Immunoglobulin single variable domains targeting CD19

Abstract

The present technology provides polypeptides that specifically bind to human CD19. The present technology also provides nucleic acids, vectors and compositions.

Description

[0001] IMMUNOGLOBULIN SINGLE VARIABLE DOMAINS TARGETING CD19

[0002] DESCRIPTION

[0003] 1 Field of the present technology

[0004] The present technology relates to immunoglobulin single variable domains (ISVDs) targeting CD19 and more in particular to polypeptides and constructs that comprise or essentially consist of one or more such ISVDs. It also relates to nucleic acid molecules encoding the ISVDs and polypeptides and vectors comprising the nucleic acids, and to compositions comprising the ISVD, polypeptide, nucleic acid or vector. The present technology further relates to these products for use in a method of treating a subject suffering from cancer. The present technology also relates to methods of producing these products.

[0005] 2 Technological Background

[0006] CD19 is a transmembrane glycoprotein expressed primarily on B lymphocytes and follicular dendritic cells. It acts as a critical coreceptor for the B-cell antigen receptor (BCR) complex, enhancing B-cell responses to antigens by lowering the activation threshold of BCR signaling. CD19 forms a complex with other membrane proteins, such as CD21 and CD81, to regulate B-cell activation and survival (Tedder, Thomas F., Makoto Inaoki, and Shinichi Sato. " The CD19-CD21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity." Immunity 6.2 (1997): 107-118).

[0007] Aberrant expression or dysregulation of CD19 is linked to various diseases. In autoimmune disorders such as systemic lupus erythematosus (SLE), overexpression of CD19 on B cells promotes autoantibody production, exacerbating disease severity. Additionally, CD19 is expressed in the majority of B-cell malignancies at normal to high levels, including diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), making it a crucial biomarker for diagnosis and a promising therapeutic target (Wang, Kemeng, Guoqing Wei, and Delong Liu. " CD19: a biomarker for B cell development, lymphoma diagnosis and therapy." Experimental hematology & oncology 1 (2012): 1-7.).

[0008] Several therapeutic agents targeting CD19 have been developed. For example, chimeric antigen receptor (CAR) T-cell therapies allow to recognize and destroy CD19-expressing malignant B cells.Moreover, monoclonal antibodies like blinatumomab, a bispecific T-cell engager, simultaneously bind CD19 and CD3 to mediate T-cell cytotoxicity against B-cell malignancies (Newman MJ, Benani DJ. A review of blinatumomab, a novel immunotherapy. Journal of Oncology Pharmacy Practice.

[0009] 2016;22(4):639-645. doi:10.1177 / 1078155215618770).

[0010] Whilst CD19 plays a pivotal role in B-cell biology and is a key target in autoimmune diseases and B-cell malignancies there is still a need for improved small-molecule biologies to CD19. Such smallmolecule biologies are also useful for combining with other (cancer)target binders in a single chain, while maintaining a relatively small size, high affinity, potency and / or efficacy, in addition to good manufacturing yields. Furthermore, the biological drug should show safety, convenience, patient compliance and improve patients' quality of life.

[0011] 3 Summary of the present technology

[0012] In some embodiments, the present technology relates to immunoglobulin single variable domains specifically targeting CD19. In some embodiments, the present technology relates to high affinity immunoglobulin single variable domains specifically targeting CD19. In some embodiments, the present technology relates to high potency immunoglobulin single variable domains specifically targeting CD19. In some embodiments, the present technology relates to high efficacy immunoglobulin single variable domains specifically targeting CD19. In some embodiments, the present technology relates to immunoglobulin single variable domains specifically targeting human and / or cyno CD19. In some embodiments, the present technology relates to immunoglobulin single variable domains specifically targeting a specific epitope on CD19, preferably human and / or cyno CD19. The immunoglobulin single variable domains can be used for targeting other moieties, such as T-cell engagers or NK-cell engagers to a target cell, such as malignant B-cell s.

[0013] Targeting CD19 with a biologic that is small (in size), such as a monovalent or bivalent immunoglobulin single variable domain, and keeping a high affinity and / or efficacy may be advantageous in certain applications where a very small binder is desired. Small binders may be advantageous, e.g. for penetration in the tumor environment, or when additional binders for other (tumor) targets are implicated in the same construct, facilitating manufacturing and further handling of the therapeutic compound.The immunoglobulin single variable domain of the present technology specifically binds to human CD19, comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively) and interacts with at least one amino acid of the CD19 protein selected from E104, Q98, P99, Q108, S185, Q186, V202, D205, S206 and S208 when numbered in accordance with SEQ ID NO.: 214.

[0014] The immunoglobulin single variable domain of the present technology specifically binds to human CD19 and blocks (as defined herein) the binding of an ISVD having SEQ ID NO: 1 to human CD19, blocks (as defined herein) the binding of an ISVD having SEQ ID NO: 116 to human CD19 or blocks (as defined herein) the binding of an ISVD having SEQ ID NO: 71 to human CD19.

[0015] Similarly, the immunoglobulin single variable domain of the present technology specifically binds to human CD19 and blocks (as defined herein) the binding to human CD19 by an ISVD having SEQ ID NO: 1, blocks (as defined herein) the binding to human CD19 by an ISVD having SEQ ID NO: 116or blocks (as defined herein) the binding to human CD19 by an ISVD having SEQ ID NO: 71.

[0016] The immunoglobulin single variable domain of the present technology specifically binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 1 or an ISVD having SEQ ID NO: 71.

[0017] The immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0018] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0019] a) the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97);

[0020] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97);

[0021] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97); and

[0022] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0023] d) the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99);

[0024] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99); andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99);

[0025] and

[0026] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0027] g) the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R;

[0028] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R; and

[0029] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R.

[0030] The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0031] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 113; or in which

[0032] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 114; or in which

[0033] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 115.

[0034] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with one of SEQ ID NOs: 71-95. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence selected from SEQ ID NOs: 71-95.In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0035] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0036] a) the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;

[0037] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D; and

[0038] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;

[0039] and

[0040] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0041] d) the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;

[0042] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K; and

[0043] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;

[0044] and

[0045] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0046] g) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S;

[0047] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; and

[0048] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0049] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 43, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0050] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0051] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0052] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 46, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0053] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 44, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0054] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68; or in which

[0055] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69; or in which- CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69; or in which

[0056] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68; or in which

[0057] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 38, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with one of SEQ ID NOs: 1-33. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence selected from SEQ ID NOs: 1-33.

[0058] In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0059] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0060] a) the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);

[0061] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136); and

[0062] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);

[0063] and

[0064] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0065] d) the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137);

[0066] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137); and

[0067] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137);and

[0068] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0069] g) the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V;

[0070] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V; and

[0071] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V.

[0072] The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0073] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0074] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0075] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 154;

[0076] or in which

[0077] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0078] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0079] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 152;

[0080] or in which

[0081] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0082] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0083] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 153;

[0084] or in which

[0085] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0086] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0087] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 155.

