein 90 (hsp90), heat shock protein 70 (hsp70), and the protein FKBP52 (FK506-binding protein 52). Binding of GCs to the glucocorticoid receptor results in the release of heat shock proteins. Therefore, it is expected that future GCs or pharmaceutically acceptable derivatives or salts of GCs can bind to the GC receptor and release the heat shock proteins described above. The activated GR complex then upregulates the expression of anti-inflammatory proteins in the nucleus or suppresses the expression of pro-inflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol to the nucleus.

[0103] The antibody construct of the invention comprises a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends (or enhances) the half-life of the antibody construct.

[0104] The term "antibody construct" refers to a molecule whose structure and / or function is based on that of an antibody (e.g., a full-length immunoglobulin molecule). Thus, an antibody construct immunospecifically binds to its target or antigen and / or comprises domains derived from or consisting of the heavy chain variable region (VH) and / or light chain variable region (VL) of an antibody. Furthermore, an antibody construct according to the present invention comprises the minimum structural requirements of an antibody that enable immunospecific target binding. This minimum requirement may be defined, for example, by the presence of at least three light chain CDRs (i.e., CDR1, CDR2, and CDR3 of the VL region) and / or three heavy chain CDRs (i.e., CDR1, CDR2, and CDR3 of the VH region), preferably all six CDRs.

[0105] Within the definition of "antibody" according to the present invention are full-length antibodies, including camelid antibodies and other immunoglobulins produced by biotechnology or protein engineering methods or processes. Such full-length antibodies may be, for example, monoclonal, recombinant, chimeric, deimmunized, humanized and human antibodies, as well as antibodies from other species such as mouse, hamster, rabbit, rat, goat or non-human primate.

[0106] An "antibody construct" of the present invention may have the general structure of a full-length immunoglobulin as it occurs in nature. For example, an antibody construct may comprise (at least) two full-length antibody heavy chains and two full-length antibody light chains. However, given that an antibody construct according to the present invention comprises one domain that binds to BCMA and another domain that binds to CD3, this does not occur in nature and differs significantly in function from the naturally occurring product. Thus, an antibody construct of the present invention is an artificial "hybrid" molecule comprising at least two distinct binding domains with different specificities.

[0107] "Antibody constructs" of the invention may also comprise fragments of full-length antibodies, such as VH, VHH, VL, (s)dAb, Fv, light chain (VL-CL), Fd (VH-CH1), heavy chain, Fab, Fab', F(ab')2 or "rIgG" (a "half antibody" consisting of a heavy and light chain). Antibody constructs according to the invention may also comprise modified fragments of antibodies, also referred to as antibody variants or antibody derivatives. Examples include, but are not limited to, scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, "minibodies" exemplified by structures such as: (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2, multibodies such as triabodies or tetrabodies, and single domain antibodies, such as nanobodies or single variable domain antibodies comprising only one variable region which may be VHH, VH or VL, which specifically bind to an antigen or target independent of other variable regions or domains. Further possible formats of antibody constructs according to the present invention are crossbodies, maxibodies, hetero-Fc constructs, mono-Fc constructs and scFc constructs.

[0108] Furthermore, the definition of the term "antibody construct" includes bivalent and multivalent / multivalent constructs that specifically bind to two, three, or more antigen structures via different binding domains. Thus, an antibody construct may have greater valency than specificity, for example, if it has two binding domains for a first target (BCMA) and one binding domain for a second target (CD3), or vice versa, in which case the construct is trivalent and bispecific. Furthermore, the definition of the term "antibody construct" includes molecules consisting of only one polypeptide chain (single-chain polypeptide), as well as molecules consisting of two, three, four, or more polypeptide chains, which may be identical (homodimers, homotrimers, or homooligomers) or different (heterodimers, heterotrimers, or heterooligomers). Examples of the above-identified antibodies and their fragments, variants, derivatives and antibody constructs derived therefrom are described, inter alia, in Harlow and Lane, Antibodies: A laboratory manual, CSHL Press (1988); Kontermann and Duebel, Antibody Engineering, Springer, 2nd ed. 2010; and Little, Recombinant Antibodies for Immunotherapy, Cambridge University Press 2009. It is envisaged that the antibody construct of the present invention is a single-chain antibody construct / single-chain polypeptide.

[0109] The term "binding domain" or "domain that binds to" in the context of the present invention characterizes a domain of an antibody construct that immunospecifically binds to / interacts with / recognizes a given epitope on a target or antigen (here, BCMA in the case of the first domain and CD3 in the case of the second domain). The structure and function of the first domain (binding to BCMA) and also preferably the structure and / or function of the second domain (binding to CD3) are based on the structure and / or function of an antibody, e.g., a full-length immunoglobulin molecule. Thus, a "binding domain" or "domain that binds to" may comprise the minimum structural requirement of an antibody that enables immunospecific target binding. This minimum structural requirement of the first domain may be defined, for example, by the presence of at least three light chain CDRs (i.e., CDR1, CDR2, and CDR3 of the VL region) and / or three heavy chain CDRs (i.e., CDR1, CDR2, and CDR3 of the VH region), preferably all six CDRs. It is envisioned that the second domain also comprises this minimum structural requirement of an antibody that enables immunospecific target binding. More preferably, the second domain also comprises at least three light chain CDRs (i.e., CDR1, CDR2, and CDR3 of the VL region) and / or three heavy chain CDRs (i.e., CDR1, CDR2, and CDR3 of the VH region), preferably all six CDRs. A "domain that binds to" (or "binding domain") will typically comprise an antibody light chain variable region (VL) and an antibody heavy chain variable region (VH); however, it need not comprise both and may comprise only VH or VL. Fd fragments, for example, often retain some antigen-binding function of an intact antigen-binding domain.

[0110] Examples of formats of a "domain that binds to" (or "binding domain") include full-length antibodies, fragments of full-length antibodies (such as VH, VHH, VL), (s)dAb, Fv, light chain (VL-CL), Fd (VH-CH1), heavy chain, Fab, Fab', F(ab')2 or "rIgG" ("half antibody"), antibody variants or derivatives such as scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies, and the like. These include, but are not limited to, di-scFvs, tandem di-scFvs, tandem tri-scFvs, "minibodies" (selected from formats such as (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), multibodies such as triabodies or tetrabodies, and single domain antibodies such as nanobodies or single variable domain antibodies that comprise only one variable region, which may be VHH, VH or VL. Further examples of formats of "domains that bind to" (or "binding domains") include: (1) antibody fragments or antibody variants (e.g., Fab) comprising a VL, VH, CL, and CH1; (2) antibody fragments or antibody variants (e.g., F(ab')2) comprising two linked Fab fragments; (3) antibody fragments or antibody variants (e.g., Fd) comprising a VH and CH1; (4) antibody fragments or antibody variants (e.g., light chain) comprising a VL and CL; (5) antibody fragments or antibody variants (e.g., Fv) comprising a VL and VH; (5) dAb fragments having a VH domain (Ward et al., (1989) Nature 341:544-546); (6) antibody variants comprising at least three isolated CDRs of the heavy and / or light chain; and (7) single-chain Fvs (scFvs).Examples of embodiments of antibody constructs or binding domains according to the invention are described, for example, in WO 00 / 006605, WO 2005 / 040220, WO 2008 / 119567, WO 2010 / 037838, WO 2013 / 026837, WO 2013 / 026833, U.S. Patent Application Publication Nos. 2014 / 0308285, 2014 / 0302037, WO 2014 / 144722, WO 2014 / 151910 and WO 2015 / 048272.

[0111] The terms "bind (specifically or immunospecifically) to," "recognize (specifically or immunospecifically) to," or "react (specifically or immunospecifically) with," according to the present invention, mean that an antibody construct or binding domain interacts or (immuno)specifically interacts with a given epitope on a target molecule (antigen), here BCMA and CD3, respectively. This interaction or association may occur more frequently, more rapidly, of longer duration, with higher affinity, or some combination of the above, for an epitope on a specific target than for an alternative substance (non-target molecule). However, due to sequence similarity between homologous proteins in different species, an antibody construct or binding domain that immunospecifically binds to its target (e.g., a human target) may cross-react with a homologous target molecule from a different species (e.g., a non-human primate, e.g., macaque). Thus, the term "specific / immunospecific binding" can include binding by an antibody construct or binding domain to epitopes in multiple species or to structurally related epitopes.

[0112] In the context of the present invention, the term "epitope" refers to a part or region of an antigen that is recognized / immunospecifically recognized by a binding domain. An "epitope" is antigenic, and therefore the term epitope is sometimes also referred to as an "antigenic structure" or "antigenic determinant." The part of the binding domain that binds to the epitope is called a paratope. Specific binding is believed to be achieved by a specific motif in the amino acid sequence of the binding domain and the antigen. Binding is therefore achieved as a result of its primary, secondary, and / or tertiary structure and potential secondary modifications of said structure. When the paratope specifically interacts with its antigenic determinant, said site may simply bind to the antigen. In some cases, the specific interaction may alternatively or additionally elicit a signal, for example, due to the induction of a conformational change in the antigen, oligomerization of the antigen, etc.

[0113] Epitopes of protein antigens are classified into two categories, conformational epitopes and linear epitopes, based on their structure and interaction with the paratope. Conformational epitopes are composed of discontinuous sections of the antigen's amino acid sequence. These epitopes interact with the paratope based on the antigen's three-dimensional surface characteristics and shape or tertiary structure (folding). Methods for determining the conformation of epitopes include, but are not limited to, X-ray crystallography, two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy, and site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy. In contrast, linear epitopes interact with the paratope based on their primary structure. Linear epitopes are formed by contiguous amino acid sequences from the antigen, typically containing at least three or at least four amino acids in a unique sequence, more commonly at least five, at least six, or at least seven, e.g., about 8 to about 10 amino acids.

[0114] The interaction between the binding domain and the epitope of the target antigen indicates that the binding domain exhibits recognizable or significant affinity for the epitope / target antigen (here, BCMA and CD3, respectively). Generally, it does not further exhibit significant affinity for proteins or antigens other than the target antigen (here, BCMA / CD3) - even if there is cross-reactivity with, for example, homologous targets from other species, as discussed above. "Significant affinity" refers to an affinity of ≦10 -6 Preferably, the binding is with an affinity (dissociation constant, KD) of ≦10 -7 M, ≤10 -8 M, ≤10 -9 M, ≤10 -10 M or even ≦10 -11 M or ≦10 -12 A binding domain (immune) is considered specific when its affinity is M. Whether a binding domain (immune) specifically reacts with or binds to a target can be easily tested, for example, by comparing the affinity of the binding domain for its desired target protein or antigen with the affinity of the binding domain for a non-target protein or antigen (here, a protein other than BCMA or CD3, respectively). Preferably, the antibody constructs of the invention do not significantly bind to proteins or antigens other than BCMA or CD3, respectively (i.e., the first domain does not bind to proteins other than BCMA, and the second domain does not bind to proteins other than CD3). For example, it is envisioned that the antibody constructs of the invention (more specifically, their first domains) do not significantly bind, interact, recognize, or cross-react with human BAFF-R and / or human TACI.

[0115] The equilibrium dissociation constant (KD) of the antibody constructs of the invention for BCMA can be determined by Scatchard or Biacore analysis, for example, as described in WO 2013 / 072406. KD values ​​for CD3 can be determined by, for example, surface plasmon resonance analysis, for example, as described in WO 2013 / 072406. It is envisioned that the antibody constructs of the invention have KD values ​​for BCMA and / or CD3 in the double-digit or single-digit nanomolar range, or the triple-digit or even double-digit picomolar range.

[0116] The term "does not significantly bind" means that the antibody construct or binding domain of the invention does not bind to proteins or antigens other than BCMA or CD3, i.e., when binding to BCMA or CD3, respectively, is taken as 100%, it shows no more than 30%, preferably no more than 20%, more preferably no more than 10%, and particularly preferably no more than 9%, 8%, 7%, 6% or 5% reactivity with proteins or antigens other than BCMA or CD3.

[0117] According to one embodiment of the antibody construct of the present invention, the first and / or second domain is in the form of an scFv (single-chain variable fragment). An scFv is not actually an antibody fragment, but instead a fusion protein of the variable regions of the heavy (VH) and light (VL) chains of an immunoglobulin linked by a short linker peptide. The linker is usually glycine-rich for flexibility and serine- or threonine-rich for solubility. The scFv is designed to retain the specificity of the original immunoglobulin despite the removal of the constant regions and the introduction of the linker. In an scFv, the VH and VL regions are arranged (from N- to C-terminus) in the order VH-VL or VL-VH. It is envisaged that the VH and VL regions of the first and / or second binding domain are linked via a linker, preferably a peptide linker. According to one embodiment of the first and / or second domain, the VH region is located N-terminally of the linker, and the VL region is located C-terminally of the linker. It is further contemplated that the first and second domains of the antibody construct are connected via a linker, preferably a peptide linker. The linker is preferably a peptide linker, more preferably a short-chain peptide linker. Examples are provided in SEQ ID NOs: 686-699. In this context, a "short" linker has 2-50 amino acids, preferably 3-35, 4-30, 5-25, 6-20, or 6-17 amino acids. The linker between the two variable regions of one binding domain may have a different length (e.g., may be longer) than the linker between the two binding domains. For example, the linker between the two variable regions of one binding domain may have a length of 7-15 amino acids, preferably 9-13 amino acids, and the linker between the two binding domains may have a length of 3-10 amino acids, preferably 4-8 amino acids. It is further contemplated that the peptide linker is a glycine / serine linker, such as those set forth in SEQ ID NOs: 687, 689-699.

[0118] Regarding the antibody construct of the present invention, a) the antibody construct is a single polypeptide chain; b) the first domain is in the form of an scFv; c) the second domain is in the form of an scFv, and / or d) It is envisaged that the first domain and the second domain are linked via a linker, preferably a peptide linker, more preferably a glycine / serine linker.

[0119] The first domain of the antibody construct of the present invention binds to BCMA (B cell maturation antigen, TNFRSF17, CD269). More preferably, it binds to BCMA on the surface of a target cell. A "target cell" can be any prokaryotic or eukaryotic cell that expresses BCMA on its surface. Preferably, the target cell is a cell of a part of the human or animal body, such as a specific BCMA-expressing cancer or tumor cell or a cell of a BCMA-positive neoplasm. It is further envisioned that the first domain binds to human BCMA, preferably human BCMA on the surface of the target cell. It is also envisioned that the first domain binds to macaque BCMA, preferably macaque BCMA on the surface of the target cell. Preferred amino acid sequences are set forth in SEQ ID NO: 647 for human BCMA, SEQ ID NO: 648 for macaque BCMA, SEQ ID NO: 649 for the extracellular domain of human BCMA, and SEQ ID NO: 650 for the extracellular domain of macaque BCMA.

[0120] In one embodiment of the invention, the first domain of the antibody construct binds to epitope cluster 3 of BCMA. More preferably, it binds to epitope cluster 3 of human BCMA. A preferred amino acid sequence for epitope cluster 3 of human BCMA is set forth in SEQ ID NO: 651. Antibody constructs having a domain that binds to said epitope cluster 3 of BCMA are detailed in WO 2013 / 072406. These antibody constructs are shown in WO 2013 / 072406 to have very advantageous epitope / activity relationships.

[0121] The method for BCMA epitope mapping is used in WO 2013 / 072406 and is described as follows: one or more predetermined regions within the extracellular domain of human BCMA (each in the form of a contiguous stretch of amino acids) are exchanged / substituted with the corresponding region of a rodent BCMA molecule (such as mouse BCMA, although other rodent species are also contemplated as long as the binding domain is not cross-reactive with the rodent species used). These human BCMA / rodent (murine) BCMA chimeras are expressed on the surface of host cells (such as CHO cells). Binding of the antibody or antibody construct can be tested via FACS analysis. If binding of the antibody or antibody construct to the chimeric molecule is completely abolished or significantly reduced binding is observed, it can be concluded that the region of human BCMA removed from the chimeric molecule is relevant to immunospecific epitope-paratope recognition. The reduction in binding (taking binding to human BCMA as 100%) is preferably at least 10%, 20%, 30%, 40% or 50%; more preferably at least 60%, 70% or 80%, and most preferably 90%, 95% or even 100% compared to binding to human (wild-type) BCMA. Alternatively or additionally, the above-described epitope mapping analysis may be modified by introducing one or more point mutations into the sequence of the extracellular domain of BCMA.