[0088] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with one of SEQ ID NOs: 116-134. In one embodiment, thepolypeptide of the present technology comprises or consists of the amino acid sequence selected from SEQ ID NOs: 116-134.

[0089] In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0090] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0091] a) the amino acid sequence of GRTFSSYVAA (SEQ ID NO: 304);

[0092] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTFSSYVAA (SEQ ID NO: 304); and

[0093] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTFSSYVAA (SEQ ID NO: 304);

[0094] and

[0095] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0096] d) the amino acid sequence AASLSGGTTD (SEQ ID NO: 305);

[0097] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AASLSGGTTD (SEQ ID NO: 305); and

[0098] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AASLSGGTTD (SEQ ID NO: 305);

[0099] and

[0100] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0101] g) the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306);

[0102] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306); and

[0103] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306).

[0104] The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0105] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 304, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 305, and - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 306.In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with SEQ ID NO: 200. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 200.

[0106] In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0107] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0108] a) the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[0109] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362); and

[0110] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[0111] and

[0112] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0113] d) the amino acid sequence of VSSLSGGTSD (SEQ ID NO: 356);

[0114] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSSLSGGTSD (SEQ ID NO: 356); and

[0115] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSSLSGGTSD (SEQ ID NO: 356);

[0116] and

[0117] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0118] g) the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[0119] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363); and

[0120] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363).

[0121] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as morethan 95% or even more than 99%) with SEQ ID NO: 202. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 202.

[0122] In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0123] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0124] a) the amino acid sequence of GLTFAGYSVG (SEQ ID NO: 324);

[0125] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFAGYSVG (SEQ ID NO: 324); and

[0126] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GLTFAGYSVG (SEQ ID NO: 324);

[0127] and

[0128] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0129] d) the amino acid sequence of VITRGGDYRY (SEQ ID NO: 325);

[0130] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VITRGGDYRY (SEQ ID NO: 325); and

[0131] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VITRGGDYRY (SEQ ID NO: 325);

[0132] and

[0133] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0134] g) the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326);

[0135] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326); and

[0136] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326).

[0137] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with SEQ ID NO: 197. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID Nos: 197.In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0138] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0139] a) the amino acid sequence of GRTLSSYTTG (SEQ ID NO: 333);

[0140] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTLSSYTTG (SEQ ID NO: 333); and

[0141] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTLSSYTTG (SEQ ID NO: 333);

[0142] and

[0143] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0144] d) the amino acid sequence of AITKNGPYLY (SEQ ID NO: 334);

[0145] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AITKNGPYLY (SEQ ID NO: 334); and

[0146] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AITKNGPYLY (SEQ ID NO: 334);

[0147] and

[0148] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0149] g) the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335);

[0150] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335); and

[0151] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335).

[0152] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with SEQ ID NO: 198. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 198.

[0153] In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0154] CDR1 (AbM definition) consists of an amino acid sequence selected from:a) the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[0155] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362); and

[0156] c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[0157] and

[0158] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0159] d) the amino acid sequence of VSSLSGGTSD (SEQ ID NO: 356); e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSSLSGGTSD (SEQ ID NO: 356); and f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSSLSGGTSD (SEQ ID NO: 356);

[0160] and

[0161] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0162] g) the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[0163] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363); and

[0164] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SSYTYNIRQRSSYDW (SEQ ID NO: 317).

[0165] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with SEQ ID NO: 196. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 196.

[0166] In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0167] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0168] a) the amino acid sequence of GLTFDNYAMG (SEQ ID NO: 341);

[0169] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFDNYAMG (SEQ ID NO: 341); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GLTFDNYAMG (SEQ ID NO: 341);

[0170] and

[0171] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0172] d) the amino acid sequence of TISAAGHRTI (SEQ ID NO: 342);

[0173] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TISAAGHRTI (SEQ ID NO: 342); and

[0174] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of TISAAGHRTI (SEQ ID NO: 342);

[0175] and

[0176] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0177] g) the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343);

[0178] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343); and

[0179] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343).

[0180] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with SEQ ID NO: 199. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 199.

[0181] In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0182] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0183] a) the amino acid sequence of GSRLSFTTMG (SEQ ID NO: 351);

[0184] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GSRLSFTTMG (SEQ ID NO: 351); and

[0185] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GSRLSFTTMG (SEQ ID NO: 351);

[0186] and

[0187] CDR2 (AbM definition) consists of an amino acid sequence selected from:d) the amino acid sequence of YITESGSTA (SEQ ID NO: 352);

[0188] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of YITESGSTA (SEQ ID NO: 352); and

[0189] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of YITESGSTA (SEQ ID NO: 352);

[0190] and

[0191] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0192] g) the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353);

[0193] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353); and

[0194] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353).

[0195] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with SEQ ID NO: 201. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 201.

[0196] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0197] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0198] a) the amino acid sequence of GRTLVEVG (SEQ ID NO: 421);

[0199] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTLVEVG (SEQ ID NO: 421);

[0200] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTLVEVG (SEQ ID NO: 421);

[0201] and

[0202] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0203] d) the amino acid sequence GITWSGFTTY (SEQ ID NO: 422);

[0204] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GITWSGFTTY (SEQ ID NO: 422);f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITWSGFTTY (SEQ ID NO: 422);

[0205] and

[0206] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0207] g) the amino acid sequence of SVSRLTTLPADYDY (SEQ ID NO: 423);

[0208] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SVSRLTTLPADYDY (SEQ ID NO: 423);

[0209] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SVSRLTTLPADYDY (SEQ ID NO: 423).

[0210] In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more than 99%) with SEQ ID NO: 286. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 286.

[0211] In some embodiments, the immunoglobulin single variable domain of the present technology may essentially consist of a VHH, such as a humanized VHH, or a VH, such as a camelized VH, a human VH, a camelized human VH, a domain antibody, a single domain antibody, and / or a dAb.

[0212] The present technology also relates to polypeptides and constructs comprising such immunoglobulin single variable domain, and optionally further comprising one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[0213] The immunoglobulin single variable domains of the present technology and polypeptides and constructs comprising said immunoglobulin single variable domains showed a high potency in FACS bindings assays and could be efficiently produced (e.g. in microbial hosts such as Pichia, e.g. P. pastoris).

[0214] In one embodiment, the immunoglobulin single variable domain, polypeptide or construct of the present technology may further comprise one or more other groups, residues, moieties or binding units, optionally linked via one or more peptidic linkers, in which said one or more other groups, residues, moieties or binding units provide the ISVD, polypeptide or construct with increased halflife, compared to the corresponding ISVD, polypeptide or construct without said one or more othergroups, residues, moieties or binding units. Said one or more other groups, residues, moieties or binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that can bind to serum proteins, an Fc portion, and small proteins or peptides that can bind to serum proteins. The binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of binding units that can bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG), e.g. human serum albumin.

[0215] In one embodiment, the binding unit that can bind to serum albumin (such as human serum albumin) is an ISVD. In one embodiment, the ISVD binding to human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which CDR1 is SEQ ID NO: 158, CDR2 is SEQ ID NO: 160, CDR3 is SEQ ID NO: 162. In one embodiment, the ISVD binding to human serum albumin comprises a sequence identity of more than 90% (such as more than 95%) with SEQ ID NO: 156. In one embodiment, the ISVD binding to human serum albumin comprises or consists of the amino acid sequence of SEQ ID NO: 156.

[0216] In one embodiment, the ISVD binding to human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB23002 (SEQ ID NO: 156). In one embodiment, the ISVD binding to human serum albumin is ALB23002 (SEQ ID NO: 156).

[0217] Also provided is a nucleic acid molecule capable of expressing the immunoglobulin single variable domain or polypeptide of the present technology, a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid or vector.

[0218] Also provided is a (non-human) host or host cell comprising such a nucleic acid.

[0219] Also provided is a method for producing an immunoglobulin single variable domain or polypeptide of the present technology, said method at least comprising the steps of:

[0220] i) expressing, in a suitable (non-human) host or host cell or in another suitable expression system, a nucleic acid encoding the immunoglobulin single variable domain or polypeptide of the present technology; optionally followed by:ii) isolating and / or purifying the ISVD or polypeptide.

[0221] Also provided is a composition comprising at least one immunoglobulin single variable domain, polypeptide or construct of the present technology, or a nucleic acid encoding an immunoglobulin single variable or polypeptide of the present technology.

[0222] The composition of the present technology is for use as a medicament. The composition can be a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[0223] The immunoglobulin single variable domain, polypeptide or construct of the present technology, the composition comprising the immunoglobulin single variable domain, polypeptide or construct, and the composition comprising a nucleic acid comprising a nucleotide sequence that encodes the immunoglobulin single variable domain or polypeptide can be used as a medicament.

[0224] The immunoglobulin single variable domain, polypeptide, construct or composition of the present technology can be used in the treatment. More specifically, the immunoglobulin single variable, polypeptide, construct or composition can be used in the treatment of proliferative diseases such as cancer, immunological diseases, infectious diseases and / or auto-immune diseases.

[0225] Accordingly, the present technology also encompasses a method of treating proliferative diseases such as cancer, immunological diseases, infectious diseases and / or auto-immune diseases. In some embodiments, the present technology encompasses a method of treating proliferative diseases such as cancer, immunological diseases, infectious diseases and / or auto-immune diseases, wherein said method comprises administering, to a subject in need thereof, a pharmaceutically active amount of an immunoglobulin single variable domain, polypeptide or construct of the present technology, a nucleic acid encoding an ISVD or polypeptide of the present technology or a composition comprising the same.

[0226] Accordingly, the present technology also encompasses the use of an immunoglobulin single domain, polypeptide or construct of the present technology in the preparation of a pharmaceuticalcomposition for treating disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[0227] In particular, the technology provides an immunoglobulin single variable domain (ISVD) specifically binding to human CD19, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human CD19, wherein at least one amino acid residue preferably located in at least one of the CDRs is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19, when numbered in accordance with SEQ ID NO: 214:

[0228] C97-W111;

[0229] W124-D128;

[0230] W159-K161;

[0231] S185-Q186;

[0232] C200-P211; and / or

[0233] D232.

[0234] In some embodiments, the at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19, when numbered in accordance with SEQ ID NO: 214:

[0235] P99-P109;

[0236] Q186; and / or

[0237] C200-V207.

[0238] or

[0239] P99;

[0240] A106-P109;

[0241] Q186;

[0242] C200-V202;

[0243] D205-V207.

[0244] In those embodiments, the at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with one or more amino acid residues in human CD19 selected from:C97, Q98, P99, G100, P1O1, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C2OO, G2O1, V2O2, P204, D205, S206, V207, S208, R209, G21O, P211, D232, when numbered in accordance with SEQ ID NO: 214.

[0245] In one embodiment, the at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with one or more amino acid residues in human CD19 selected from: P99, A106, W107, Q108, P109, Q186, C200, G201, V202, D205, S206, and V207. Preferably, the at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with all amino acid residues Q98, P99, A106, W107, Q108, P109, Q186, C200, G201, V202, D205, S206, and V207, preferably with all of Q98, P99, Q108, Q186, V202, D205, S206, and V207, in human CD19 when numbered in accordance with SEQ ID NO: 214.

[0246] In particular, the present technology provides the following embodiments:

[0247] 3.1 Embodiment 1 (A0289040C01 family)

[0248] 1. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human CD19, wherein at least one amino acid residue is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19 when numbered in accordance with SEQ ID NO: 214:

[0249] Q98-W111;

[0250] W124-D128;

[0251] W159-K161;

[0252] S185-Q186; and / or

[0253] C200-V207.

[0254] 2. The ISVD of item 1, wherein the at least one amino acid residue in at least one, preferably in each amino acids stretch of human CD19 is selected from:

[0255] • From stretch Q98-W111: Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109 and Will;

[0256] • From stretch W124-D128: W124, N125 and D128;From stretch W159-K161: W159 and K161;

[0257] From stretch S185-Q186: S185 and Q186;

[0258] From stretch C200-V207: C200, G201, V202, P204, D205, S206 and V207, when numbered in accordance with SEQ ID NO: 214.

[0259] The ISVD of item 1 or item 2, wherein at least one amino acid residue is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or preferably all of the following amino acid residues in stretch Q98-W111 of human CD19, when numbered in accordance with SEQ ID NO: 214: Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109 and Will.

[0260] The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of interacting with at least one, at least two, or preferably all of the following amino acid residues in stretch W124-D128 of human CD19, when numbered in accordance with SEQ ID NO: 214: W124, N125 and D128.

[0261] The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of interacting with at least one, or preferably all of the following amino acid residues in stretch W159-K161 of human CD19, when numbered in accordance with SEQ ID NO: 214: W159 and K161.

[0262] The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of interacting with at least one, or preferably all of the following amino acid residues in stretch S185-Q186 of human CD19, when numbered in accordance with SEQ ID NO: 214: S185 and Q186.

[0263] The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, or preferably all of the following amino acid residues in stretch C200-V207 of human CD19, when numbered in accordance with SEQ ID NO: 214: C200, G201, V202, P204, D205, S206 and8. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least one amino acid of the CD19 protein selected from E104, Q98, P99, Q108, S185 and Q186, when numbered in accordance with SEQ ID NO.: 214.

[0264] 9. The immunoglobulin single variable domain (ISVD) of item 8, that interacts with at least two amino acids, optionally, at least three amino acids, at least four amino acids, at least five amino acids, or preferably all amino acids of the CD19 protein selected from E104, Q98, P99, Q108, S185 and Q186.

[0265] 10. The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of forming a salt bridge with E104 of human CD19, when numbered in accordance with SEQ ID NO: 214.