[0122] For the antibody constructs of the present invention, the first domain that binds to BCMA comprises: (1) CDR-H1 as set forth in SEQ ID NO: 1, CDR-H2 as set forth in SEQ ID NO: 2, CDR-H3 as set forth in SEQ ID NO: 3, CDR-L1 as set forth in SEQ ID NO: 4, CDR-L2 as set forth in SEQ ID NO: 5, and CDR-L3 as set forth in SEQ ID NO: 6; (2) CDR-H1 as set forth in SEQ ID NO: 11, CDR-H2 as set forth in SEQ ID NO: 12, CDR-H3 as set forth in SEQ ID NO: 13, CDR-L1 as set forth in SEQ ID NO: 14, CDR-L2 as set forth in SEQ ID NO: 15, and CDR-L3 as set forth in SEQ ID NO: 16; (3) CDR-H1 as set forth in SEQ ID NO: 21, CDR-H2 as set forth in SEQ ID NO: 22, CDR-H3 as set forth in SEQ ID NO: 23, CDR-L1 as set forth in SEQ ID NO: 24, CDR-L2 as set forth in SEQ ID NO: 25, and CDR-L3 as set forth in SEQ ID NO: 26; (4) CDR-H1 as set forth in SEQ ID NO: 31, CDR-H2 as set forth in SEQ ID NO: 32, CDR-H3 as set forth in SEQ ID NO: 33, CDR-L1 as set forth in SEQ ID NO: 34, CDR-L2 as set forth in SEQ ID NO: 35, and CDR-L3 as set forth in SEQ ID NO: 36; (5) CDR-H1 as set forth in SEQ ID NO: 41, CDR-H2 as set forth in SEQ ID NO: 42, CDR-H3 as set forth in SEQ ID NO: 43, CDR-L1 as set forth in SEQ ID NO: 44, CDR-L2 as set forth in SEQ ID NO: 45, and CDR-L3 as set forth in SEQ ID NO: 46; (6) CDR-H1 as set forth in SEQ ID NO: 51, CDR-H2 as set forth in SEQ ID NO: 52, CDR-H3 as set forth in SEQ ID NO: 53, CDR-L1 as set forth in SEQ ID NO: 54, CDR-L2 as set forth in SEQ ID NO: 55, and CDR-L3 as set forth in SEQ ID NO: 56; (7) CDR-H1 as set forth in SEQ ID NO: 61, CDR-H2 as set forth in SEQ ID NO: 62, CDR-H3 as set forth in SEQ ID NO: 63, CDR-L1 as set forth in SEQ ID NO: 64, CDR-L2 as set forth in SEQ ID NO: 65, and CDR-L3 as set forth in SEQ ID NO: 66; (8) CDR-H1 as shown in SEQ ID NO: 71, CDR-H2 as shown in SEQ ID NO: 72, CDR-H3 as shown in SEQ ID NO: 73, CDR-L1 as shown in SEQ ID NO: 74, CDR-L2 as shown in SEQ ID NO: 75, and CDR-L3 as shown in SEQ ID NO: 76; (9) CDR-H1 as set forth in SEQ ID NO: 81, CDR-H2 as set forth in SEQ ID NO: 82, CDR-H3 as set forth in SEQ ID NO: 83, CDR-L1 as set forth in SEQ ID NO: 84, CDR-L2 as set forth in SEQ ID NO: 85, and CDR-L3 as set forth in SEQ ID NO: 86; (10) CDR-H1 as set forth in SEQ ID NO: 91, CDR-H2 as set forth in SEQ ID NO: 92, CDR-H3 as set forth in SEQ ID NO: 93, CDR-L1 as set forth in SEQ ID NO: 94, CDR-L2 as set forth in SEQ ID NO: 95, and CDR-L3 as set forth in SEQ ID NO: 96; (11) CDR-H1 as shown in SEQ ID NO: 101, CDR-H2 as shown in SEQ ID NO: 102, CDR-H3 as shown in SEQ ID NO: 103, CDR-L1 as shown in SEQ ID NO: 104, CDR-L2 as shown in SEQ ID NO: 105, and CDR-L3 as shown in SEQ ID NO: 106; (12) CDR-H1 as set forth in SEQ ID NO: 111, CDR-H2 as set forth in SEQ ID NO: 112, CDR-H3 as set forth in SEQ ID NO: 113, CDR-L1 as set forth in SEQ ID NO: 114, CDR-L2 as set forth in SEQ ID NO: 115, and CDR-L3 as set forth in SEQ ID NO: 116; (13) CDR-H1 as set forth in SEQ ID NO: 121, CDR-H2 as set forth in SEQ ID NO: 122, CDR-H3 as set forth in SEQ ID NO: 123, CDR-L1 as set forth in SEQ ID NO: 124, CDR-L2 as set forth in SEQ ID NO: 125, and CDR-L3 as set forth in SEQ ID NO: 126; (14) CDR-H1 as set forth in SEQ ID NO: 131, CDR-H2 as set forth in SEQ ID NO: 132, CDR-H3 as set forth in SEQ ID NO: 133, CDR-L1 as set forth in SEQ ID NO: 134, CDR-L2 as set forth in SEQ ID NO: 135, and CDR-L3 as set forth in SEQ ID NO: 136; (15) CDR-H1 as set forth in SEQ ID NO: 141, CDR-H2 as set forth in SEQ ID NO: 142, CDR-H3 as set forth in SEQ ID NO: 143, CDR-L1 as set forth in SEQ ID NO: 144, CDR-L2 as set forth in SEQ ID NO: 145, and CDR-L3 as set forth in SEQ ID NO: 146; (16) CDR-H1 as set forth in SEQ ID NO: 151, CDR-H2 as set forth in SEQ ID NO: 152, CDR-H3 as set forth in SEQ ID NO: 153, CDR-L1 as set forth in SEQ ID NO: 154, CDR-L2 as set forth in SEQ ID NO: 155, and CDR-L3 as set forth in SEQ ID NO: 156; (17) CDR-H1 as set forth in SEQ ID NO: 161, CDR-H2 as set forth in SEQ ID NO: 162, CDR-H3 as set forth in SEQ ID NO: 163, CDR-L1 as set forth in SEQ ID NO: 164, CDR-L2 as set forth in SEQ ID NO: 165, and CDR-L3 as set forth in SEQ ID NO: 166; (18) CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, CDR-H3 as set forth in SEQ ID NO: 173, CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 175, and CDR-L3 as set forth in SEQ ID NO: 176; (19) CDR-H1 as set forth in SEQ ID NO: 181, CDR-H2 as set forth in SEQ ID NO: 182, CDR-H3 as set forth in SEQ ID NO: 183, CDR-L1 as set forth in SEQ ID NO: 184, CDR-L2 as set forth in SEQ ID NO: 185, and CDR-L3 as set forth in SEQ ID NO: 186; (20) CDR-H1 as set forth in SEQ ID NO: 191, CDR-H2 as set forth in SEQ ID NO: 192, CDR-H3 as set forth in SEQ ID NO: 193, CDR-L1 as set forth in SEQ ID NO: 194, CDR-L2 as set forth in SEQ ID NO: 195, and CDR-L3 as set forth in SEQ ID NO: 196; (21) CDR-H1 as set forth in SEQ ID NO: 201, CDR-H2 as set forth in SEQ ID NO: 202, CDR-H3 as set forth in SEQ ID NO: 203, CDR-L1 as set forth in SEQ ID NO: 204, CDR-L2 as set forth in SEQ ID NO: 205, and CDR-L3 as set forth in SEQ ID NO: 206; (22) CDR-H1 as set forth in SEQ ID NO: 211, CDR-H2 as set forth in SEQ ID NO: 212, CDR-H3 as set forth in SEQ ID NO: 213, CDR-L1 as set forth in SEQ ID NO: 214, CDR-L2 as set forth in SEQ ID NO: 215, and CDR-L3 as set forth in SEQ ID NO: 216; (23) CDR-H1 as set forth in SEQ ID NO: 221, CDR-H2 as set forth in SEQ ID NO: 222, CDR-H3 as set forth in SEQ ID NO: 223, CDR-L1 as set forth in SEQ ID NO: 224, CDR-L2 as set forth in SEQ ID NO: 225, and CDR-L3 as set forth in SEQ ID NO: 226; (24) CDR-H1 as set forth in SEQ ID NO: 231, CDR-H2 as set forth in SEQ ID NO: 232, CDR-H3 as set forth in SEQ ID NO: 233, CDR-L1 as set forth in SEQ ID NO: 234, CDR-L2 as set forth in SEQ ID NO: 235, and CDR-L3 as set forth in SEQ ID NO: 236; (25) CDR-H1 as set forth in SEQ ID NO: 241, CDR-H2 as set forth in SEQ ID NO: 242, CDR-H3 as set forth in SEQ ID NO: 243, CDR-L1 as set forth in SEQ ID NO: 244, CDR-L2 as set forth in SEQ ID NO: 245, and CDR-L3 as set forth in SEQ ID NO: 246; (26) CDR-H1 as set forth in SEQ ID NO: 251, CDR-H2 as set forth in SEQ ID NO: 252, CDR-H3 as set forth in SEQ ID NO: 253, CDR-L1 as set forth in SEQ ID NO: 254, CDR-L2 as set forth in SEQ ID NO: 255, and CDR-L3 as set forth in SEQ ID NO: 256; (27) CDR-H1 as set forth in SEQ ID NO: 261, CDR-H2 as set forth in SEQ ID NO: 262, CDR-H3 as set forth in SEQ ID NO: 263, CDR-L1 as set forth in SEQ ID NO: 264, CDR-L2 as set forth in SEQ ID NO: 265, and CDR-L3 as set forth in SEQ ID NO: 266; (28) CDR-H1 as set forth in SEQ ID NO: 271, CDR-H2 as set forth in SEQ ID NO: 272, CDR-H3 as set forth in SEQ ID NO: 273, CDR-L1 as set forth in SEQ ID NO: 274, CDR-L2 as set forth in SEQ ID NO: 275, and CDR-L3 as set forth in SEQ ID NO: 276; (29) CDR-H1 as set forth in SEQ ID NO: 281, CDR-H2 as set forth in SEQ ID NO: 282, CDR-H3 as set forth in SEQ ID NO: 283, CDR-L1 as set forth in SEQ ID NO: 284, CDR-L2 as set forth in SEQ ID NO: 285, and CDR-L3 as set forth in SEQ ID NO: 286; (30) CDR-H1 as set forth in SEQ ID NO: 291, CDR-H2 as set forth in SEQ ID NO: 292, CDR-H3 as set forth in SEQ ID NO: 293, CDR-L1 as set forth in SEQ ID NO: 294, CDR-L2 as set forth in SEQ ID NO: 295, and CDR-L3 as set forth in SEQ ID NO: 296; (31) CDR-H1 as set forth in SEQ ID NO: 301, CDR-H2 as set forth in SEQ ID NO: 302, CDR-H3 as set forth in SEQ ID NO: 303, CDR-L1 as set forth in SEQ ID NO: 304, CDR-L2 as set forth in SEQ ID NO: 305, and CDR-L3 as set forth in SEQ ID NO: 306; (32) CDR-H1 as set forth in SEQ ID NO: 311, CDR-H2 as set forth in SEQ ID NO: 312, CDR-H3 as set forth in SEQ ID NO: 313, CDR-L1 as set forth in SEQ ID NO: 314, CDR-L2 as set forth in SEQ ID NO: 315, and CDR-L3 as set forth in SEQ ID NO: 316; (33) CDR-H1 as set forth in SEQ ID NO: 321, CDR-H2 as set forth in SEQ ID NO: 322, CDR-H3 as set forth in SEQ ID NO: 323, CDR-L1 as set forth in SEQ ID NO: 324, CDR-L2 as set forth in SEQ ID NO: 325, and CDR-L3 as set forth in SEQ ID NO: 326; (34) CDR-H1 as set forth in SEQ ID NO: 331, CDR-H2 as set forth in SEQ ID NO: 332, CDR-H3 as set forth in SEQ ID NO: 333, CDR-L1 as set forth in SEQ ID NO: 334, CDR-L2 as set forth in SEQ ID NO: 335, and CDR-L3 as set forth in SEQ ID NO: 336; (35) CDR-H1 as set forth in SEQ ID NO: 341, CDR-H2 as set forth in SEQ ID NO: 342, CDR-H3 as set forth in SEQ ID NO: 343, CDR-L1 as set forth in SEQ ID NO: 344, CDR-L2 as set forth in SEQ ID NO: 345, and CDR-L3 as set forth in SEQ ID NO: 346; (36) CDR-H1 as set forth in SEQ ID NO: 351, CDR-H2 as set forth in SEQ ID NO: 352, CDR-H3 as set forth in SEQ ID NO: 353, CDR-L1 as set forth in SEQ ID NO: 354, CDR-L2 as set forth in SEQ ID NO: 355, and CDR-L3 as set forth in SEQ ID NO: 356; (37) CDR-H1 as set forth in SEQ ID NO: 361, CDR-H2 as set forth in SEQ ID NO: 362, CDR-H3 as set forth in SEQ ID NO: 363, CDR-L1 as set forth in SEQ ID NO: 364, CDR-L2 as set forth in SEQ ID NO: 365, and CDR-L3 as set forth in SEQ ID NO: 366; (38) CDR-H1 as set forth in SEQ ID NO: 371, CDR-H2 as set forth in SEQ ID NO: 372, CDR-H3 as set forth in SEQ ID NO: 373, CDR-L1 as set forth in SEQ ID NO: 374, CDR-L2 as set forth in SEQ ID NO: 375, and CDR-L3 as set forth in SEQ ID NO: 376; (39) CDR-H1 as set forth in SEQ ID NO: 381, CDR-H2 as set forth in SEQ ID NO: 382, ​​CDR-H3 as set forth in SEQ ID NO: 383, CDR-L1 as set forth in SEQ ID NO: 384, CDR-L2 as set forth in SEQ ID NO: 385, and CDR-L3 as set forth in SEQ ID NO: 386; (40) CDR-H1 as set forth in SEQ ID NO: 391, CDR-H2 as set forth in SEQ ID NO: 392, CDR-H3 as set forth in SEQ ID NO: 393, CDR-L1 as set forth in SEQ ID NO: 394, CDR-L2 as set forth in SEQ ID NO: 395, and CDR-L3 as set forth in SEQ ID NO: 396; (41) CDR-H1 as set forth in SEQ ID NO: 401, CDR-H2 as set forth in SEQ ID NO: 402, CDR-H3 as set forth in SEQ ID NO: 403, CDR-L1 as set forth in SEQ ID NO: 404, CDR-L2 as set forth in SEQ ID NO: 405, and CDR-L3 as set forth in SEQ ID NO: 406; (42) CDR-H1 as set forth in SEQ ID NO: 411, CDR-H2 as set forth in SEQ ID NO: 412, CDR-H3 as set forth in SEQ ID NO: 413, CDR-L1 as set forth in SEQ ID NO: 414, CDR-L2 as set forth in SEQ ID NO: 415, and CDR-L3 as set forth in SEQ ID NO: 416; (43) CDR-H1 as set forth in SEQ ID NO: 421, CDR-H2 as set forth in SEQ ID NO: 422, CDR-H3 as set forth in SEQ ID NO: 423, CDR-L1 as set forth in SEQ ID NO: 424, CDR-L2 as set forth in SEQ ID NO: 425, and CDR-L3 as set forth in SEQ ID NO: 426; (44) CDR-H1 as set forth in SEQ ID NO: 431, CDR-H2 as set forth in SEQ ID NO: 432, CDR-H3 as set forth in SEQ ID NO: 433, CDR-L1 as set forth in SEQ ID NO: 434, CDR-L2 as set forth in SEQ ID NO: 435, and CDR-L3 as set forth in SEQ ID NO: 436; (45) CDR-H1 as set forth in SEQ ID NO: 441, CDR-H2 as set forth in SEQ ID NO: 442, CDR-H3 as set forth in SEQ ID NO: 443, CDR-L1 as set forth in SEQ ID NO: 444, CDR-L2 as set forth in SEQ ID NO: 445, and CDR-L3 as set forth in SEQ ID NO: 446; (46) CDR-H1 as set forth in SEQ ID NO: 451, CDR-H2 as set forth in SEQ ID NO: 452, CDR-H3 as set forth in SEQ ID NO: 453, CDR-L1 as set forth in SEQ ID NO: 454, CDR-L2 as set forth in SEQ ID NO: 455, and CDR-L3 as set forth in SEQ ID NO: 456; (47) CDR-H1 as set forth in SEQ ID NO: 461, CDR-H2 as set forth in SEQ ID NO: 462, CDR-H3 as set forth in SEQ ID NO: 463, CDR-L1 as set forth in SEQ ID NO: 464, CDR-L2 as set forth in SEQ ID NO: 465, and CDR-L3 as set forth in SEQ ID NO: 466; (48) CDR-H1 as set forth in SEQ ID NO: 471, CDR-H2 as set forth in SEQ ID NO: 472, CDR-H3 as set forth in SEQ ID NO: 473, CDR-L1 as set forth in SEQ ID NO: 474, CDR-L2 as set forth in SEQ ID NO: 475, and CDR-L3 as set forth in SEQ ID NO: 476; (49) CDR-H1 as set forth in SEQ ID NO: 481, CDR-H2 as set forth in SEQ ID NO: 482, CDR-H3 as set forth in SEQ ID NO: 483, CDR-L1 as set forth in SEQ ID NO: 484, CDR-L2 as set forth in SEQ ID NO: 485, and CDR-L3 as set forth in SEQ ID NO: 486; (50) CDR-H1 as set forth in SEQ ID NO: 491, CDR-H2 as set forth in SEQ ID NO: 492, CDR-H3 as set forth in SEQ ID NO: 493, CDR-L1 as set forth in SEQ ID NO: 494, CDR-L2 as set forth in SEQ ID NO: 495, and CDR-L3 as set forth in SEQ ID NO: 496; (51) CDR-H1 as set forth in SEQ ID NO: 501, CDR-H2 as set forth in SEQ ID NO: 502, CDR-H3 as set forth in SEQ ID NO: 503, CDR-L1 as set forth in SEQ ID NO: 504, CDR-L2 as set forth in SEQ ID NO: 505, and CDR-L3 as set forth in SEQ ID NO: 506; (52) CDR-H1 as set forth in SEQ ID NO: 511, CDR-H2 as set forth in SEQ ID NO: 512, CDR-H3 as set forth in SEQ ID NO: 513, CDR-L1 as set forth in SEQ ID NO: 514, CDR-L2 as set forth in SEQ ID NO: 515, and CDR-L3 as set forth in SEQ ID NO: 516; and (53) CDR-H1 as shown in SEQ ID NO: 521, CDR-H2 as shown in SEQ ID NO: 522, CDR-H3 as shown in SEQ ID NO: 523, CDR-L1 as shown in SEQ ID NO: 524, CDR-L2 as shown in SEQ ID NO: 525, and CDR-L3 as shown in SEQ ID NO: 526 It is further envisioned that the antibody comprises a VH region comprising CDR-H1, CDR-H2, and CDR-H3, and a VL region comprising CDR-L1, CDR-L2, and CDR-L3 selected from:

[0123] It is also envisaged that for the antibody constructs of the invention, the first domain that binds to BCMA comprises a VL region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 8, 18, 28, 38, 48, 58, 68, 78, 88, 98, 108, 118, 128, 138, 148, 158, 168, 178, 188, 198, 208, 218, 228, 238, 248, 258, 268, 278, 288, 298, 308, 318, 328, 338, 348, 358, 368, 378, 388, 398, 408, 418, 428, 438, 448, 458, 468, 478, 488, 498, 508, 518 and 528. The first domain is envisioned to comprise a VL region having an amino acid sequence as set forth in SEQ ID NO:178.

[0124] It is further envisaged that the first domain that binds to BCMA comprises a VH region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 307, 317, 327, 337, 347, 357, 367, 377, 387, 397, 407, 417, 427, 437, 447, 457, 467, 477, 487, 497, 507, 517 and 527. The first domain is envisioned to comprise a VH region having the amino acid sequence as set forth in SEQ ID NO:177.

[0125] Furthermore, with regard to the antibody construct of the present invention, the first domain that binds to BCMA is (1) a VH region as set forth in SEQ ID NO: 7 and a VL region as set forth in SEQ ID NO: 8; (2) a VH region as set forth in SEQ ID NO: 17 and a VL region as set forth in SEQ ID NO: 18; (3) a VH region as set forth in SEQ ID NO: 27 and a VL region as set forth in SEQ ID NO: 28; (4) a VH region as set forth in SEQ ID NO: 37 and a VL region as set forth in SEQ ID NO: 38; (5) a VH region as set forth in SEQ ID NO: 47 and a VL region as set forth in SEQ ID NO: 48; (6) a VH region as set forth in SEQ ID NO: 57 and a VL region as set forth in SEQ ID NO: 58; (7) a VH region as set forth in SEQ ID NO: 67 and a VL region as set forth in SEQ ID NO: 68; (8) a VH region as set forth in SEQ ID NO: 77 and a VL region as set forth in SEQ ID NO: 78; (9) a VH region as set forth in SEQ ID NO: 87 and a VL region as set forth in SEQ ID NO: 88; (10) a VH region as set forth in SEQ ID NO: 97 and a VL region as set forth in SEQ ID NO: 98; (11) a VH region as set forth in SEQ ID NO: 107 and a VL region as set forth in SEQ ID NO: 108; (12) a VH region as set forth in SEQ ID NO: 117 and a VL region as set forth in SEQ ID NO: 118; (13) a VH region as set forth in SEQ ID NO: 127 and a VL region as set forth in SEQ ID NO: 128; (14) a VH region as set forth in SEQ ID NO: 137 and a VL region as set forth in SEQ ID NO: 138; (15) a VH region as set forth in SEQ ID NO: 147 and a VL region as set forth in SEQ ID NO: 148; (16) a VH region as set forth in SEQ ID NO: 157 and a VL region as set forth in SEQ ID NO: 158; (17) A VH region as set forth in SEQ ID NO: 167 and a VL region as set forth in SEQ ID NO: 168; (18) A VH region as set forth in SEQ ID NO: 177 and a VL region as set forth in SEQ ID NO: 178; (19) A VH region as set forth in SEQ ID NO: 187 and a VL region as set forth in SEQ ID NO: 188; (20) a VH region as set forth in SEQ ID NO: 197 and a VL region as set forth in SEQ ID NO: 198; (21) a VH region as set forth in SEQ ID NO: 207 and a VL region as set forth in SEQ ID NO: 208; (22) a VH region as set forth in SEQ ID NO: 217 and a VL region as set forth in SEQ ID NO: 218; (23) a VH region as set forth in SEQ ID NO: 227 and a VL region as set forth in SEQ ID NO: 228; (24) a VH region as set forth in SEQ ID NO: 237 and a VL region as set forth in SEQ ID NO: 238; (25) a VH region as set forth in SEQ ID NO: 247 and a VL region as set forth in SEQ ID NO: 248; (26) a VH region as set forth in SEQ ID NO: 257 and a VL region as set forth in SEQ ID NO: 258; (27) A VH region as set forth in SEQ ID NO: 267 and a VL region as set forth in SEQ ID NO: 268; (28) a VH region as set forth in SEQ ID NO: 277 and a VL region as set forth in SEQ ID NO: 278; (29) a VH region as set forth in SEQ ID NO: 287 and a VL region as set forth in SEQ ID NO: 288; (30) a VH region as set forth in SEQ ID NO: 297 and a VL region as set forth in SEQ ID NO: 298; (31) A VH region as set forth in SEQ ID NO: 307 and a VL region as set forth in SEQ ID NO: 308; (32) a VH region as set forth in SEQ ID NO: 317 and a VL region as set forth in SEQ ID NO: 318; (33) a VH region as set forth in SEQ ID NO: 327 and a VL region as set forth in SEQ ID NO: 328; (34) a VH region as set forth in SEQ ID NO: 337 and a VL region as set forth in SEQ ID NO: 338; (35) a VH region as set forth in SEQ ID NO: 347 and a VL region as set forth in SEQ ID NO: 348; (36) a VH region as set forth in SEQ ID NO: 357 and a VL region as set forth in SEQ ID NO: 358; (37) A VH region as set forth in SEQ ID NO: 367 and a VL region as set forth in SEQ ID NO: 368; (38) a VH region as set forth in SEQ ID NO: 377 and a VL region as set forth in SEQ ID NO: 378; (39) a VH region as set forth in SEQ ID NO: 387 and a VL region as set forth in SEQ ID NO: 388; (40) a VH region as set forth in SEQ ID NO: 397 and a VL region as set forth in SEQ ID NO: 398; (41) A VH region as set forth in SEQ ID NO: 407 and a VL region as set forth in SEQ ID NO: 408; (42) a VH region as set forth in SEQ ID NO: 417 and a VL region as set forth in SEQ ID NO: 418; (43) a VH region as set forth in SEQ ID NO: 427 and a VL region as set forth in SEQ ID NO: 428; (44) a VH region as set forth in SEQ ID NO: 437 and a VL region as set forth in SEQ ID NO: 438; (45) a VH region as set forth in SEQ ID NO: 447 and a VL region as set forth in SEQ ID NO: 448; (46) A VH region as set forth in SEQ ID NO: 457 and a VL region as set forth in SEQ ID NO: 458; (47) A VH region as set forth in SEQ ID NO: 467 and a VL region as set forth in SEQ ID NO: 468; (48) a VH region as set forth in SEQ ID NO: 477 and a VL region as set forth in SEQ ID NO: 478; (49) A VH region as set forth in SEQ ID NO: 487 and a VL region as set forth in SEQ ID NO: 488; (50) a VH region as set forth in SEQ ID NO: 497 and a VL region as set forth in SEQ ID NO: 498; (51) A VH region as set forth in SEQ ID NO: 507 and a VL region as set forth in SEQ ID NO: 508; (52) a VH region as set forth in SEQ ID NO: 517 and a VL region as set forth in SEQ ID NO: 518; and (53) A VH region as shown in SEQ ID NO: 527 and a VL region as shown in SEQ ID NO: 528 It is also envisioned that the VH and VL regions comprise a VH region and a VL region selected from the group consisting of:

[0126] It is also envisioned that the first domain comprises a VH region having the amino acid sequence as set forth in SEQ ID NO:177 and a VL region having the amino acid sequence as set forth in SEQ ID NO:178.

[0127] It is also envisaged for the antibody constructs of the invention that the BCMA-binding first domain comprises a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 19, 29, 39, 49, 59, 69, 79, 89, 109, 129, 139, 149, 159, 169, 179, 189, 199, 209, 219, 229, 239, 249, 259, 269, 279, 289, 299, 309, 319, 329, 339, 349, 359, 369, 379, 389, 399, 409, 419, 429, 439, 449, 459, 469, 479, 489, 499, 519 and 529. It is envisaged that the first domain comprises a polypeptide having an amino acid sequence as set forth in SEQ ID NO: 179.

[0128] "T cells" or T lymphocytes are a type of lymphocyte (itself a type of white blood cell) that plays a central role in cell-mediated immunity. There are several subsets of T cells, each with different functions. T cells can be distinguished from other lymphocytes, such as B cells and NK cells, by the presence of T cell receptors (TCRs) on their cell surface. The TCR is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules and is composed of two distinct protein chains. In 95% of T cells, the TCR consists of an alpha (α) chain and a beta (β) chain. When the TCR binds an antigen peptide and MHC (peptide / MHC complex), the T lymphocyte is activated through a series of biochemical events mediated by associated enzymes, co-receptors, specialized adaptor molecules, and activated or released transcription factors.

[0129] "CD3" (cluster of differentiation 3) is a T cell coreceptor composed of four chains. In mammals, the CD3 protein complex contains the CD3γ (gamma) chain, the CD3δ (delta) chain, and two CD3ε (epsilon) chains. These four chains associate with the T cell receptor (TCR) and the so-called ζ (zeta) chain to form the "T cell receptor complex," which generates activation signals in T lymphocytes. The CD3γ (gamma), CD3δ (delta), and CD3ε (epsilon) chains are highly related cell surface proteins of the immunoglobulin superfamily, each containing a single extracellular immunoglobulin domain. The intracellular tail of the CD3 molecule contains a single conserved motif, known as an immunoreceptor tyrosine-based activation motif (ITAM), which is essential for the signal transduction ability of the TCR. The CD3 epsilon molecule is a polypeptide encoded by the CD3E gene, located on chromosome 11 in humans.

[0130] Redirected target cell lysis via T cell recruitment by antibody constructs that bind to CD3 on T cells and target proteins on target cells generally involves cytolytic synapse formation and delivery of perforin and granzymes. Engaged T cells are capable of continuous target cell lysis and are unaffected by immune evasion mechanisms that prevent peptide antigen processing and presentation or clonal T cell differentiation (see, e.g., WO 2007 / 042261).

[0131] Cytotoxicity mediated by BCMAxCD3 antibody constructs can be measured in a variety of ways. 50 ) is commonly used as a measure of potency of biologically active molecules, such as the antibody constructs of the present invention. It is expressed in molar units. In this case, the EC EC 50The value refers to the concentration of antibody construct that produces a cytotoxic response (lysis of target cells) halfway between baseline and maximum. Effector cells in cytotoxicity assays can be, for example, stimulated enriched (human) CD8-positive T cells or unstimulated (human) peripheral blood mononuclear cells (PBMCs). Target cells should express BCMA on their surface. Preferably, target cells express (at least) the extracellular domain of BCMA on their surface. Target cells can be cell lines (such as CHO) that have been stably or transiently transfected with BCMA, e.g., human BCMA. Alternatively, target cells can be cell lines that are natural expressers of BCMA, such as the human multiple myeloma cell lines L363 or NCI-H929.

[0132] The effector to target cell (E:T) ratio in cytotoxicity assays is usually about 10:1, but this can also vary. The cytotoxic activity of BCMAxCD3 antibody constructs can be measured in a 51-chromium release assay (e.g., with an incubation time of about 18 hours) or a FACS-based cytotoxicity assay (e.g., with an incubation time of about 48 hours). Modifications of the incubation time (cytotoxic response) are also contemplated. Other methods for measuring cytotoxicity are well known and include MTT or MTS assays, ATP-based assays including bioluminescence assays, sulforhodamine B (SRB) assays, WST assays, clonogenic assays, and ECIS techniques.

[0133] According to one embodiment, the cytotoxic activity mediated by the BCMAxCD3 antibody constructs of the present invention is measured in a FACS-based cytotoxicity assay. 50It is contemplated that values ​​will be ≦5000 pM or ≦4000 pM, more preferably ≦3000 pM or ≦2000 pM, even more preferably ≦1000 pM or ≦500 pM, even more preferably ≦400 pM or ≦300 pM, even more preferably ≦200 pM, even more preferably ≦100 pM, even more preferably ≦50 pM, even more preferably ≦20 pM or ≦10 pM, and most preferably ≦5 pM. It is also contemplated that the antibody constructs of the present invention will have EC50 values ​​in the triple-, double-, or single-digit pg / ml range as measured in a FACS-based cytotoxicity assay. The assay may be performed using L363 or NCI-H929 cell lines or BCMA-transfected CHO cells as target cells and stimulated, enriched (human) CD8+ T cells or unstimulated (human) (PBMCs) as effector cells. See also WO 2013 / 072406.

[0134] The second domain of the antibody construct of the present invention binds to CD3. More preferably, it binds to CD3 on the surface of T cells. It is further envisaged that the second domain binds to human CD3, preferably human CD3 on the surface of T cells. It is also envisaged that the second domain binds to CD3 epsilon. More preferably, it binds to human CD3 epsilon, for example human CD3 epsilon on the surface of T cells. A preferred amino acid sequence for the extracellular domain of human CD3 epsilon is set forth in SEQ ID NO: 653.

[0135] In one embodiment of the present invention, the second domain of the antibody construct binds to human CD3 epsilon (or human CD3 epsilon on the surface of T cells) and Callithrix jacchus or Saimiri sciureus CD3 epsilon. It is also contemplated that the second domain binds to an extracellular epitope of CD3 epsilon, preferably an extracellular epitope of human CD3 epsilon. It is also contemplated that the second domain binds to an extracellular epitope of the human and Macaca CD3 epsilon chain. One preferred epitope of CD3 epsilon is contained within amino acid residues 1 to 27 of the human CD3 epsilon extracellular domain (see SEQ ID NO: 654). Even more specifically, the epitope comprises at least the amino acid sequence Gln-Asp-Gly-Asn-Glu. Callithrix jacchus is a New World primate belonging to the marmoset family (Callitrichidae), while Saimiri sciureus is a New World primate belonging to the capuchin monkey family (Cebidae). These conjugates are described in detail in WO 2008 / 119567.

[0136] Antibodies or bispecific antibody constructs directed against (human) CD3 or specifically against CD3 epsilon are known in the art, and their CDR, VH, and VL sequences can serve as the basis for the second binding domain of the antibody construct of the present invention. For example, in 1979, Kung et al. reported the development of OKT3 (Ortho Kung T3), the first mAb that recognizes CD3 (specifically the epsilon chain of CD3) on human T cells. OKT3 (muromonab) was the first murine-derived monoclonal antibody available for human therapy. Newer anti-CD3 monoclonal antibodies include otelixizumab (TRX4), teplizumab (MGA031), foralaumab, and visilizumab, all of which target the epsilon chain of CD3. Bispecific antibody constructs against a (cancer) target and CD3 are also being developed and (pre)clinical tested, and their CD3-binding domains (CDR, VH, VL) may serve as the basis for the second binding domain of the antibody construct of the invention. Examples include, but are not limited to, blinatumomab, solitomab (MT110, AMG110), catumaxomab, duvortuxizumab, ertumaxomab, mosunetuzumab, FBTA05 (Bi20, TPBs05), CEA-TCB (RG7802, RO6958688), AFM11, and MGD006 (S80880). Other examples of CD3 binding domains are disclosed, for example, in U.S. Patent Nos. 7,994,289 B2, 7,728,114 B2, 7,381,803 B1, and 6,706,265 B1.

[0137] For the antibody construct of the present invention, the second domain that binds to CD3 is (a) CDR-L1 as set forth in SEQ ID NO: 542, CDR-L2 as set forth in SEQ ID NO: 543, and CDR-L3 as set forth in SEQ ID NO: 544; (b) CDR-L1 as set forth in SEQ ID NO: 599, CDR-L2 as set forth in SEQ ID NO: 600, and CDR-L3 as set forth in SEQ ID NO: 601; and (c) CDR-L1 as set forth in SEQ ID NO: 621, CDR-L2 as set forth in SEQ ID NO: 622, and CDR-L3 as set forth in SEQ ID NO: 623 It is envisaged that the VL region comprises CDR-L1, CDR-L2 and CDR-L3 selected from:

[0138] For the antibody construct of the present invention, the second domain that binds to CD3 is (a) CDR-H1 as set forth in SEQ ID NO: 534, CDR-H2 as set forth in SEQ ID NO: 535, and CDR-H3 as set forth in SEQ ID NO: 536; (b) CDR-H1 as set forth in SEQ ID NO: 545, CDR-H2 as set forth in SEQ ID NO: 546, and CDR-H3 as set forth in SEQ ID NO: 547; (c) CDR-H1 as set forth in SEQ ID NO: 557, CDR-H2 as set forth in SEQ ID NO: 558, and CDR-H3 as set forth in SEQ ID NO: 559; (d) CDR-H1 as set forth in SEQ ID NO: 568, CDR-H2 as set forth in SEQ ID NO: 569, and CDR-H3 as set forth in SEQ ID NO: 570; (e) CDR-H1 as set forth in SEQ ID NO: 579, CDR-H2 as set forth in SEQ ID NO: 580, and CDR-H3 as set forth in SEQ ID NO: 581; (f) CDR-H1 as set forth in SEQ ID NO: 591, CDR-H2 as set forth in SEQ ID NO: 592, and CDR-H3 as set forth in SEQ ID NO: 593; (g) CDR-H1 as set forth in SEQ ID NO: 602, CDR-H2 as set forth in SEQ ID NO: 603, and CDR-H3 as set forth in SEQ ID NO: 604; (h) CDR-H1 as set forth in SEQ ID NO: 613, CDR-H2 as set forth in SEQ ID NO: 614, and CDR-H3 as set forth in SEQ ID NO: 615; (i) CDR-H1 as set forth in SEQ ID NO: 624, CDR-H2 as set forth in SEQ ID NO: 625, and CDR-H3 as set forth in SEQ ID NO: 626; and (j) CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638 It is also contemplated that the VH region comprises a CDR-H1, CDR-H2, and CDR-H3 selected from:

[0139] For the antibody construct of the present invention, the second domain that binds to CD3 is (a) CDR-L1 as set forth in SEQ ID NO: 531, CDR-L2 as set forth in SEQ ID NO: 532, CDR-L3 as set forth in SEQ ID NO: 533, CDR-H1 as set forth in SEQ ID NO: 534, CDR-H2 as set forth in SEQ ID NO: 535, and CDR-H3 as set forth in SEQ ID NO: 536; (b) CDR-L1 as set forth in SEQ ID NO: 542, CDR-L2 as set forth in SEQ ID NO: 543, CDR-L3 as set forth in SEQ ID NO: 544, CDR-H1 as set forth in SEQ ID NO: 545, CDR-H2 as set forth in SEQ ID NO: 546, and CDR-H3 as set forth in SEQ ID NO: 547; (c) CDR-L1 as set forth in SEQ ID NO: 554, CDR-L2 as set forth in SEQ ID NO: 555, CDR-L3 as set forth in SEQ ID NO: 556, CDR-H1 as set forth in SEQ ID NO: 557, CDR-H2 as set forth in SEQ ID NO: 558, and CDR-H3 as set forth in SEQ ID NO: 559; (d) CDR-L1 as set forth in SEQ ID NO: 565, CDR-L2 as set forth in SEQ ID NO: 566, CDR-L3 as set forth in SEQ ID NO: 567, CDR-H1 as set forth in SEQ ID NO: 568, CDR-H2 as set forth in SEQ ID NO: 569, and CDR-H3 as set forth in SEQ ID NO: 570; (e) CDR-L1 as set forth in SEQ ID NO: 576, CDR-L2 as set forth in SEQ ID NO: 577, CDR-L3 as set forth in SEQ ID NO: 578, CDR-H1 as set forth in SEQ ID NO: 579, CDR-H2 as set forth in SEQ ID NO: 580, and CDR-H3 as set forth in SEQ ID NO: 581; (f) CDR-L1 as set forth in SEQ ID NO: 588, CDR-L2 as set forth in SEQ ID NO: 589, CDR-L3 as set forth in SEQ ID NO: 590, CDR-H1 as set forth in SEQ ID NO: 591, CDR-H2 as set forth in SEQ ID NO: 592, and CDR-H3 as set forth in SEQ ID NO: 593; (g) CDR-L1 as set forth in SEQ ID NO: 599, CDR-L2 as set forth in SEQ ID NO: 600, CDR-L3 as set forth in SEQ ID NO: 601, CDR-H1 as set forth in SEQ ID NO: 602, CDR-H2 as set forth in SEQ ID NO: 603, and CDR-H3 as set forth in SEQ ID NO: 604; (h) CDR-L1 as set forth in SEQ ID NO: 610, CDR-L2 as set forth in SEQ ID NO: 611, CDR-L3 as set forth in SEQ ID NO: 612, CDR-H1 as set forth in SEQ ID NO: 613, CDR-H2 as set forth in SEQ ID NO: 614, and CDR-H3 as set forth in SEQ ID NO: 615; (i) CDR-L1 as set forth in SEQ ID NO: 621, CDR-L2 as set forth in SEQ ID NO: 622, CDR-L3 as set forth in SEQ ID NO: 623, CDR-H1 as set forth in SEQ ID NO: 624, CDR-H2 as set forth in SEQ ID NO: 625, and CDR-H3 as set forth in SEQ ID NO: 626; and (j) CDR-L1 as set forth in SEQ ID NO: 633, CDR-L2 as set forth in SEQ ID NO: 634, CDR-L3 as set forth in SEQ ID NO: 635, CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638 and a VH region comprising CDR-H1, CDR-H2 and CDR-H3 selected from:

[0140] It is also envisaged that for the antibody constructs of the present invention, the second domain that binds to CD3 comprises a VL region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO: 550, SEQ ID NO: 551, SEQ ID NO: 584, SEQ ID NO: 585, SEQ ID NO: 629 and SEQ ID NO: 630, preferably SEQ ID NO: 629.

[0141] It is further envisaged that the second domain that binds to CD3 comprises a VH region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:537, SEQ ID NO:538, SEQ ID NO:548, SEQ ID NO:549, SEQ ID NO:560, SEQ ID NO:561, SEQ ID NO:571, SEQ ID NO:572, SEQ ID NO:582, SEQ ID NO:583, SEQ ID NO:594, SEQ ID NO:595, SEQ ID NO:605, SEQ ID NO:606, SEQ ID NO:616, SEQ ID NO:617, SEQ ID NO:627, SEQ ID NO:628, SEQ ID NO:639, SEQ ID NO:640 and SEQ ID NO:644.

[0142] For the antibody construct of the present invention, the second domain that binds to CD3 is (a) a VL region as set forth in SEQ ID NO: 539 or 521 and a VH region as set forth in SEQ ID NO: 537 or 538; (b) a VL region as set forth in SEQ ID NO: 550 or 521 and a VH region as set forth in SEQ ID NO: 548 or 549; (c) a VL region as set forth in SEQ ID NO: 562 or 521 and a VH region as set forth in SEQ ID NO: 560 or 561; (d) a VL region as set forth in SEQ ID NO: 573 or 521 and a VH region as set forth in SEQ ID NO: 571 or 572; (e) a VL region as set forth in SEQ ID NO: 584 or 585 and a VH region as set forth in SEQ ID NO: 582 or 583; (f) a VL region as set forth in SEQ ID NO: 596 or 521 and a VH region as set forth in SEQ ID NO: 594 or 595; (g) a VL region as set forth in SEQ ID NO: 607 or 585 and a VH region as set forth in SEQ ID NO: 605 or 606; (h) a VL region as set forth in SEQ ID NO: 618 or 521 and a VH region as set forth in SEQ ID NO: 616 or 617; (i) a VL region as set forth in SEQ ID NO: 629 or 630 and a VH region as set forth in SEQ ID NO: 627 or 628; (j) a VL region as set forth in SEQ ID NO: 641 or 630 and a VH region as set forth in SEQ ID NO: 639 or 640; and (k) a VL region as set forth in SEQ ID NO: 645 and a VH region as set forth in SEQ ID NO: 644 It is also envisioned that the VL and VH regions comprise a VL region and a VH region selected from the group consisting of:

[0143] It is also envisaged that for the antibody constructs of the invention, the second domain that binds to CD3 comprises or consists of a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 540, 541, 552, 553, 563, 564, 574, 575, 586, 587, 597, 598, 608, 609, 619, 620, 631, 632, 642, 643 and 646, preferably SEQ ID NO: 642.

[0144] The antibody construct of the present invention comprises: a) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 633, CDR-L2 as set forth in SEQ ID NO: 634, and CDR-L3 as set forth in SEQ ID NO: 635; b) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region as set forth in SEQ ID NO: 639 and a VL region as set forth in SEQ ID NO: 641; c) an antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising the amino acid sequence as set forth in SEQ ID NO: 642; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; It is also expected that the antibody will compete with the antibody for binding to CD3.

[0145] The antibody construct of the present invention comprises: a) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 633, CDR-L2 as set forth in SEQ ID NO: 634, and CDR-L3 as set forth in SEQ ID NO: 635; b) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region as set forth in SEQ ID NO: 639 and a VL region as set forth in SEQ ID NO: 641; c) an antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising the amino acid sequence as set forth in SEQ ID NO: 642; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; It is also expected that the antibody binds to the same epitope on CD3 as the antibody.

[0146] It is further contemplated that the antibody constructs of the present invention comprise a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520 and 530. It is envisaged that the antibody construct of the invention comprises a polypeptide having an amino acid sequence as set forth in SEQ ID NO:180.

[0147] The antibody constructs of the present invention may be selected from the group consisting of SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 It is also contemplated that the protein purification tag may comprise or consist of a polypeptide having an amino acid sequence selected from the group consisting of those shown in Tables 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, and 530, linked at its N-terminus or its C-terminus to a protein purification tag, preferably via a peptide bond (amide bond). Linkage of the protein purification tag at the C-terminus of the polypeptide is preferred. It is contemplated that the protein purification tag is a short peptide. For example, the length of the short peptide may be 2 to 30 amino acids, 4 to 25 amino acids, 5 to 20 amino acids, or 6 to 19 amino acids.Examples of protein purification tags include, but are not limited to, an AU1 epitope (e.g., as set forth in SEQ ID NO: 666), an AU5 epitope (e.g., as set forth in SEQ ID NO: 667), a T7 tag (e.g., as set forth in SEQ ID NO: 668), a V5 tag (e.g., as set forth in SEQ ID NO: 669), a B tag (e.g., as set forth in SEQ ID NO: 670), an E2 epitope (e.g., as set forth in SEQ ID NO: 671), a FLAG epitope / FLAG tag (e.g., as set forth in SEQ ID NO: 672), a Glu-Glu tag (e.g., as set forth in SEQ ID NO: 673 or 674), an HA tag, a histidine affinity tag (e.g., as set forth in SEQ ID NO: 675), an HSV epitope (e.g., as set forth in SEQ ID NO: 676), a KT3 epitope (e.g., as set forth in SEQ ID NO: 677), a GLUT3 epitope (e.g., as set forth in SEQ ID NO: 678), a GLUT3 epitope (e.g., as set forth in SEQ ID NO: 679), a GLUT3 epitope (e.g., as set forth in SEQ ID NO: 680), a GLUT3 epitope (e.g., as set forth in SEQ ID NO: 681), a GLUT3 epitope (e.g., as set forth in SEQ ID NO: 682), a GLUT3 epitope (e.g., as set forth in SEQ ID NO: 683), a GLUT3 epitope (e.g., as set forth in SEQ ID NO: 684), a GLUT3 677), Myc epitope (e.g., as set forth in SEQ ID NO: 678), polyarginine tag (5-6 Arg residues), polyaspartate tag (5-16 Asp residues), polyhistidine tag (2-10 His residues, typically 6 His residues, see e.g., SEQ ID NOs: 662-665), polyphenylalanine tag (typically 11 Phe residues), S1 tag (e.g., as set forth in SEQ ID NO: 679), S tag (e.g., as set forth in SEQ ID NO: 680), Strep tag (e.g., as set forth in SEQ ID NO: 681 or 682), universal tag (e.g., as set forth in SEQ ID NO: 683), VSV-G (e.g., as set forth in SEQ ID NO: 684), protein C (e.g., as set forth in SEQ ID NO: 685), and protein A. Histidine tags, particularly the 6xHis tag (SEQ ID NO: 663), are preferred.

[0148] The antibody construct of the present invention comprises: a) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172 and CDR-H3 as set forth in SEQ ID NO: 173, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 175 and CDR-L3 as set forth in SEQ ID NO: 176; b) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region as set forth in SEQ ID NO: 177 and a VL region as set forth in SEQ ID NO: 178; c) an antibody construct comprising a domain that binds to BCMA on the surface of a target cell, wherein said domain comprises an amino acid sequence as set forth in SEQ ID NO: 179; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; It is also expected that the antibody binds to the same epitope on BCMA as the antibody.

[0149] Whether an antibody, antibody construct, or binding domain binds to the same epitope of BCMA / BCMA on the surface of a target cell as another given antibody, antibody construct, or binding domain can be determined by various analyses, such as epitope mapping with chimeric or mutant BCMA molecules as described in WO 2013 / 072406. Another possibility for identifying epitopes within a target is an alanine scanning assay, in which each residue in the target to be analyzed (here, BCMA) is substituted with alanine, for example, via site-directed mutagenesis (see, e.g., Morrison KL & Weiss GA. Curr Opin Chem Biol. 2001 Jun; 5(3):302-7). Alanine is used because it mimics the secondary structure criterion of many other amino acids, yet is not bulky and has a chemically inert methyl functional group. If it is desired to preserve the size of the mutated residue, bulky amino acids such as valine or leucine can sometimes be used. Alanine scanning is usually achieved by site-directed mutagenesis or randomly by PCR library generation. Furthermore, computational methods have been developed to estimate thermodynamic parameters based on theoretical alanine substitutions. Data can be examined by IR, NMR spectroscopy, mathematical methods, bioassays, etc. Of course, the same analysis can be applied to other targets, such as CD3.