[0266] 11. The ISVD of any one of the preceding items, wherein:

[0267] the amino acid residue at position R73 (Kabat numbering) is capable of interacting, preferably by forming a salt bridge, with E104 in human CD19,

[0268] when numbered in accordance with SEQ ID NO: 214;

[0269] 12. The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of forming hydrogen bonds with at least one, or all of the following amino acid residues of human CD19, when numbered in accordance with SEQ ID NO: 214: Q98, P99, E104, Q108, S185 and Q186.

[0270] 13. The ISVD of any one of the preceding items, wherein:

[0271] the amino acid residue at position Y100 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with S185 in human CD19; and / or

[0272] the amino acid residue at position F98 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q186 in human CD19,

[0273] the amino acid residue at position T53 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q108 in human CD19,

[0274] the amino acid residue at position R73 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q98 and / or P99 in human CD19,the amino acid residue at position R96 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N125 N-acetylglucosamine in human CD19, when numbered in accordance with SEQ. ID NO: 214.

[0275] 14. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least one amino acid of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0276] 15. The immunoglobulin single variable domain (ISVD) of item 14, that interacts with at least two amino acids, optionally, at least five amino acids, at least ten amino acids, at least twenty amino acids of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0277] 16. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with the following amino acids of the CD19 protein: Q98, P99, Q108, S185 and Q186.

[0278] 17. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with the following amino acid of the CD19 protein: E104.

[0279] 18. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with the following amino acids of the CD19 protein: Q98, P99, E104, Q108, S185 and Q186.

[0280] 19. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with the following amino acids of the CD19 protein: K105, A106, W107, P109, W111, W124, N125, W159, K161, C200, V202, P204, D205, S206 and V207, optionally that interacts with the following amino acids of the CD19 protein Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.An immunoglobulin single variable domain (ISVD) specifically binding to human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), and that comprises at least one amino acid residue selected from the group consisting of: T53, R73, R96, F98 and Y100 (Kabat numbering), optionally at least two, at least three, at least four, further optionally, that comprises the amino acid residues selected from the group consisting of: T53, R73, R96, F98 and Y100 (Kabat numbering), even further optionally that interacts with the CD19 protein as defined in items 1-8, preferably wherein:

[0281] R73 (Kabat numbering) in the ISVD interacts, preferably by forming a salt bridge, with E104 in human CD19, and / or

[0282] Y100 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with S185 in human CD19; and / or

[0283] F98 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q186 in human CD19; and / or

[0284] T53 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q108 in human CD19; and / or

[0285] R73 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q98 and / or P99 in human CD19; and / or

[0286] R96 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with N125 N-acetylglucosamine in human CD19,

[0287] when numbered in accordance with SEQ. ID NO: 214.

[0288] The immunoglobulin single variable domain (ISVD) of item 20, that comprises D27, F29, G30, and T31 (Kabat numbering) in CDR1 (Abm definition).

[0289] The immunoglobulin single variable domain (ISVD) of item 20 or 21, that comprises T52, W52a, T53, A54 and L56 (Kabat numbering) in CDR2 (Abm definition).

[0290] The immunoglobulin single variable domain (ISVD) of any one of items 20 to 22, that comprises F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).

[0291] The immunoglobulin single variable domain (ISVD) of any one of items 20 to 23, that comprises R96, F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).25. The immunoglobulin single variable domain (ISVD) of any one of items 20 to 24, that comprises D27, F29, G30, and T31 (Kabat numbering) in CDR1 (Abm definition), T52, W52a, T53, A54 and L56 (Kabat numbering) in CDR2 (Abm definition) and F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).

[0292] 26. The immunoglobulin single variable domain (ISVD) of any one of items 20 to 25, that comprises D27, F29, G30, and T31 (Kabat numbering) in CDR1 (Abm definition), T52, W52a, T53, A54 and L56 (Kabat numbering) in CDR2 (Abm definition) and R96, F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).

[0293] 27. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that comprises R73.

[0294] 28. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that comprises K71, V74 and / or N76.

[0295] 29. The immunoglobulin single variable domain (ISVD) of any one of items 20 to 28, that comprises T53, R73, F98 and Y100 (Kabat numbering), wherein T53, R73, F98 and Y100 form an interaction site, preferably a salt bridge or an hydrogen bound, with at least one amino acid selected from the group consisting of Q108, Q98 and P99, Q186 and S185 of the CD19 protein.

[0296] 30. The immunoglobulin single variable domain (ISVD) of item 29, wherein the interaction site is formed by at least two, at least three, at least four, at least five amino acids selected from the group consisting of Q108, Q98 and P99, Q186 and S185 of the CD19 protein.

[0297] 31. The immunoglobulin single variable domain (ISVD) of any one of items 20 to 28, that comprises T53, R73, R96, F98 and Y100 (Kabat numbering), wherein T53, R73, R96, F98 and Y100 form an interaction site, preferably a salt bridge or an hydrogen bound, with at least one residue selected from the group consisting of E104, Q108, Q98, P99, N-acetyl glucosamine on N125, Q186, and S185 of the CD19 protein.

[0298] 32. The immunoglobulin single variable domain (ISVD) of item 31, wherein the interaction site is formed by at least two, at least three, at least four, at least five, at least six, or all residuesselected from the group consisting of E104, Q108, Q98 and P99, N-acetyl glucosamine on N125, Q186, and S185 of the CD19 protein.

[0299] he immunoglobulin single variable domain (ISVD) of any one of items 20 to 32, that comprises T53, R73, F98 and Y100 (Kabat numbering), wherein T53, R73, F98 and Y100 form an interaction site, preferably an hydrogen bound, with Q108, Q98 and P99, Q186 and S185 of the CD19 protein as follows:

[0300] o Y100 (Kabat numbering) interacts with S185 in CD19

[0301] o F98 (Kabat numbering) interacts with Q186 in CD19;

[0302] o T53 (Kabat numbering) interacts with Q108 in CD19;

[0303] o R73 (Kabat numbering) interacts with Q98 in CD19; and

[0304] o R73 (Kabat numbering) interacts with P99 in CD19.

[0305] The immunoglobulin single variable domain (ISVD) of any one of items 20 to 33, that comprises T53, R73, R96, F98 and Y100 (Kabat numbering), wherein T53, R73, R96, F98 and Y100 form an interaction site, preferably an hydrogen bound, with Q108, Q98 and P99, N-acetylglucosamine of N125, Q186 and S185 of the CD19 protein as follows:

[0306] o Y100 (Kabat numbering) interacts with S185 in CD19

[0307] o F98 (Kabat numbering) interacts with Q186 in CD19;

[0308] o T53 (Kabat numbering) interacts with Q108 in CD19;

[0309] o R73 (Kabat numbering) interacts with Q98 in CD19;

[0310] o R73 (Kabat numbering) interacts with P99 in CD19; and

[0311] o R96 (Kabat numbering) interacts with N-acetyl glucosamine on N125 in CD19.

[0312] The immunoglobulin single variable domain (ISVD) of any one of items 20 to 33, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, F98, Y100 and H100b (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0313] The immunoglobulin single variable domain (ISVD) of item 35, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen, at least twenty amino acidsof the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0314] The immunoglobulin single variable domain (ISVD) of item 35 or 36, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, F98, Y100 and H100b (Kabat numbering) form the interaction site with following amino acids of the CD19 protein: Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0315] The immunoglobulin single variable domain (ISVD) of any one of items 20 to 34, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, R96, F98, Y100 and H100b (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0316] The immunoglobulin single variable domain (ISVD) of item 38, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen, at least twenty amino acids of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0317] The immunoglobulin single variable domain (ISVD) of item 38 or 39, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, R96, F98, Y100 and H100b (Kabat numbering) form the interaction site with following amino acids of the CD19 protein: Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

[0318] The ISVD of any one of the preceding items, wherein two amino acids are considered to interact when the distance between them is 4.0 A or less.

[0319] The ISVD of any one of the preceding items, wherein the interacting amino acid residue(s) in the ISVD and in human CD19 are identified by cryo-EM by:

[0320] Mixing CD19 recombinant protein, the ISVD and an anti-VHH Fab at a molar ratio of 1:2:1 in 20 mM Hepes (pH 7.4), 150 mM NaCI;Diluting the protein complex to 0.5 mg / mL in buffer containing 150 mM NaCI and 20 mM Hepes (pH 7.4);

[0321] Applying the protein complex to glow-discharged Ultrafoil Rl.2 / 1.3 grids, blotting for 4 seconds under 100% humidity and 4°C, plunge-freezing in liquid-ethane cooled by liquid nitrogen;

[0322] Collecting cryo-EM data using a cryo-transmission electron microscope, optionally at a pixel size of ~ 0.59 A in movie mode yielding a cumulative dose of ~50 e“ / A2; and Processing the collected data,

[0323] preferably as described in Example 3.

[0324] he immunoglobulin single variable domain (ISVD) of any one of the previous items, wherein CDR1 (AbM definition) consists of an amino acid sequence X1DX2FGTX3X4X5X6 (SEQ ID NO:203); wherein the amino acid residue:

[0325] ■ Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as G;

[0326] ■ X2 is selected from any amino acid, preferably X2 is selected from S, T, C, N, Q, such as T;

[0327] ■ X3 is selected from any amino acid, preferably X3 is selected from K, R and H, such as K;

[0328] ■ X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as A;

[0329] ■ X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as M;

[0330] ■ Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as G;

[0331] and

[0332] - CDR2 (AbM definition) consists of an amino acid sequence X1X2TWTAX3LX4X5 (SEQ ID NO:

[0333] 204); wherein the amino acid residue:

[0334] ■ Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as A;

[0335] ■ X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as I;■ Xa is selected from any amino acid, preferably X3 is selected from G, A, V, L, I, M and P, such as G;

[0336] ■ X4is selected from any amino acid, preferably X4is selected from S, T, C, N, Q, such as T;

[0337] ■ X5is selected from any amino acid, preferably X5is selected from F, Y and W, such as Y;

[0338] and

[0339] - CDR3 (AbM definition) consists of an amino acid sequence X1X2X3FX4YX5HX6X7X8X9X10X11X12X13X14X15X16 (SEQ ID NO: 205); wherein the amino acid residue:

[0340] ■ Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as R;

[0341] ■ X2 is selected from any amino acid, preferably X2 is selected from K, R and H, such as R;

[0342] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as T;

[0343] ■ X4is selected from any amino acid, preferably X4is selected from S, T, C, N, Q, such as S;

[0344] ■ X5is selected from any amino acid, preferably X5is selected from E and D, such as E;

[0345] ■ Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as P;

[0346] ■ X7is selected from any amino acid, preferably X7is selected from S, T, C, N, Q, such as N;

[0347] ■ Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y;

[0348] ■ Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y;

[0349] ■ X10 is selected from any amino acid, preferably X10 is selected from S, T, C, N, Q, such as T;

[0350] ■ Xn is selected from any amino acid, preferably Xn is selected from G, A, V, L, I, M, K, R, H and P, such as A, P, or R;■ X12 is selected from any amino acid, preferably X12 is selected from S, T, C, N, Q, such as S;

[0351] ■ X13 is selected from any amino acid, preferably X13 is selected from G, A, V, L, I, M and P, such as A;

[0352] ■ XMis selected from any amino acid, preferably X14is selected from F, Y and W, such as Y;

[0353] ■ X15 is selected from any amino acid, preferably X15 is selected from K, R and H, such as H;

[0354] ■ Xis is selected from any amino acid, preferably Xis is selected from F, Y and W, such as F.

[0355] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0356] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0357] a) the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97);

[0358] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97); and

[0359] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97);

[0360] and

[0361] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0362] d) the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99);

[0363] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99); and

[0364] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99);

[0365] and

[0366] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0367] g) the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R; and

[0368] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R.

[0369] 45. The ISVD of item 44, in which:

[0370] - CDR1 (AbM definition) consists of an amino acid sequence of GDTFGTKAMG (SEQ ID NO:

[0371] 97);

[0372] - CDR2 (AbM definition) consists of the amino acid sequence of AITWTAGLTY (SEQ ID NO:

[0373] 99); and

[0374] - CDR3 (AbM definition) consists of an amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R.

[0375] 46. The ISVD of any one of item 44 or 45, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NOs: 71-95.

[0376] 47. The ISVD of any one of items 44 to 46, in which

[0377] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 113; or in which

[0378] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 114; or in which

[0379] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97,- CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 115.

[0380] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0381] CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[0382] a) the amino acid sequence of TKAMG (SEQ ID NO: 255);

[0383] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TKAMG (SEQ ID NO: 255); and

[0384] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of TKAMG (SEQ ID NO: 255);

[0385] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[0386] d) the amino acid sequence of AITWTAGLTYX1ADSX2KG (SEQ ID NO: 287); wherein the amino acid residue Xi is selected from L and Y; and wherein the amino acid residue X2 is selected from A and V, preferably A;

[0387] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AITWTAGLTYX1ADSX2KG (SEQ ID NO: 287); wherein the amino acid residue Xi is selected from L and Y; and wherein the amino acid residue X2 is selected from A and V, preferably A; and

[0388] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AITWTAGLTYX1ADSX2KG (SEQ ID NO: 287); wherein the amino acid residue Xi is selected from L and Y; and wherein the amino acid residue X2 is selected from A and V, preferably A;

[0389] and

[0390] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[0391] g) the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R, preferably A;

[0392] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R, preferably A; andi) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R, preferably A.

[0393] 49. The ISVD of item 48, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 71-95.

[0394] 50. The ISVD of item 48 or 49, in which:

[0395] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 258, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in which

[0396] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 260, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in which

[0397] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 259, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in which

[0398] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 261, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in which

[0399] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 261, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 114; or in which- CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 260, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 114; or in which

[0400] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 261, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 115; or in which

[0401] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 260, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 115.

[0402] 1. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that comprises R73.