[0150] The antibody construct of the present invention comprises: a) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172 and CDR-H3 as set forth in SEQ ID NO: 173, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 175 and CDR-L3 as set forth in SEQ ID NO: 176; b) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region as set forth in SEQ ID NO: 177 and a VL region as set forth in SEQ ID NO: 178; c) an antibody construct comprising a domain that binds to BCMA on the surface of a target cell, wherein said domain comprises an amino acid sequence as set forth in SEQ ID NO: 179; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; It is also envisaged that the IL-16 receptor agonist (IL-16) competes with the IL-16 receptor agonist (IL-16) for binding to BCMA.

[0151] Whether an antibody or antibody construct competes with another given antibody or antibody construct for binding to BCMA / BCMA on the surface of target cells can be measured by a competition assay such as a competitive ELISA or a cell-based competition assay (using either cells naturally expressing BCMA or cells stably or transiently transfected with BCMA). Avidin-coupled microparticles (beads) can also be used. Similar to an avidin-coated ELISA plate, each of these beads can be used as a substrate when reacted with biotinylated proteins, on which the assay can be performed. The antigen is coated on the beads, then pre-coated with the first antibody. A second antibody is added, and any further binding is determined. A read is performed by flow cytometry. The term "compete for binding" in this context means that there is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% competition between the two test antibodies, as determined by any one of the assays disclosed above. Of course, the same analysis can be applied to other targets such as CD3.

[0152] The antibody constructs described herein comprise a third domain that extends or enhances the half-life (or "serum half-life") of the antibody construct. Examples of means or domains that extend the serum half-life of the antibody construct of the present invention include peptides, proteins, or protein domains fused or otherwise attached to the antibody construct. The group of peptides, proteins, or protein domains includes peptides that bind to other proteins with favorable pharmacokinetic profiles in the human body, such as serum albumin (see WO 2009 / 127691). An alternative concept for such half-life extending peptides includes peptides that bind to the neonatal Fc receptor (FcRn, see WO 2007 / 098420), which may also be used for the antibody constructs of the present invention. The concept of adding large domains of proteins or complete proteins includes fusions of human serum albumin, variants or mutants of human serum albumin (see WO 2011 / 051489, WO 2012 / 059486, WO 2012 / 150319, WO 2013 / 135896, WO 2014 / 072481, WO 2013 / 075066) or domains thereof, as well as fusions of immunoglobulin constant regions (Fc domains) and variants thereof. Such variants of the Fc domain are called Fc-based domains and may be further optimized / modified to abolish Fc receptor binding (e.g., to avoid ADCC or CDC) or for other reasons, to allow the desired pairing of dimers or multimers. A further concept known in the art for extending the half-life of substances or molecules in the human body is the pegylation of such molecules (such as the antibody constructs of the present invention).

[0153] In one embodiment, an antibody construct according to the present invention is linked (e.g., via a peptide bond) to a fusion partner (e.g., a protein, polypeptide, or peptide) for the purpose of extending the serum half-life of the construct. These fusion partners (corresponding to the "third domain") may be selected from human serum albumin ("HSA" or "HALB") and sequence variants thereof, peptides that bind to HSA, peptides that bind to FcRn ("FcRn BP"), or constructs containing an Fc region (derived from an antibody). Generally, the fusion partner may be linked to the N- or C-terminus of an antibody construct according to the present invention either directly (e.g., via a peptide bond) or through a peptide linker such as (GGGGS)n (where "n" is an integer equal to or greater than 2, e.g., 2, 3, or 4). Suitable peptide linkers are set forth in SEQ ID NOs: 686 to 694.

[0154] According to a further embodiment, the third domain of the antibody construct of the present invention comprises two peptide monomers each comprising a hinge, a CH2 domain, and a CH3 domain, wherein the two polypeptide monomers are fused to each other via a peptide linker. It is envisioned that the third domain comprises, from N- to C-terminus, "first polypeptide monomer-linker-second polypeptide monomer" or hinge-CH2-CH3-linker-hinge-CH2-CH3. Amino acid sequences that can be used for the third domain are set forth in SEQ ID NOs: 700-707. Each of the polypeptide monomers can have an amino acid sequence selected from the group consisting of SEQ ID NOs: 708-715, or an amino acid sequence at least 90% identical thereto. In another embodiment, the first and second domains of the antibody construct of the present invention are fused to the third domain via a peptide linker, e.g., selected from the group consisting of SEQ ID NOs: 686, 687, 688, 689, 690, 691, 692, 693, or 694.

[0155] According to the present invention, a "hinge" is an IgG hinge region. This region can be identified by analogy using the Kabat numbering, see e.g., Kabat positions 223-243. In accordance with the above, the minimum requirements for a "hinge" are the amino acid residues corresponding to the IgG1 sequence stretch from D231 to P243, based on the Kabat numbering. The terms "CH2" and "CH3" (or "CH2 domain" and "CH3 domain") refer to immunoglobulin heavy chain constant regions 2 and 3. These regions can likewise be identified by analogy using the Kabat numbering, see e.g., Kabat positions 244-360 for CH2 and Kabat positions 361-478 for CH3. It is understood that there is some variation among immunoglobulins with respect to their IgG1 Fc region, IgG2 Fc region, IgG3 Fc region, IgG4 Fc region, IgM Fc region, IgA Fc region, IgD Fc region, and IgE Fc region (see, e.g., Padlan, Molecular Immunology, 31(3), 169-217 (1993)). The term Fc region refers to the last two heavy chain constant regions of IgA, IgD, and IgG, and the last three heavy chain constant regions of IgE and IgM. The Fc region may also include a flexible hinge N-terminal to these domains. For IgA and IgM, the Fc region may include the J chain. For IgG, the Fc region includes immunoglobulin domains CH2 and CH3 and the hinge between the first two domains and CH2. The boundaries of the Fc region of an immunoglobulin might vary, and an example for a human IgG heavy chain Fc portion comprising a functional hinge, CH2 domain, and CH3 domain might be defined to include residues D231 (in the hinge domain) to P476, or D231 to L476 (at the C-terminus of the CH3 domain), respectively, where numbering is according to Kabat.

[0156] Thus, the antibody construct of the present invention comprises, in order from the N-terminus to the C-terminus: (a) First domain; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 687, 693, and 694; (c) second domain; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 686, 687, 688, 689, 690, 691, 692, 693, or 694; (e) a first polypeptide monomer of the third domain (comprising a hinge, a CH2 domain, and a CH3 domain); (f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 695, 696, 697, 698, or 699; and (g) a second polypeptide monomer of the third domain (comprising a hinge, a CH2 domain, and a CH3 domain) may include:

[0157] The antibody construct of the present invention comprises, in order from the N-terminus to the C-terminus: f) SEQ ID NOs: 9, 19, 29, 39, 49, 59, 69, 79, 89, 109, 129, 139, 149, 159, 169, 179, 189, 199, 209, 219, 229, 239, 249, 259, 269, 279, 289, 299, 309, 319, 329, 339, 349, 359, 369, 379, 389, 399, 409, 41 a first domain having an amino acid sequence selected from the group consisting of 9, 429, 439, 449, 459, 469, 479, 489, 499, 519, and 529; and a first domain contained within these sequences, wherein the peptide linker having SEQ ID NO: 694 may be replaced by any one of SEQ ID NOs: 686-693 and 695-699; (g) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 687, 693, and 694; (h) a second domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 540, 541, 552, 553, 563, 564, 574, 575, 586, 587, 597, 598, 608, 609, 619, 620, 631, 632, 642, 643, and 646; wherein the peptide linker having SEQ ID NO: 694, contained within these sequences, can be replaced by any one of SEQ ID NOs: 686-693 and 695-699; (i) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 686, 687, 688, 689, 690, 691, 692, 693, and 694; and (j) a third domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 700 to 707; It is also assumed to include.

[0158] Thus, in one embodiment, an antibody construct of the invention comprises, from N-terminus to C-terminus: (a) a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, and 530; (b) a linker having an amino acid sequence as set forth in SEQ ID NO: 686; and (c) a third domain having an amino acid sequence as set forth in SEQ ID NO: 700. Includes:

[0159] A preferred antibody construct of the invention comprises or consists of a polypeptide having an amino acid sequence as set forth in SEQ ID NO:661.

[0160] One or both of the antibody constructs or binding domains thereof of the present invention may be "humanized" or "human." "Humanized" antibodies, variants or fragments thereof, antibody constructs, and binding domains are based primarily on human-sequence immunoglobulins and contain minimal sequence derived from non-human immunoglobulin. In most cases, humanized antibodies, variants or fragments thereof, antibody constructs, and binding domains are based on a human immunoglobulin (recipient antibody), in which residues from a hypervariable region or CDR are replaced by hypervariable region or CDR residues of a non-human species (donor antibody), such as a rodent (e.g., mouse, hamster, rat, or rabbit) having the desired specificity, affinity, capacity, and / or biological activity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, as used herein, "humanized" antibodies, variants or fragments thereof, antibody constructs, and binding domains may also comprise residues that are not found in either the recipient antibody or the donor antibody. These modifications are made to further refine and optimize antibody performance. Humanized antibodies, variants or fragments thereof, antibody constructs, and binding domains can also comprise at least a portion of an immunoglobulin constant region (e.g., Fc), typically that of a human immunoglobulin. For further details, see Nature, 321:522-525 (1986); Reichmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992).

[0161] The human anti-mouse antibody (HAMA) response has led the industry to prepare chimeric or other humanized antibodies / antibody constructs. However, it is expected that some human anti-chimeric antibody (HACA) response will be observed, particularly with chronic or high-dose use of antibodies or antibody constructs. Therefore, it would be desirable to provide antibody constructs that contain a human binding domain for BCMA and / or a human binding domain for CD3 to address the concerns and / or effects of HAMA or HACA responses.

[0162] Thus, according to one embodiment, the antibody construct, first binding domain, and / or second binding domain are "human." The terms "human antibody," "human antibody construct," and "human binding domain" include antibodies, antibody constructs, and binding domains, respectively, having antibody-derived regions, such as variable and constant regions or domains, that substantially correspond to human germline immunoglobulin sequences known in the art, including, for example, those described by Kabat et al. (1991) (supra). Human antibody constructs or binding domains of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced in vitro by random or site-directed mutagenesis or in vivo by somatic mutation), for example, in the CDRs, particularly CDR3. Human antibody constructs or binding domains may have at least one, two, three, four, five, or more positions replaced with amino acid residues not encoded by human germline immunoglobulin sequences. The definition of human antibodies, antibody constructs and binding domains as used herein also contemplates fully human antibodies, antibody constructs and binding domains that contain only artificially and / or genetically unmodified human sequences of antibodies, such as those that may be derived using techniques or systems such as Xenomouse.

[0163] Antibody constructs comprising at least one human binding domain avoid some of the problems associated with antibodies or antibody constructs having non-human, e.g., rodent (e.g., mouse, rat, hamster, or rabbit) variable and / or constant regions. The presence of such rodent-derived proteins can lead to rapid clearance of the antibody or antibody construct or to the development of an immune response against the antibody or antibody construct by the patient. To avoid the use of rodent-derived antibody constructs, human antibody function can be introduced into rodents to generate humanized or fully human antibody constructs, such that the rodents produce fully human antibodies.

[0164] In some embodiments, the antibody construct of the present invention is an "isolated" or "substantially pure" antibody construct. "Isolated" or "substantially pure," when used to describe an antibody construct disclosed herein, refers to an antibody construct that has been identified, separated, and / or recovered from components of its production environment. Preferably, the antibody construct is free or substantially free from association with all other components from its production environment. Contaminant components of the production environment, such as those arising from recombinantly transfected cells, are materials that may interfere with the diagnostic or therapeutic use of the antibody construct and may include enzymes, hormones, and other proteinaceous or non-proteinaceous compounds. It is understood that an isolated or substantially pure antibody construct may, depending on the circumstances, represent 5% to 99.9% by weight of the total protein / polypeptide content in a given sample. The desired antibody construct may be produced at significantly higher concentrations by using inducible or high-expression promoters. This definition includes the production of antibody constructs in a variety of organisms and / or host cells known in the art. In certain embodiments, the antibody construct will be purified (1) sufficiently to obtain at least 15 residues of N-terminal or internal amino acid sequence by using a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver staining. Typically, however, an isolated antibody construct will be prepared by at least one purification step.

[0165] According to one embodiment, the entire antibody construct and / or binding domain is in the form of one or more polypeptides or proteins. In addition to proteinaceous moieties, such polypeptides or proteins may contain non-proteinaceous moieties (e.g., chemical linkers or chemical cross-linking agents, such as glutaraldehyde).

[0166] Peptides are short chains of amino acid monomers linked by covalent peptide (amide) bonds. Thus, peptides are classified within the broad chemical class of biological oligomers and polymers. Amino acids that are part of a peptide or polypeptide chain are referred to as "residues" and may be consecutively numbered. All peptides, except cyclic peptides, have an N-terminal residue at one end and a C-terminal residue at the other end. Oligopeptides consist of only a small number of amino acids (usually 2-20). Polypeptides are longer, continuous, unbranched peptide chains. Peptides are distinguished from proteins based on size and can be understood to contain approximately 50 amino acids or less as an arbitrary standard. Proteins typically consist of one or more polypeptides arranged in a biologically functional manner. While the specifics of the experimental techniques applied to peptides versus polypeptides and proteins (e.g., details of electrophoresis, chromatography, etc.) differ, the size boundary that distinguishes peptides from polypeptides and proteins is not absolute. Therefore, in the context of the present invention, the terms "peptide," "polypeptide," and "protein" may be used interchangeably, with the term "polypeptide" often being preferred.

[0167] Polypeptides can further form multimers consisting of multiple polypeptide molecules, such as dimers, trimers, and higher oligomers. The polypeptide molecules forming such dimers, trimers, etc. may or may not be identical. Therefore, the corresponding structures of such higher multimers are referred to as homodimers or heterodimers, homotrimers, heterotrimers, etc. An example of a heteromultimer is an antibody or immunoglobulin molecule, which in its naturally occurring form consists of two identical light polypeptide chains and two identical heavy polypeptide chains. The terms "peptide," "polypeptide," and "protein" also refer to naturally occurring modified peptides / polypeptides / proteins, where modification is achieved by post-translational modifications such as glycosylation, acetylation, phosphorylation, and the like. As referred to herein, a "peptide," "polypeptide," or "protein" may also be chemically modified, such as pegylation. Such modifications are well known in the art.

[0168] The antibody constructs of the present invention are typically formulated in pharmaceutical compositions or formulations. The materials of pharmaceutical compositions are usually formulated in concentrations that are acceptable to the site of administration. Thus, formulations and compositions according to the present invention can be designed for delivery by any suitable route of administration.

[0169] As used herein, the term "pharmaceutical composition" refers to a composition suitable for administration to a patient, preferably a human patient. Particularly preferred pharmaceutical compositions of the present invention comprise one or more antibody constructs of the present invention, typically in a therapeutically effective amount. The pharmaceutical composition may further comprise a suitable formulation of one or more (pharmaceutically effective) carriers, stabilizers, excipients, diluents, solubilizers, surfactants, emulsifiers, preservatives, and / or adjuvants. Acceptable components of the composition are typically non-toxic to recipients at the dosages and concentrations used. Pharmaceutical compositions of the present invention include, but are not limited to, liquid, frozen, and lyophilized compositions. If the pharmaceutical composition is lyophilized, the lyophilized material is reconstituted with an appropriate liquid prior to administration. The lyophilized material can be reconstituted, for example, with bacteriostatic water for injection (BWFI), saline, phosphate-buffered saline (PBS), or the same formulation the protein was in before lyophilization.

[0170] The composition may contain a pharmaceutically acceptable carrier. Generally, as used herein, "pharmaceutically acceptable carrier" refers to any aqueous or non-aqueous solution, sterile solution, solvent, buffer solution, such as phosphate-buffered saline (PBS) solution, water, suspension, emulsion such as oil / water emulsion, various wetting agents, liposomes, dispersion media and coatings that are compatible with pharmaceutical administration, particularly parenteral administration. The use of such media and agents in pharmaceutical compositions is well known in the art, and compositions containing such carriers can be formulated by well-known conventional methods.

[0171] Certain embodiments provide pharmaceutical compositions comprising an antibody construct of the invention and one or more additional excipients. Excipients may be used for a variety of purposes, such as adjusting the physical, chemical, or biological properties of the formulations, such as adjusting viscosity, to improve efficacy and / or stabilize such formulations and processes against degradation and deterioration due to stresses encountered during and after manufacturing, shipping, storage, preparation for use, and administration. Excipients should generally be used at their lowest effective concentration.