[0403] 2. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that comprises K71, V74 and / or N76.

[0404] 3. The ISVD of any one of the previous items, which amino acid sequence

[0405] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 71-95, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;

[0406] and in which:

[0407] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[0408] 4. The ISVD of any one of item 44 to 53, wherein the ISVD forms an interaction site with the CD19 protein as defined in any one of items 29-40.

[0409] 5. The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody.56. The ISVD of any one of the previous items, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 71-95 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 71-95.

[0410] 57. The ISVD of any one of the previous items, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 71-95.

[0411] 58. The ISVD of any one of the previous items, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

[0412] 59. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of IO-7to 1011moles / litre or less, and preferably IO-8to IO10moles / litre or less, such as more preferably IO-9to IO10moles / litre, even more preferably wherein the ISVD specifically binds to human CD19 with a KDof about 5.5xlO10moles / litre, as determined by SPR.

[0413] 60. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 on B-cells with a EC50 of 10'7to 1011M or less, and preferably 10'7to IO10M or less, such as more preferably 10'8to IO10M, even more preferably wherein the ISVD specifically binds to human CD19 with a EC50 of about 6.1xlO’9M, 3.9xlO'9IVI, 4.6xlO'9IVI, or 1.1X10’9M, as determined by FACS assay on PBMCs or DLBCLs expressing human CD19.

[0414] 61. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as a 8-fold difference in affinity (KD).

[0415] 62. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less such as more preferably IO-8to IO-9moles / litre, even more preferably wherein the ISVD specifically binds to cyno CD19 with a KDof about 4.4xl0-9moles / litre moles / litre, as determined by SPR.

[0416] 63. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[0417] 64. The polypeptide or construct of item 63, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[0418] 65. The polypeptide or construct of item 63, in which said one or more linkers are one or more amino acid sequences.

[0419] 66. The polypeptide or construct of item 63 or 64, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[0420] 67. The polypeptide or construct of item 66, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[0421] 68. The polypeptide or construct of any one of items 63 to 67, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[0422] 69. The polypeptide or construct of any one of items 63 to 68, which is a multivalent construct.

[0423] 70. The polypeptide or construct of any one of items 63 to 69, which is a multispecific construct.

[0424] 71. The polypeptide or construct of any one of items 63 to 70, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[0425] 72. The polypeptide or construct of any one of items 63 to 71, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or NK-cell.The polypeptide or construct of item 72, wherein said polypeptide or construct directs the T-cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[0426] The polypeptide or construct of item 72 or 73, wherein said polypeptide or construct induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[0427] The polypeptide or construct of items 71 or 72, wherein said antigen is selected from CD3, T-cell receptor, CD16a, NKp30, and NKp46.

[0428] The polypeptide or construct of any one of items 63 to 75, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti-CD3 scFv.

[0429] The polypeptide or construct of any one of items 63 to 70, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[0430] The polypeptide or construct of item 77, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

[0431] The polypeptide or construct of item 77 or 78, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.The polypeptide or construct of any one of items 77 to 78, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[0432] The polypeptide or construct of items 80, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[0433] The polypeptide or construct of item 80 or 81, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[0434] The polypeptide or construct of item 82, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0435] CDR1 (AbM numbering) has an amino acid sequence selected from:

[0436] a) the amino acid sequence of SEQ ID NO: 158;

[0437] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[0438] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[0439] and

[0440] CDR2 (AbM numbering) has an amino acid sequence selected from:

[0441] d) the amino acid sequence of SEQ ID NO: 160;

[0442] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; and

[0443] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[0444] and

[0445] CDR3 (AbM numbering) has an amino acid sequence selected from:g) the amino acid sequence of SEQ ID NO: 162;

[0446] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[0447] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[0448] 84. The polypeptide or construct of item 83, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[0449] 85. The polypeptide or construct of item 83 or 84, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB23002 (SEQ ID NO: 156).

[0450] 86. The polypeptide or construct of any one of items 63 to 85, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[0451] 87. The polypeptide or construct of any one of items 63 to 86, further comprising a C-terminal extension.

[0452] 88. The polypeptide or construct of item 87, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

[0453] 89. A nucleic acid that encodes an ISVD of any one of items 1 to 62, or a polypeptide of any one of items 63 to 88.

[0454] 90. The nucleic acid according to item 89, that is in the form of a genetic construct.91. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 62, or a polypeptide of any one of items 63 to 88; and / or that comprises the nucleic acid of item 89 or 90.

[0455] 92. A method for producing an ISVD of any one of items 1 to 62, or a polypeptide of any one of items 63 to 88, at least comprising the steps of:

[0456] i) expressing, in a suitable (non human) host or host cell or in another suitable expression system, a nucleic acid of item 89 or 90;

[0457] optionally followed by:

[0458] ii) isolating and / or purifying the ISVD of any one of items 1 to 62, or the polypeptide of any one of items 63 to 88.

[0459] 93. A method for producing an ISVD of any one of items 1 to 62 or a polypeptide of any one of items 63 to 88, said method at least comprising the steps of:

[0460] i) cultivating and / or maintaining a (non-human) host or host cell according to item 91 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 62, or at least one polypeptide of any one of items 63 to 88;

[0461] optionally followed by:

[0462] ii) isolating and / or purifying the ISVD of any one of items 1 to 62, or polypeptide of any one of items items 63 to 88.

[0463] 94. A composition comprising at least one ISVD of any one of items Ito 62, at least one polypeptide or construct of any one of items 63 to 88, or at least one nucleic acid of item 89 or 90.

[0464] 95. The composition according to item 94, which is a pharmaceutical composition.

[0465] 96. The composition of item 94 or 95, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.The ISVD of any one of items 1 to 62, the polypeptide or construct of any one of items 63 to 88, or the composition of any one of items 94 to 96, for use as a medicament.

[0466] The ISVD of any one of items 1 to 62, the polypeptide or construct of any one of items 63 to 88 or the composition of any one of items 94 to 96, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[0467] The ISVD of any one of items 1 to 62, the polypeptide or construct of any one of items 63 to 88, or the composition of any one of items 94 to 96, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[0468] . The ISVD of any one of items 1 to 62, the polypeptide or construct of any one of items 63 to 88 or the composition of any one of items 94 to 96, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[0469] . Use of the ISVD of any one of it items 1 to 62, a polypeptide or construct of any one of items 63 to 88, or a composition of any one of items 94 to 96 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[0470] . The ISVD, polypeptide or construct, or composition for use according to item 83 or the use according to item 84, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

[0471] . A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of items 1 to 62, a polypeptide or construct of any one of items 63 to 88, or a composition of any one of items 94 to 96.104. The method according to item 103, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 62, a polypeptide or construct of any one of items 63 to 88, or composition of any one of items 94 to 96.

[0472] 105. The method of item 103 or 104 for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 62, a polypeptide or construct of any one of items 63 to 88, or composition of any one of items 94 to 96.

[0473] 106. The ISVD of any one of items 1 to 62, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 71.