[0172] In certain embodiments, pharmaceutical compositions may also contain formulatory materials / substances for the purpose of modifying, maintaining, or preserving certain characteristics of the composition, such as pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or permeability (see Remington's Pharmaceutical Sciences, 18th Edition, 1990, Mack Publishing Company).

[0173] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "reagent" includes one or more of such various reagents, and reference to a "method" includes reference to equivalent steps and methods known to those skilled in the art that may be modified or substituted for the method described herein.

[0174] Unless otherwise indicated, the term "at least" preceding a series of elements should be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by this invention.

[0175] The term "and / or", wherever used in this specification, includes the meaning of "and", "or" and "any other combination of the elements connected by said term".

[0176] The terms "about" or "approximately," as used herein, mean within ±20%, preferably within ±15%, more preferably within ±10%, and most preferably within ±5% of a given value or range. This includes specific values, for example, "about 50" includes the value "50."

[0177] Throughout this specification and the claims, unless the context otherwise requires, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of the stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps. As used herein, the term "comprising" can be substituted with the term "containing" or "including," or, as sometimes used herein, the term "having."

[0178] As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0179] In each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms.

[0180] The foregoing description and the following examples provide exemplary configurations; however, it should be understood that the invention is not limited to the particular methodology, techniques, protocols, materials, reagents, substances, etc. described herein, as such may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention, which is defined solely by the claims. Aspects of the invention are provided in the independent claims. Some optional features of the invention are provided in the dependent claims.

[0181] All publications and patents (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), cited throughout the text of this specification, whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent that material incorporated by reference contradicts or is inconsistent with the present specification, the present specification will take precedence over any such material.

[0182] A better understanding of the present invention and its advantages will be obtained from the following examples, which are provided for illustrative purposes only and are not intended, and should not be construed, to limit the scope of the invention in any way. [Example]

[0183] Background: AMG 701, an HLE BiTE® molecule that binds to BCMA on multiple myeloma (MM) cells and CD3 on T cells, has activity in preclinical MM models. The goals of this first-in-human study include evaluating safety and estimating the maximum tolerated dose (MTD) of AMG 701 in patients with relapsed / refractory (R / R) multiple myeloma (NCT03287908).

[0184] Methods: Up to 10 patients received weekly short-course IV infusions of AMG701 in 4-week cycles, initially in single-patient cohorts (5, 15, 45 μg), then in cohorts of ≥3 patients (140, 400, 800, 1200 μg), and potentially in higher-dose cohorts (1600, 3000, 4500, 6500, 9000, 12000 μg), as long as the patient benefited. Eligible patients were those with MM who had relapsed after or were intolerant to ≥2 regimens of proteasome inhibitors, IMiDs, and anti-CD38 MAbs (if approved and available). Patients with isolated extramedullary disease (subsequent dose escalation was possible), CNS involvement, previous BCMA-directed therapy, and immunosuppressive therapy were excluded. After a grade 3 dose-limiting toxicity (DLT) of cytokine release syndrome (CRS) at 1600 μg, an initial run-in dose of 800 μg was added for all target doses ≥ 1200 μg, followed by escalation to the target dose. MRD was defined as < 1 / 105 cells as measured by an FDA-approved next-generation sequencing assay.

[0185] Results (not including follow-up results shown in Table 2): 47 patients received AMG 701 at doses ranging from 5 to 6500 μg, with a run-in dose of 800 μg used for escalation to a target dose of ≥1200 μg; further planned doses of 9000 and 12000 μg have not yet enrolled patients (see also Figure 1). Median age was 62 years, and 21 patients (78%) had received ≥5 prior regimens. Twelve patients are ongoing and have not yet reached the MTD as defined by the protocol. Anti-AMG 701 antibodies were not detected. Responses included one stringent complete response (sCR) and four partial responses (PRs) at 800 μg, two PRs at 3000 μg, one PR at 4500 μg, and one PR and minimal response at 6500 μg. Patients in CR had an initial PR at 1 month and deepened to sCR at 4.3 months; this ongoing response lasted for 13.2 months, of which 9.8 months were MRD-negative. Four PRs began between 1 and 3.7 months (first assessed at 1 month), and responses lasted up to 4 months (3 ongoing).

[0186] Conclusions: In this FIH trial, where dose escalation is ongoing and the MTD has not yet been identified, AMG701, an HLE antibody construct targeting CD3 and BCMA, showed promising activity in heavily pre-treated patients with R / R MM.

[0187] Table 1: Results of the AMG701 FIH study. This table does not include single-patient cohorts 1-3 at 5, 15, and 45 μg. + indicates ongoing response. *Except for one patient at 1600 μg, who had a DLT of CRS, all patients receiving doses ≥ 1200 μg received an 800 μg step-up dose before receiving their target dose on days 5 or 8. The number of patients who received their target dose on day 5 was as follows: 1600 μg (n=3), 3000 μg (n=2), and 4500 μg (n=2); all other patients received their target dose on day 8.

[0188] [Table 1]

[0189] Table 2: Follow-up results from the AMG 701 FIH trial. This table does not include single-patient cohorts 1-3 at 5, 15, and 45 μg, and this table does not include cohorts 4-9 at 140 μg-1600 μg (see Table 1). The duration of response for sCR responders in cohort 6 (800 μg) in Table 1 is 19.6+ months. + indicates ongoing response. All patients shown in this Table 2 received the 800 μg step-up dose before receiving the target dose on days 3, 5, or 8.

[0190] [Table 2]

[0191] The IMWG response criteria for complete response (see also http: / / imwg.myeloma.org / international-myeloma-working-group-imwg-uniform-response-criteria-for-multiple-myeloma / ) are as follows: ·M protein immunofixation in serum and urine was negative Disappearance of soft tissue plasmacytomas, and ·<5% plasma cells in bone marrow.

[0192] The IMWG response criteria for partial response are as follows: M protein electrophoresis: ≥50% reduction in serum M protein and ≥90% reduction in 24-hour urinary M protein or reduction to <200 mg / 24 hours Free light chains (FLC): If serum and urine M-protein are not measurable, a ≥ 50% reduction in the difference between tumor- and non-tumor-derived FLC levels is required in lieu of the M-protein criterion. If serum and urine M protein are not measurable and serum-free photoassay is also not measurable: If baseline bone marrow plasma cell percentage is ≥ 30%, a ≥ 50% reduction in plasma cells is required instead of M protein. In addition to the criteria listed above, a ≥50% reduction in the size of soft tissue plasmacytomas, if present at baseline, is also required.

[0193] The IMWG response criteria for very good partial response are: Serum and urine M-protein detectable by immunofixation but not by electrophoresis, or 90% or greater reduction in serum M-protein + urine M-protein levels <100 mg / 24 hours is.

Claims

1. 1. An antibody construct comprising a first domain that binds to BCMA, a second domain that binds to CD3, and a third domain that extends the half-life of the antibody construct, for use in treating or ameliorating a BCMA-positive neoplasm, wherein the antibody construct is administered at a minimum dose of 800 μg / day in at least one cycle, wherein one cycle comprises at least three individual administrations of the antibody construct.

2. 2. The antibody construct of claim 1, wherein the antibody construct is administered for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more cycles.

3. The antibody construct according to claim 1 or 2, wherein one cycle lasts for about 25 to 30 days, preferably 26 or 27 days to about 29 days, and more preferably about 28 days.

4. 4. The antibody construct of any one of claims 1 to 3, administered at a dose of 800μg / day to 12mg / day, such as 1000μg, 1200μg, 1500μg, 1600μg, 2000μg, 2500μg, 3000μg, 3500μg, 4000μg, 4500μg, 5000μg, 5500μg, 6000μg, 6500μg, 7000μg, 7500μg, 8000μg, 8500μg, 9000μg, 9500μg, 10mg, 11mg or 12mg / day.

5. The antibody construct of any one of claims 1 to 4, which is administered in one or two dose steps during the initial cycle.

6. 6. The antibody construct of claim 5, wherein the first dose is 800 μg / day to 1200 μg / day, the optional second dose is 2500 μg / day to 5000 μg / day, preferably about 3000 μg / day or about 4500 μg / day, and the final dose (target dose) is 6500 μg / day to 12 mg / day, for example 6500 μg / day, 7000 μg / day, 7500 μg / day, 8000 μg / day, 8500 μg / day, 9000 μg / day, 9500 μg / day, 10 mg / day, 11 mg / day or 12 mg / day.

7. 7. The antibody construct of any one of claims 1 to 6, wherein the initial cycle comprises or consists of 3 to 6 individual administrations, preferably 4 or 5 individual administrations, of the antibody construct.

8. The antibody construct of any one of claims 2 to 7, which is administered at a constant dose during the second cycle and optionally during any subsequent cycles.

9. The antibody construct of any one of claims 1 to 8, which is administered parenterally, preferably intravenously, more preferably via intravenous bolus injection, bolus infusion or short-term intravenous infusion.

10. The antibody construct of any one of claims 1 to 9, wherein the BCMA-positive neoplasm is selected from the group consisting of multiple myeloma, relapsed and / or refractory multiple myeloma, heavy chain multiple myeloma, light chain multiple myeloma, extramedullary myeloma, plasmacytoma, plasma cell leukemia, Waldenstrom's macroglobulinemia, and smoldering myeloma.

11. The antibody construct according to any one of claims 1 to 10, a) the antibody construct is a single-chain polypeptide; b) the first domain is in the form of an scFv; c) the second domain is in the form of an scFv, and / or d) the first domain and the second domain are linked via a linker, preferably a peptide linker, more preferably a glycine / serine linker; Antibody constructs.

12. The antibody construct according to any one of claims 1 to 11, a) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 171, CDR-H2 as set forth in SEQ ID NO: 172, and CDR-H3 as set forth in SEQ ID NO: 173, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 174, CDR-L2 as set forth in SEQ ID NO: 175, and CDR-L3 as set forth in SEQ ID NO: 176; b) an antibody or antibody construct comprising a domain that binds to BCMA on the surface of a target cell, said domain comprising a VH region as set forth in SEQ ID NO: 177 and a VL region as set forth in SEQ ID NO: 178; c) an antibody construct comprising a domain that binds to BCMA on the surface of a target cell, wherein the domain comprises the amino acid sequence as set forth in SEQ ID NO: 179; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; An antibody construct that competes for binding to BCMA with or binds to the same epitope on BCMA as

13. The antibody construct according to any one of claims 1 to 12, a) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region comprising CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638, and a VL region comprising CDR-L1 as set forth in SEQ ID NO: 633, CDR-L2 as set forth in SEQ ID NO: 634, and CDR-L3 as set forth in SEQ ID NO: 635; b) an antibody or antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising a VH region as set forth in SEQ ID NO: 639 and a VL region as set forth in SEQ ID NO: 641; c) an antibody construct comprising a domain that binds to CD3 on the surface of a T cell, said domain comprising the amino acid sequence as set forth in SEQ ID NO: 642; or d) an antibody construct having the amino acid sequence as set forth in SEQ ID NO: 661; An antibody construct that competes for binding to CD3 with or binds to the same epitope on CD3 as

14. the first domain that binds to BCMA is (1) CDR-H1 as shown in SEQ ID NO: 1, CDR-H2 as shown in SEQ ID NO: 2, CDR-H3 as shown in SEQ ID NO: 3, CDR-L1 as shown in SEQ ID NO: 4, CDR-L2 as shown in SEQ ID NO: 5, and CDR-L3 as shown in SEQ ID NO: 6; (2) CDR-H1 as shown in SEQ ID NO: 11, CDR-H2 as shown in SEQ ID NO: 12, CDR-H3 as shown in SEQ ID NO: 13, CDR-L1 as shown in SEQ ID NO: 14, CDR-L2 as shown in SEQ ID NO: 15, and CDR-L3 as shown in SEQ ID NO: 16; (3) CDR-H1 as shown in SEQ ID NO: 21, CDR-H2 as shown in SEQ ID NO: 22, CDR-H3 as shown in SEQ ID NO: 23, CDR-L1 as shown in SEQ ID NO: 24, CDR-L2 as shown in SEQ ID NO: 25, and CDR-L3 as shown in SEQ ID NO: 26; (4) CDR-H1 as shown in SEQ ID NO: 31, CDR-H2 as shown in SEQ ID NO: 32, CDR-H3 as shown in SEQ ID NO: 33, CDR-L1 as shown in SEQ ID NO: 34, CDR-L2 as shown in SEQ ID NO: 35, and CDR-L3 as shown in SEQ ID NO: 36; (5) CDR-H1 as shown in SEQ ID NO: 41, CDR-H2 as shown in SEQ ID NO: 42, CDR-H3 as shown in SEQ ID NO: 43, CDR-L1 as shown in SEQ ID NO: 44, CDR-L2 as shown in SEQ ID NO: 45, and CDR-L3 as shown in SEQ ID NO: 46; (6) CDR-H1 as shown in SEQ ID NO: 51, CDR-H2 as shown in SEQ ID NO: 52, CDR-H3 as shown in SEQ ID NO: 53, CDR-L1 as shown in SEQ ID NO: 54, CDR-L2 as shown in SEQ ID NO: 55, and CDR-L3 as shown in SEQ ID NO: 56; (7) CDR-H1 as shown in SEQ ID NO: 61, CDR-H2 as shown in SEQ ID NO: 62, CDR-H3 as shown in SEQ ID NO: 63, CDR-L1 as shown in SEQ ID NO: 64, CDR-L2 as shown in SEQ ID NO: 65, and CDR-L3 as shown in SEQ ID NO: 66; (8) CDR-H1 as shown in SEQ ID NO: 71, CDR-H2 as shown in SEQ ID NO: 72, CDR-H3 as shown in SEQ ID NO: 73, CDR-L1 as shown in SEQ ID NO: 74, CDR-L2 as shown in SEQ ID NO: 75, and CDR-L3 as shown in SEQ ID NO: 76; (9) CDR-H1 as shown in SEQ ID NO: 81, CDR-H2 as shown in SEQ ID NO: 82, CDR-H3 as shown in SEQ ID NO: 83, CDR-L1 as shown in SEQ ID NO: 84, CDR-L2 as shown in SEQ ID NO: 85, and CDR-L3 as shown in SEQ ID NO: 86; (10) CDR-H1 as shown in SEQ ID NO: 91, CDR-H2 as shown in SEQ ID NO: 92, CDR-H3 as shown in SEQ ID NO: 93, CDR-L1 as shown in SEQ ID NO: 94, CDR-L2 as shown in SEQ ID NO: 95, and CDR-L3 as shown in SEQ ID NO: 96; (11) CDR-H1 as shown in SEQ ID NO: 101, CDR-H2 as shown in SEQ ID NO: 102, CDR-H3 as shown in SEQ ID NO: 103, CDR-L1 as shown in SEQ ID NO: 104, CDR-L2 as shown in SEQ ID NO: 105, and CDR-L3 as shown in SEQ ID NO: 106; (12) CDR-H1 as shown in SEQ ID NO: 111, CDR-H2 as shown in SEQ ID NO: 112, CDR-H3 as shown in SEQ ID NO: 113, CDR-L1 as shown in SEQ ID NO: 114, CDR-L2 as shown in SEQ ID NO: 115, and CDR-L3 as shown in SEQ ID NO: 116; (13) CDR-H1 as shown in SEQ ID NO: 121, CDR-H2 as shown in SEQ ID NO: 122, CDR-H3 as shown in SEQ ID NO: 123, CDR-L1 as shown in SEQ ID NO: 124, CDR-L2 as shown in SEQ ID NO: 125, and CDR-L3 as shown in SEQ ID NO: 126; (14) CDR-H1 as shown in SEQ ID NO: 131, CDR-H2 as shown in SEQ ID NO: 132, CDR-H3 as shown in SEQ ID NO: 133, CDR-L1 as shown in SEQ ID NO: 134, CDR-L2 as shown in SEQ ID NO: 135, and CDR-L3 as shown in SEQ ID NO: 136; (15) CDR-H1 as shown in SEQ ID NO: 141, CDR-H2 as shown in SEQ ID NO: 142, CDR-H3 as shown in SEQ ID NO: 143, CDR-L1 as shown in SEQ ID NO: 144, CDR-L2 as shown in SEQ ID NO: 145, and CDR-L3 as shown in SEQ ID NO: 146; (16) CDR-H1 as shown in SEQ ID NO: 151, CDR-H2 as shown in SEQ ID NO: 152, CDR-H3 as shown in SEQ ID NO: 153, CDR-L1 as shown in SEQ ID NO: 154, CDR-L2 as shown in SEQ ID NO: 155, and CDR-L3 as shown in SEQ ID NO: 156; (17) CDR-H1 as shown in SEQ ID NO: 161, CDR-H2 as shown in SEQ ID NO: 162, CDR-H3 as shown in SEQ ID NO: 163, CDR-L1 as shown in SEQ ID NO: 164, CDR-L2 as shown in SEQ ID NO: 165, and CDR-L3 as shown in SEQ ID NO: 166; (18) CDR-H1 as shown in SEQ ID NO: 171, CDR-H2 as shown in SEQ ID NO: 172, CDR-H3 as shown in SEQ ID NO: 173, CDR-L1 as shown in SEQ ID NO: 174, CDR-L2 as shown in SEQ ID NO: 175, and CDR-L3 as shown in SEQ ID NO: 176; (19) CDR-H1 as shown in SEQ ID NO: 181, CDR-H2 as shown in SEQ ID NO: 182, CDR-H3 as shown in SEQ ID NO: 183, CDR-L1 as shown in SEQ ID NO: 184, CDR-L2 as shown in SEQ ID NO: 185, and CDR-L3 as shown in SEQ ID NO: 186; (20) CDR-H1 as shown in SEQ ID NO: 191, CDR-H2 as shown in SEQ ID NO: 192, CDR-H3 as shown in SEQ ID NO: 193, CDR-L1 as shown in SEQ ID NO: 194, CDR-L2 as shown in SEQ ID NO: 195, and CDR-L3 as shown in SEQ ID NO: 196; (21) CDR-H1 as shown in SEQ ID NO: 201, CDR-H2 as shown in SEQ ID NO: 202, CDR-H3 as shown in SEQ ID NO: 203, CDR-L1 as shown in SEQ ID NO: 204, CDR-L2 as shown in SEQ ID NO: 205, and CDR-L3 as shown in SEQ ID NO: 206; (22) CDR-H1 as set forth in SEQ ID NO: 211, CDR-H2 as set forth in SEQ ID NO: 212, CDR-H3 as set forth in SEQ ID NO: 213, CDR-L1 as set forth in SEQ ID NO: 214, CDR-L2 as set forth in SEQ ID NO: 215, and CDR-L3 as set forth in SEQ ID NO: 216; (23) CDR-H1 as shown in SEQ ID NO: 221, CDR-H2 as shown in SEQ ID NO: 222, CDR-H3 as shown in SEQ ID NO: 223, CDR-L1 as shown in SEQ ID NO: 224, CDR-L2 as shown in SEQ ID NO: 225, and CDR-L3 as shown in SEQ ID NO: 226; (24) CDR-H1 as shown in SEQ ID NO: 231, CDR-H2 as shown in SEQ ID NO: 232, CDR-H3 as shown in SEQ ID NO: 233, CDR-L1 as shown in SEQ ID NO: 234, CDR-L2 as shown in SEQ ID NO: 235, and CDR-L3 as shown in SEQ ID NO: 236; (25) CDR-H1 as shown in SEQ ID NO: 241, CDR-H2 as shown in SEQ ID NO: 242, CDR-H3 as shown in SEQ ID NO: 243, CDR-L1 as shown in SEQ ID NO: 244, CDR-L2 as shown in SEQ ID NO: 245, and CDR-L3 as shown in SEQ ID NO: 246; (26) CDR-H1 as shown in SEQ ID NO: 251, CDR-H2 as shown in SEQ ID NO: 252, CDR-H3 as shown in SEQ ID NO: 253, CDR-L1 as shown in SEQ ID NO: 254, CDR-L2 as shown in SEQ ID NO: 255, and CDR-L3 as shown in SEQ ID NO: 256; (27) CDR-H1 as shown in SEQ ID NO: 261, CDR-H2 as shown in SEQ ID NO: 262, CDR-H3 as shown in SEQ ID NO: 263, CDR-L1 as shown in SEQ ID NO: 264, CDR-L2 as shown in SEQ ID NO: 265, and CDR-L3 as shown in SEQ ID NO: 266; (28) CDR-H1 as set forth in SEQ ID NO: 271, CDR-H2 as set forth in SEQ ID NO: 272, CDR-H3 as set forth in SEQ ID NO: 273, CDR-L1 as set forth in SEQ ID NO: 274, CDR-L2 as set forth in SEQ ID NO: 275, and CDR-L3 as set forth in SEQ ID NO: 276; (29) CDR-H1 as shown in SEQ ID NO: 281, CDR-H2 as shown in SEQ ID NO: 282, CDR-H3 as shown in SEQ ID NO: 283, CDR-L1 as shown in SEQ ID NO: 284, CDR-L2 as shown in SEQ ID NO: 285, and CDR-L3 as shown in SEQ ID NO: 286; (30) CDR-H1 as shown in SEQ ID NO: 291, CDR-H2 as shown in SEQ ID NO: 292, CDR-H3 as shown in SEQ ID NO: 293, CDR-L1 as shown in SEQ ID NO: 294, CDR-L2 as shown in SEQ ID NO: 295, and CDR-L3 as shown in SEQ ID NO: 296; (31) CDR-H1 as shown in SEQ ID NO: 301, CDR-H2 as shown in SEQ ID NO: 302, CDR-H3 as shown in SEQ ID NO: 303, CDR-L1 as shown in SEQ ID NO: 304, CDR-L2 as shown in SEQ ID NO: 305, and CDR-L3 as shown in SEQ ID NO: 306; (32) CDR-H1 as set forth in SEQ ID NO: 311, CDR-H2 as set forth in SEQ ID NO: 312, CDR-H3 as set forth in SEQ ID NO: 313, CDR-L1 as set forth in SEQ ID NO: 314, CDR-L2 as set forth in SEQ ID NO: 315, and CDR-L3 as set forth in SEQ ID NO: 316; (33) CDR-H1 as shown in SEQ ID NO: 321, CDR-H2 as shown in SEQ ID NO: 322, CDR-H3 as shown in SEQ ID NO: 323, CDR-L1 as shown in SEQ ID NO: 324, CDR-L2 as shown in SEQ ID NO: 325, and CDR-L3 as shown in SEQ ID NO: 326; (34) CDR-H1 as shown in SEQ ID NO: 331, CDR-H2 as shown in SEQ ID NO: 332, CDR-H3 as shown in SEQ ID NO: 333, CDR-L1 as shown in SEQ ID NO: 334, CDR-L2 as shown in SEQ ID NO: 335, and CDR-L3 as shown in SEQ ID NO: 336; (35) CDR-H1 as shown in SEQ ID NO: 341, CDR-H2 as shown in SEQ ID NO: 342, CDR-H3 as shown in SEQ ID NO: 343, CDR-L1 as shown in SEQ ID NO: 344, CDR-L2 as shown in SEQ ID NO: 345, and CDR-L3 as shown in SEQ ID NO: 346; (36) CDR-H1 as shown in SEQ ID NO: 351, CDR-H2 as shown in SEQ ID NO: 352, CDR-H3 as shown in SEQ ID NO: 353, CDR-L1 as shown in SEQ ID NO: 354, CDR-L2 as shown in SEQ ID NO: 355, and CDR-L3 as shown in SEQ ID NO: 356; (37) CDR-H1 as shown in SEQ ID NO: 361, CDR-H2 as shown in SEQ ID NO: 362, CDR-H3 as shown in SEQ ID NO: 363, CDR-L1 as shown in SEQ ID NO: 364, CDR-L2 as shown in SEQ ID NO: 365, and CDR-L3 as shown in SEQ ID NO: 366; (38) CDR-H1 as set forth in SEQ ID NO: 371, CDR-H2 as set forth in SEQ ID NO: 372, CDR-H3 as set forth in SEQ ID NO: 373, CDR-L1 as set forth in SEQ ID NO: 374, CDR-L2 as set forth in SEQ ID NO: 375, and CDR-L3 as set forth in SEQ ID NO: 376; (39) CDR-H1 as shown in SEQ ID NO: 381, CDR-H2 as shown in SEQ ID NO: 382, ​​CDR-H3 as shown in SEQ ID NO: 383, CDR-L1 as shown in SEQ ID NO: 384, CDR-L2 as shown in SEQ ID NO: 385, and CDR-L3 as shown in SEQ ID NO: 386; (40) CDR-H1 as shown in SEQ ID NO: 391, CDR-H2 as shown in SEQ ID NO: 392, CDR-H3 as shown in SEQ ID NO: 393, CDR-L1 as shown in SEQ ID NO: 394, CDR-L2 as shown in SEQ ID NO: 395, and CDR-L3 as shown in SEQ ID NO: 396; (41) CDR-H1 as shown in SEQ ID NO: 401, CDR-H2 as shown in SEQ ID NO: 402, CDR-H3 as shown in SEQ ID NO: 403, CDR-L1 as shown in SEQ ID NO: 404, CDR-L2 as shown in SEQ ID NO: 405, and CDR-L3 as shown in SEQ ID NO: 406; (42) CDR-H1 as set forth in SEQ ID NO: 411, CDR-H2 as set forth in SEQ ID NO: 412, CDR-H3 as set forth in SEQ ID NO: 413, CDR-L1 as set forth in SEQ ID NO: 414, CDR-L2 as set forth in SEQ ID NO: 415, and CDR-L3 as set forth in SEQ ID NO: 416; (43) CDR-H1 as shown in SEQ ID NO: 421, CDR-H2 as shown in SEQ ID NO: 422, CDR-H3 as shown in SEQ ID NO: 423, CDR-L1 as shown in SEQ ID NO: 424, CDR-L2 as shown in SEQ ID NO: 425, and CDR-L3 as shown in SEQ ID NO: 426; (44) CDR-H1 as set forth in SEQ ID NO: 431, CDR-H2 as set forth in SEQ ID NO: 432, CDR-H3 as set forth in SEQ ID NO: 433, CDR-L1 as set forth in SEQ ID NO: 434, CDR-L2 as set forth in SEQ ID NO: 435, and CDR-L3 as set forth in SEQ ID NO: 436; (45) CDR-H1 as shown in SEQ ID NO: 441, CDR-H2 as shown in SEQ ID NO: 442, CDR-H3 as shown in SEQ ID NO: 443, CDR-L1 as shown in SEQ ID NO: 444, CDR-L2 as shown in SEQ ID NO: 445, and CDR-L3 as shown in SEQ ID NO: 446; (46) CDR-H1 as set forth in SEQ ID NO: 451, CDR-H2 as set forth in SEQ ID NO: 452, CDR-H3 as set forth in SEQ ID NO: 453, CDR-L1 as set forth in SEQ ID NO: 454, CDR-L2 as set forth in SEQ ID NO: 455, and CDR-L3 as set forth in SEQ ID NO: 456; (47) CDR-H1 as shown in SEQ ID NO: 461, CDR-H2 as shown in SEQ ID NO: 462, CDR-H3 as shown in SEQ ID NO: 463, CDR-L1 as shown in SEQ ID NO: 464, CDR-L2 as shown in SEQ ID NO: 465, and CDR-L3 as shown in SEQ ID NO: 466; (48) CDR-H1 as set forth in SEQ ID NO: 471, CDR-H2 as set forth in SEQ ID NO: 472, CDR-H3 as set forth in SEQ ID NO: 473, CDR-L1 as set forth in SEQ ID NO: 474, CDR-L2 as set forth in SEQ ID NO: 475, and CDR-L3 as set forth in SEQ ID NO: 476; (49) CDR-H1 as set forth in SEQ ID NO: 481, CDR-H2 as set forth in SEQ ID NO: 482, CDR-H3 as set forth in SEQ ID NO: 483, CDR-L1 as set forth in SEQ ID NO: 484, CDR-L2 as set forth in SEQ ID NO: 485, and CDR-L3 as set forth in SEQ ID NO: 486; (50) CDR-H1 as set forth in SEQ ID NO: 491, CDR-H2 as set forth in SEQ ID NO: 492, CDR-H3 as set forth in SEQ ID NO: 493, CDR-L1 as set forth in SEQ ID NO: 494, CDR-L2 as set forth in SEQ ID NO: 495, and CDR-L3 as set forth in SEQ ID NO: 496; (51) CDR-H1 as shown in SEQ ID NO: 501, CDR-H2 as shown in SEQ ID NO: 502, CDR-H3 as shown in SEQ ID NO: 503, CDR-L1 as shown in SEQ ID NO: 504, CDR-L2 as shown in SEQ ID NO: 505, and CDR-L3 as shown in SEQ ID NO: 506; (52) CDR-H1 as set forth in SEQ ID NO: 511, CDR-H2 as set forth in SEQ ID NO: 512, CDR-H3 as set forth in SEQ ID NO: 513, CDR-L1 as set forth in SEQ ID NO: 514, CDR-L2 as set forth in SEQ ID NO: 515, and CDR-L3 as set forth in SEQ ID NO: 516; and (53) CDR-H1 as shown in SEQ ID NO: 521, CDR-H2 as shown in SEQ ID NO: 522, CDR-H3 as shown in SEQ ID NO: 523, CDR-L1 as shown in SEQ ID NO: 524, CDR-L2 as shown in SEQ ID NO: 525, and CDR-L3 as shown in SEQ ID NO: 526 The antibody construct of any one of claims 1 to 13, comprising a VH region comprising CDR-H1, CDR-H2 and CDR-H3, and a VL region comprising CDR-L1, CDR-L2 and CDR-L3, selected from:

15. 15. The antibody construct of any one of claims 1 to 14, wherein the first domain that binds to BCMA comprises a VH region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207, 217, 227, 237, 247, 257, 267, 277, 287, 307, 317, 327, 337, 347, 357, 367, 377, 387, 397, 407, 417, 427, 437, 447, 457, 467, 477, 487, 497, 507, 517, and 527.

16. 16. The antibody construct of any one of claims 1 to 15, wherein the first domain that binds to BCMA comprises a VL region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 8, 18, 28, 38, 48, 58, 68, 78, 88, 98, 108, 118, 128, 138, 148, 158, 168, 178, 188, 198, 208, 218, 228, 238, 248, 258, 268, 278, 288, 298, 308, 318, 328, 338, 348, 358, 368, 378, 388, 398, 408, 418, 428, 438, 448, 458, 468, 478, 488, 498, 508, 518, and 528.