[0474] 107. The ISVD of any one of items 1 to 62 or 106, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 71.

[0475] 3.2 Embodiment 2 (A0289038C12 family)

[0476] 1. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human CD19, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19 when numbered in accordance with SEQ ID NO: 214:

[0477] L78;

[0478] C97-P109;

[0479] Q186;

[0480] C200-P211; and / or

[0481] D232..The ISVD of item 1, wherein the at least one amino acid residue in at least one, preferably in each, amino acids stretch of human CD19 is selected from:

[0482] • L78;

[0483] • From stretch C97-P109: C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, and P109;

[0484] • Q186;

[0485] • From stretch C200-P211: C200, G201, V202, P204, D205, S206, V207, S208, R209, G210 and P211; and

[0486] • D232;

[0487] when numbered in accordance with SEQ ID NO: 214.

[0488] The ISVD of item 1 or item 2, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or preferably all of the following amino acid residues in stretch C97-P109 of human CD19, when numbered in accordance with SEQ ID NO: 214: C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, and P109.

[0489] The ISVD of any one of the preceding items, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with Q186 of human CD19, when numbered in accordance with SEQ ID NO: 214.

[0490] The ISVD of any one of the preceding items, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with D232 of human CD19, when numbered in accordance with SEQ ID NO: 214.

[0491] The ISVD of any one of the preceding items, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with L78 of human CD19, when numbered in accordance with SEQ ID NO: 214.

[0492] The ISVD of any one of the preceding items, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, or preferably all of the following amino acid residues in stretch C200- P211 of human CD19 when numbered in accordance with SEQ ID NO: 214: C200, G201, V202, P204, D205, S206, V207, S208, R209, G210 and P211.

[0493] 8. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least one amino acid of the CD19 protein selected from P99, Q108 and S208 when numbered in accordance with SEQ ID NO.: 214.

[0494] 9. The immunoglobulin single variable domain (ISVD) of of any one of the preceding items, that interacts with at least two amino acids of the CD19 protein selected from P99, Q108 and S208, further optionally, that interacts with the amino acids of the CD19 protein selected from P99, Q108 and S208.

[0495] 10. The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of forming hydrogen bonds with at least one, or all of the following amino acid residues of human CD19, when numbered in accordance with SEQ ID NO: 214: P99, Q108 and S208.

[0496] 11. The ISVD of any one of the preceding items, wherein:

[0497] the amino acid residue at position R100 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with P99 in human CD19; and / or

[0498] the amino acid residue at position S99 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q108 in human CD19,

[0499] the amino acid residue at position NIOOa (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with S208 in human CD19,

[0500] when numbered in accordance with SEQ ID NO: 214.

[0501] 12. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least one amino of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

[0502] 13. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least two amino acids, optionally, at least five amino acids, at least ten aminoacids, at least twenty amino acids of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

[0503] 14. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with following amino acids of the CD19 protein: P99, Q108 and S208.

[0504] 15. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with the following amino acids of the CD19 protein: G100, P101, K105, A106, W107, P109, C200, G201, V202, P204, D205, S206, V207, R209, G210, P211 and D232, optionally that interacts with following amino acids of the CD19 protein: L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

[0505] 16. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), and that comprises at least one amino acid residue selected from the group consisting of: S99, NIOOa and RIOOc (Kabat numbering), optionally at least two, further optionally, that comprises the amino acid residues selected from the group consisting of: S99, NIOOa and RIOOc (Kabat numbering), even further optionally that interacts with the CD19 protein as defined in items 1-15, preferably wherein:

[0506] RIOOc (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with P99 in human CD19; and / or

[0507] S99 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q108 in human CD19; and / or

[0508] NIOOa (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with S208 in human CD19;

[0509] when numbered in accordance with SEQ. ID NO: 214.

[0510] 17. The immunoglobulin single variable domain (ISVD) of item 16, that comprises N53, Y55, Y58, G59, E60 and S63, (Kabat numbering) in CDR2 (Kabat definition).18. The immunoglobulin single variable domain (ISVD) of item 16 or 17, that comprises R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering) in CDR3 (Kabat definition).

[0511] 19. The immunoglobulin single variable domain (ISVD) of any one of items 16 to 18, that comprises N53, Y55, Y58, G59, E60 and S63, (Kabat numbering) in CDR2 (Kabat definition) and R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering) in CDR3 (Kabat definition).

[0512] 20. The immunoglobulin single variable domain (ISVD) according to any one of items 16 to 19, that comprises S99, NIOOa and RIOOc (Kabat numbering), wherein S99, NIOOa and RIOOc form an interaction site with at least one amino acid selected from the group consisting of Q108, S208 and P99 of the CD19 protein.

[0513] 21. The immunoglobulin single variable domain (ISVD) of item 20, wherein the interaction site is formed by at least two, at least three amino acids selected from the group consisting of Q108, S208 and P99 of the CD19 protein.

[0514] 22. The immunoglobulin single variable domain (ISVD) of any one of items 16 to 21, that comprises S99, NIOOa and RIOOc (Kabat numbering), wherein S99, NIOOa and RIOOc form an interaction site, preferably an hydrogen bound, with Q108, S208 and P99 of the CD19 protein as follows:

[0515] o RIOOc (Kabat numbering) interacts with P99 in CD19;

[0516] o S99 in (Kabat numbering) interacts with Q108 in CD19; and o NIOOa (Kabat numbering) interacts with S208 in CD19.

[0517] 23. The immunoglobulin single variable domain (ISVD) of any one of items 16 to 22, in which N53, Y55, Y58, G59, E60, S63, R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

[0518] 24. The immunoglobulin single variable domain (ISVD) of item 23, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen, at least twenty amino acids of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107,Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

[0519] The immunoglobulin single variable domain (ISVD) of item 23 or 24, that comprise N53, Y55, Y58, G59, E60, S63, R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering), in which N53, Y55, Y58, G59, E60, S63, R97, 198, S99, Y1OO, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg form the interaction site with following amino acids of the CD19 protein: L78, C97, Q98, P99, G1OO, P1O1, E104, K105, A106, W107, Q108, P109, Q186, C2OO, G2O1, V2O2, P204, D205, S206, V207, S208, R209, G21O, P211 and D232.

[0520] The ISVD of any one of the preceding items, wherein two amino acids are considered to interact when the distance between them is 4.0 A or less.

[0521] The ISVD of any one of the preceding items, wherein the interacting amino acid residue(s) in the ISVD and in human CD19 are identified by cryo-EM by:

[0522] Mixing CD19 recombinant protein, the ISVD and an anti-VHH Fab at a molar ratio of 1:2:1 in 20 mM Hepes (pH 7.4), 150 mM NaCI;

[0523] Diluting the protein complex to 0.5 mg / mL in buffer containing 150 mM NaCI and 20 mM Hepes (pH 7.4);

[0524] Applying the protein complex to glow-discharged Ultrafoil Rl.2 / 1.3 grids, blotting for 4 seconds under 100% humidity and 4°C, plunge-freezing in liquid-ethane cooled by liquid nitrogen;

[0525] Collecting cryo-EM data using a cryo-transmission electron microscope, optionally at a pixel size of ~ 0.59 A in movie mode yielding a cumulative dose of ~50 e“ / A2; and Processing the collected data,

[0526] preferably as described in Example 3.