17. the first domain that binds to BCMA is (1) a VH region as set forth in SEQ ID NO: 7 and a VL region as set forth in SEQ ID NO: 8; (2) a VH region as set forth in SEQ ID NO: 17 and a VL region as set forth in SEQ ID NO: 18; (3) a VH region as set forth in SEQ ID NO: 27 and a VL region as set forth in SEQ ID NO: 28; (4) a VH region as set forth in SEQ ID NO: 37 and a VL region as set forth in SEQ ID NO: 38; (5) a VH region as set forth in SEQ ID NO: 47 and a VL region as set forth in SEQ ID NO: 48; (6) a VH region as set forth in SEQ ID NO: 57 and a VL region as set forth in SEQ ID NO: 58; (7) A VH region as set forth in SEQ ID NO: 67 and a VL region as set forth in SEQ ID NO: 68; (8) A VH region as set forth in SEQ ID NO: 77 and a VL region as set forth in SEQ ID NO: 78; (9) A VH region as set forth in SEQ ID NO: 87 and a VL region as set forth in SEQ ID NO: 88; (10) A VH region as set forth in SEQ ID NO: 97 and a VL region as set forth in SEQ ID NO: 98; (11) A VH region as set forth in SEQ ID NO: 107 and a VL region as set forth in SEQ ID NO: 108; (12) A VH region as set forth in SEQ ID NO: 117 and a VL region as set forth in SEQ ID NO: 118; (13) A VH region as set forth in SEQ ID NO: 127 and a VL region as set forth in SEQ ID NO: 128; (14) A VH region as set forth in SEQ ID NO: 137 and a VL region as set forth in SEQ ID NO: 138; (15) A VH region as set forth in SEQ ID NO: 147 and a VL region as set forth in SEQ ID NO: 148; (16) A VH region as set forth in SEQ ID NO: 157 and a VL region as set forth in SEQ ID NO: 158; (17) A VH region as set forth in SEQ ID NO: 167 and a VL region as set forth in SEQ ID NO: 168; (18) A VH region as set forth in SEQ ID NO: 177 and a VL region as set forth in SEQ ID NO: 178; (19) A VH region as set forth in SEQ ID NO: 187 and a VL region as set forth in SEQ ID NO: 188; (20) A VH region as set forth in SEQ ID NO: 197 and a VL region as set forth in SEQ ID NO: 198; (21) A VH region as set forth in SEQ ID NO: 207 and a VL region as set forth in SEQ ID NO: 208; (22) A VH region as set forth in SEQ ID NO: 217 and a VL region as set forth in SEQ ID NO: 218; (23) A VH region as set forth in SEQ ID NO: 227 and a VL region as set forth in SEQ ID NO: 228; (24) A VH region as set forth in SEQ ID NO: 237 and a VL region as set forth in SEQ ID NO: 238; (25) A VH region as set forth in SEQ ID NO: 247 and a VL region as set forth in SEQ ID NO: 248; (26) A VH region as set forth in SEQ ID NO: 257 and a VL region as set forth in SEQ ID NO: 258; (27) A VH region as set forth in SEQ ID NO: 267 and a VL region as set forth in SEQ ID NO: 268; (28) A VH region as set forth in SEQ ID NO: 277 and a VL region as set forth in SEQ ID NO: 278; (29) A VH region as set forth in SEQ ID NO: 287 and a VL region as set forth in SEQ ID NO: 288; (30) A VH region as set forth in SEQ ID NO: 297 and a VL region as set forth in SEQ ID NO: 298; (31) A VH region as set forth in SEQ ID NO: 307 and a VL region as set forth in SEQ ID NO: 308; (32) A VH region as set forth in SEQ ID NO: 317 and a VL region as set forth in SEQ ID NO: 318; (33) A VH region as set forth in SEQ ID NO: 327 and a VL region as set forth in SEQ ID NO: 328; (34) A VH region as set forth in SEQ ID NO: 337 and a VL region as set forth in SEQ ID NO: 338; (35) A VH region as set forth in SEQ ID NO: 347 and a VL region as set forth in SEQ ID NO: 348; (36) A VH region as set forth in SEQ ID NO: 357 and a VL region as set forth in SEQ ID NO: 358; (37) A VH region as set forth in SEQ ID NO: 367 and a VL region as set forth in SEQ ID NO: 368; (38) A VH region as set forth in SEQ ID NO: 377 and a VL region as set forth in SEQ ID NO: 378; (39) A VH region as set forth in SEQ ID NO: 387 and a VL region as set forth in SEQ ID NO: 388; (40) A VH region as set forth in SEQ ID NO: 397 and a VL region as set forth in SEQ ID NO: 398; (41) A VH region as set forth in SEQ ID NO: 407 and a VL region as set forth in SEQ ID NO: 408; (42) A VH region as set forth in SEQ ID NO: 417 and a VL region as set forth in SEQ ID NO: 418; (43) A VH region as set forth in SEQ ID NO: 427 and a VL region as set forth in SEQ ID NO: 428; (44) A VH region as set forth in SEQ ID NO: 437 and a VL region as set forth in SEQ ID NO: 438; (45) A VH region as set forth in SEQ ID NO: 447 and a VL region as set forth in SEQ ID NO: 448; (46) A VH region as set forth in SEQ ID NO: 457 and a VL region as set forth in SEQ ID NO: 458; (47) A VH region as set forth in SEQ ID NO: 467 and a VL region as set forth in SEQ ID NO: 468; (48) A VH region as set forth in SEQ ID NO: 477 and a VL region as set forth in SEQ ID NO: 478; (49) A VH region as set forth in SEQ ID NO: 487 and a VL region as set forth in SEQ ID NO: 488; (50) A VH region as set forth in SEQ ID NO: 497 and a VL region as set forth in SEQ ID NO: 498; (51) A VH region as set forth in SEQ ID NO: 507 and a VL region as set forth in SEQ ID NO: 508; (52) A VH region as set forth in SEQ ID NO: 517 and a VL region as set forth in SEQ ID NO: 518; and (53) A VH region as shown in SEQ ID NO: 527 and a VL region as shown in SEQ ID NO: 528 The antibody construct of any one of claims 1 to 16, comprising a VH region and a VL region selected from the group consisting of:

18. 18. The antibody construct of any one of claims 1 to 17, wherein the first domain that binds to BCMA comprises or consists of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 19, 29, 39, 49, 59, 69, 79, 89, 109, 129, 139, 149, 159, 169, 179, 189, 199, 209, 219, 229, 239, 249, 259, 269, 279, 289, 299, 309, 319, 329, 339, 349, 359, 369, 379, 389, 399, 409, 419, 429, 439, 449, 459, 469, 479, 489, 499, 519 and 529.

19. the second domain that binds to CD3 is (a) a CDR-L1 as set forth in SEQ ID NO:542, a CDR-L2 as set forth in SEQ ID NO:543, and a CDR-L3 as set forth in SEQ ID NO:544; (b) CDR-L1 as set forth in SEQ ID NO: 599, CDR-L2 as set forth in SEQ ID NO: 600, and CDR-L3 as set forth in SEQ ID NO: 601; and (c) CDR-L1 as set forth in SEQ ID NO: 621, CDR-L2 as set forth in SEQ ID NO: 622, and CDR-L3 as set forth in SEQ ID NO: 623 The antibody construct of any one of claims 1 to 18, comprising a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from the group consisting of:

20. the second domain that binds to CD3 is (a) a CDR-H1 as set forth in SEQ ID NO:534, a CDR-H2 as set forth in SEQ ID NO:535, and a CDR-H3 as set forth in SEQ ID NO:536; (b) CDR-H1 as set forth in SEQ ID NO:545, CDR-H2 as set forth in SEQ ID NO:546, and CDR-H3 as set forth in SEQ ID NO:547; (c) CDR-H1 as set forth in SEQ ID NO: 557, CDR-H2 as set forth in SEQ ID NO: 558, and CDR-H3 as set forth in SEQ ID NO: 559; (d) CDR-H1 as set forth in SEQ ID NO:568, CDR-H2 as set forth in SEQ ID NO:569, and CDR-H3 as set forth in SEQ ID NO:570; (e) CDR-H1 as set forth in SEQ ID NO: 579, CDR-H2 as set forth in SEQ ID NO: 580, and CDR-H3 as set forth in SEQ ID NO: 581; (f) CDR-H1 as set forth in SEQ ID NO:591, CDR-H2 as set forth in SEQ ID NO:592, and CDR-H3 as set forth in SEQ ID NO:593; (g) CDR-H1 as set forth in SEQ ID NO: 602, CDR-H2 as set forth in SEQ ID NO: 603, and CDR-H3 as set forth in SEQ ID NO: 604; (h) CDR-H1 as set forth in SEQ ID NO: 613, CDR-H2 as set forth in SEQ ID NO: 614, and CDR-H3 as set forth in SEQ ID NO: 615; (i) CDR-H1 as set forth in SEQ ID NO: 624, CDR-H2 as set forth in SEQ ID NO: 625, and CDR-H3 as set forth in SEQ ID NO: 626; and (j) CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638 The antibody construct of any one of claims 1 to 19, comprising a VH region comprising CDR-H1, CDR-H2 and CDR-H3 selected from the group consisting of:

21. the second domain that binds to CD3 is (a) CDR-L1 as set forth in SEQ ID NO:531, CDR-L2 as set forth in SEQ ID NO:532, CDR-L3 as set forth in SEQ ID NO:533, CDR-H1 as set forth in SEQ ID NO:534, CDR-H2 as set forth in SEQ ID NO:535, and CDR-H3 as set forth in SEQ ID NO:536; (b) CDR-L1 as set forth in SEQ ID NO:542, CDR-L2 as set forth in SEQ ID NO:543, CDR-L3 as set forth in SEQ ID NO:544, CDR-H1 as set forth in SEQ ID NO:545, CDR-H2 as set forth in SEQ ID NO:546, and CDR-H3 as set forth in SEQ ID NO:547; (c) CDR-L1 as set forth in SEQ ID NO: 554, CDR-L2 as set forth in SEQ ID NO: 555, CDR-L3 as set forth in SEQ ID NO: 556, CDR-H1 as set forth in SEQ ID NO: 557, CDR-H2 as set forth in SEQ ID NO: 558, and CDR-H3 as set forth in SEQ ID NO: 559; (d) CDR-L1 as set forth in SEQ ID NO:565, CDR-L2 as set forth in SEQ ID NO:566, CDR-L3 as set forth in SEQ ID NO:567, CDR-H1 as set forth in SEQ ID NO:568, CDR-H2 as set forth in SEQ ID NO:569, and CDR-H3 as set forth in SEQ ID NO:570; (e) CDR-L1 as set forth in SEQ ID NO:576, CDR-L2 as set forth in SEQ ID NO:577, CDR-L3 as set forth in SEQ ID NO:578, CDR-H1 as set forth in SEQ ID NO:579, CDR-H2 as set forth in SEQ ID NO:580, and CDR-H3 as set forth in SEQ ID NO:581; (f) CDR-L1 as set forth in SEQ ID NO: 588, CDR-L2 as set forth in SEQ ID NO: 589, CDR-L3 as set forth in SEQ ID NO: 590, CDR-H1 as set forth in SEQ ID NO: 591, CDR-H2 as set forth in SEQ ID NO: 592, and CDR-H3 as set forth in SEQ ID NO: 593; (g) CDR-L1 as set forth in SEQ ID NO:599, CDR-L2 as set forth in SEQ ID NO:600, CDR-L3 as set forth in SEQ ID NO:601, CDR-H1 as set forth in SEQ ID NO:602, CDR-H2 as set forth in SEQ ID NO:603, and CDR-H3 as set forth in SEQ ID NO:604; (h) CDR-L1 as set forth in SEQ ID NO: 610, CDR-L2 as set forth in SEQ ID NO: 611, CDR-L3 as set forth in SEQ ID NO: 612, CDR-H1 as set forth in SEQ ID NO: 613, CDR-H2 as set forth in SEQ ID NO: 614, and CDR-H3 as set forth in SEQ ID NO: 615; (i) CDR-L1 as set forth in SEQ ID NO: 621, CDR-L2 as set forth in SEQ ID NO: 622, CDR-L3 as set forth in SEQ ID NO: 623, CDR-H1 as set forth in SEQ ID NO: 624, CDR-H2 as set forth in SEQ ID NO: 625, and CDR-H3 as set forth in SEQ ID NO: 626; and (j) CDR-L1 as set forth in SEQ ID NO: 633, CDR-L2 as set forth in SEQ ID NO: 634, CDR-L3 as set forth in SEQ ID NO: 635, CDR-H1 as set forth in SEQ ID NO: 636, CDR-H2 as set forth in SEQ ID NO: 637, and CDR-H3 as set forth in SEQ ID NO: 638 The antibody construct of any one of claims 1 to 20, comprising a VL region comprising CDR-L1, CDR-L2, and CDR-L3, and a VH region comprising CDR-H1, CDR-H2, and CDR-H3, selected from the group consisting of:

22. 22. The antibody construct of any one of claims 1 to 21, wherein the second domain that binds to CD3 comprises a VL region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:550, SEQ ID NO:551, SEQ ID NO:584, SEQ ID NO:585, SEQ ID NO:629 and SEQ ID NO:

630.

23. 23. The antibody construct of any one of claims 1 to 22, wherein the second domain that binds to CD3 comprises a VH region having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NO:537, SEQ ID NO:538, SEQ ID NO:548, SEQ ID NO:549, SEQ ID NO:560, SEQ ID NO:561, SEQ ID NO:571, SEQ ID NO:572, SEQ ID NO:582, SEQ ID NO:583, SEQ ID NO:594, SEQ ID NO:595, SEQ ID NO:605, SEQ ID NO:606, SEQ ID NO:616, SEQ ID NO:617, SEQ ID NO:627, SEQ ID NO:628, SEQ ID NO:639, SEQ ID NO:640, and SEQ ID NO:

644.

24. the second domain that binds to CD3 is (a) a VL region as set forth in SEQ ID NO: 539 or 521 and a VH region as set forth in SEQ ID NO: 537 or 538; (b) a VL region as set forth in SEQ ID NO: 550 or 521 and a VH region as set forth in SEQ ID NO: 548 or 549; (c) a VL region as set forth in SEQ ID NO: 562 or 521 and a VH region as set forth in SEQ ID NO: 560 or 561; (d) a VL region as set forth in SEQ ID NO: 573 or 521 and a VH region as set forth in SEQ ID NO: 571 or 572; (e) a VL region as set forth in SEQ ID NO: 584 or 585 and a VH region as set forth in SEQ ID NO: 582 or 583; (f) a VL region as set forth in SEQ ID NO: 596 or 521 and a VH region as set forth in SEQ ID NO: 594 or 595; (g) a VL region as set forth in SEQ ID NO: 607 or 585 and a VH region as set forth in SEQ ID NO: 605 or 606; (h) a VL region as set forth in SEQ ID NO: 618 or 521 and a VH region as set forth in SEQ ID NO: 616 or 617; (i) a VL region as set forth in SEQ ID NO: 629 or 630 and a VH region as set forth in SEQ ID NO: 627 or 628; (j) a VL region as set forth in SEQ ID NO: 641 or 630 and a VH region as set forth in SEQ ID NO: 639 or 640; and (k) a VL region as set forth in SEQ ID NO: 645 and a VH region as set forth in SEQ ID NO: 644 The antibody construct of any one of claims 1 to 23, comprising a VL region and a VH region selected from the group consisting of:

25. 25. The antibody construct of any one of claims 1 to 24, wherein the second domain that binds to CD3 comprises or consists of a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 540, 541, 552, 553, 563, 564, 574, 575, 586, 587, 597, 598, 608, 609, 619, 620, 631, 632, 642, 643 and 646.

26. 26. The antibody construct of any one of claims 1 to 25, comprising a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520 and 530.

27. From the N-terminus to the C-terminus, (a) the first domain; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 687, 693, and 694; (c) the second domain; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 686, 687, 688, 689, 690, 691, 692, 693, or 694; (e) a first polypeptide monomer (comprising a hinge, a CH2 domain, and a CH3 domain); (f) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 695, 696, 697, 698, or 699; and (g) a second polypeptide monomer (comprising a hinge, a CH2 domain, and a CH3 domain); The antibody construct of any one of claims 1 to 26, comprising:

28. From the N-terminus to the C-terminus, (a) SEQ ID NOs: 9, 19, 29, 39, 49, 59, 69, 79, 89, 109, 129, 139, 149, 159, 169, 179, 189, 199, 209, 219, 229, 239, 249, 259, 269, 279, 289, 299, 309, 319, 329, 339, 349, 359, 369, 379, 389, 399, 409, 4 a first domain having an amino acid sequence selected from the group consisting of: 19, 429, 439, 449, 459, 469, 479, 489, 499, 519, and 529; and wherein the peptide linker having SEQ ID NO:694 contained within these sequences may be replaced with any one of SEQ ID NOs:686-693 and 695-699; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 687, 693, and 694; (c) a second domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 540, 541, 552, 553, 563, 564, 574, 575, 586, 587, 597, 598, 608, 609, 619, 620, 631, 632, 642, 643, and 646; wherein the peptide linker having SEQ ID NO: 694 contained within these sequences may be replaced with any one of SEQ ID NOs: 686-693 and 695-699; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 686, 687, 688, 689, 690, 691, 692, 693, and 694; and (e) a third domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 700-707; 28. The antibody construct of any one of claims 1 to 27, comprising:

29. From the N-terminus to the C-terminus, (a) a polypeptide having an amino acid sequence selected from the group consisting of those set forth in SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, and 530; (b) a linker having an amino acid sequence as set forth in SEQ ID NO: 686; and (c) a polypeptide having an amino acid sequence as set forth in SEQ ID NO:

700. The antibody construct of any one of claims 1 to 28, comprising:

30. 30. The antibody construct of any one of claims 1 to 29, having a molecular weight of about 75 to about 200 kDa, about 80 to about 175 kDa, about 85 to about 150 kDa, about 90 to about 130 kDa, about 95 to about 120 kDa, and preferably about 100 to about 115 kDa or about 105 to about 110 kDa.

31. Excretion half-life (T １／２ 31. The antibody construct of claim 1, wherein the incubation time is about 3 to about 14 days, about 4 to about 12 days, about 3 or 4 to about 10 days, about 3 or 4 to about 8 days, or about 5 to about 7 days.

Images