[0527] The immunoglobulin single variable domain (ISVD) according to any one of the previous items, wherein

[0528] CDR2 (AbM definition) consists of an amino acid sequence X1X2X3X4NX5YX6X7 (SEQ. ID NO: 210); wherein the amino acid residue:

[0529] ■ Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;■ X2 is selected from any amino acid, preferably X2 is selected from S, T, C, N, Q, such as S;

[0530] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as T;

[0531] ■ X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;

[0532] ■ X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M, K, R, H, T and P, such as G, A, R, T, and K;

[0533] ■ Xs is selected from any amino acid, preferably Xs is selected from S, T, C, N, Q, such as T;

[0534] ■ X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as Y;

[0535] and

[0536] CDR3 (AbM definition) consists of an amino acid sequence X1X2RISYNVRDDX3FX4X5X6 (SEQ. ID NO: 211); wherein the amino acid residue:

[0537] ■ Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;

[0538] ■ X2 is selected from any amino acid, preferably X2 is selected from F, Y, S, T, C, N, Q and W, such as F, Q, and S;

[0539] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;

[0540] ■ X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;

[0541] ■ X5is selected from any amino acid, preferably X5is selected from E and D, such as D;

[0542] ■ Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as L.

[0543] The immunoglobulin single variable domain (ISVD) according to any one of items 16 to 29, wherein

[0544] CDR2 (Kabat definition) consists of an amino acid sequence XIX2X3X4NX5YX6X7YGEX8X9SXIO(SEQ ID NO: 212); wherein the amino acid residue:■ Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;

[0545] ■ X2 is selected from any amino acid, preferably X2 is selected from S, T, C, N, Q, such as S;

[0546] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as T;

[0547] ■ X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as W;

[0548] ■ X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M, K, R, H, T and P, such as G, A, R, T, and K;

[0549] ■ Xs is selected from any amino acid, preferably Xs is selected from S, T, C, N, Q, such as T;

[0550] ■ X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as Y;

[0551] ■ Xg is selected from any amino acid, preferably Xg is selected from G, A, V, L, I, M, K, R, H, P, S, T, C, N, Q, such as G, K, A and S;

[0552] ■ Xg is selected from any amino acid, preferably Xg is selected from G, A, V, L, I, M and P, such as V;

[0553] ■ X10 is selected from any amino acid, preferably Xw is selected from G, A, V, L, I, M and P, such as G;

[0554] and

[0555] CDR3 (Kabat definition) consists of an amino acid sequence X1X2RISYNVRDDX3FX4X5X6 (SEQ. ID NO: 213); wherein the amino acid residue:

[0556] ■ Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;

[0557] ■ X2 is selected from any amino acid, preferably X2 is selected from F, Y, S, T, C, N, Q and W, such as F, Q, and S;

[0558] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;

[0559] ■ X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;

[0560] ■ X5is selected from any amino acid, preferably X5is selected from E and D, such as D;■ Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as L.

[0561] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0562] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0563] a) the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;

[0564] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K; and

[0565] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;

[0566] and

[0567] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0568] d) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S;

[0569] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; and

[0570] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

[0571] The ISVD of item 30, in which the amino acid sequences of the CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.The ISVD of item 30 or 31, in which

[0572] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 43,

[0573] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0574] or in which

[0575] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42,

[0576] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0577] or in which

[0578] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45,

[0579] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0580] or in which

[0581] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 46,

[0582] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0583] or in which

[0584] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 44,

[0585] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0586] or in which

[0587] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45,

[0588] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68;

[0589] or in which

[0590] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42,

[0591] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69;

[0592] or in which

[0593] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45,

[0594] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69;

[0595] or in which

[0596] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42,

[0597] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68.

[0598] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0599] CDR2 (Kabat definition) consists of an amino acid sequence selected from:a) the amino acid sequence of VSTWNX1YTYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2 is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S and wherein the amino acid residue X5is selected from K and S;

[0600] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNX1YTYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2 is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S; and

[0601] c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of VSTWNX1YTYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2 is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S;

[0602] and

[0603] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[0604] d) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from X is F, Q, and S; the amino acid residue X2 is selected from F, Q, and S;

[0605] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; and

[0606] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

[0607] 34. The ISVD of item 33, in which the amino acid sequences of the CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acidsequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.

[0608] The ISVD of item 33 or 34, in which

[0609] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 242, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0610] or in which

[0611] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0612] or in which

[0613] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;

[0614] or in which

[0615] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69;

[0616] or in which

[0617] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 244, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0618] or in which

[0619] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 245, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0620] or in which

[0621] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 246, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0622] or in which

[0623] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 247, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0624] or in which

[0625] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 248, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0626] or in which

[0627] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 249,- CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0628] or in which

[0629] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250,

[0630] - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0631] or in which

[0632] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250,

[0633] - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69;

[0634] or in which

[0635] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250,

[0636] - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;

[0637] or in which

[0638] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 251,

[0639] - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0640] or in which

[0641] - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 252,

[0642] - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67.

[0643] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0644] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0645] a) the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;

[0646] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D; and

[0647] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;

[0648] and

[0649] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0650] d) the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K; and

[0651] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;

[0652] and

[0653] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0654] g) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S;

[0655] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; and

[0656] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

[0657] The ISVD of item 36 in which:

[0658] CDR1 (AbM definition) consists of the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;

[0659] CDR2 (AbM definition) consists of the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K; and

[0660] CDR3 (AbM definition) consists of the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

[0661] The ISVD of item 36 or 38, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.

[0662] The ISVD of any one of items 37 to 39, in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 43, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0663] CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0664] CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0665] CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 46, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0666] CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 44, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0667] CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68; or in which

[0668] CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69; or in which

[0669] CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69; or in which- CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37,

[0670] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42,

[0671] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68;

[0672] or in which

[0673] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 38,

[0674] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45,

[0675] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68.

[0676] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0677] - CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[0678] a) the amino acid sequence of XYTLA (SEQ ID NO: 289); wherein the amino acid residue Xis selected from Y and D;

[0679] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of XYTLA (SEQ ID NO: 289); wherein the amino acid residue X is selected from Y and D; and

[0680] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of XYTLA (SEQ ID NO: 289); wherein the amino acid residue X is selected from Y and D;

[0681] and

[0682] - CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[0683] d) the amino acid sequence of VSTWNX1ITYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S;and wherein the amino acid residue X5is selected from K and S;

[0684] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNX1ITYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSTWNX1ITYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S;

[0685] and

[0686] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[0687] g) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from X is F, Q, and S; wherein the amino acid residue X2is selected from F, Q, and S;

[0688] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; and

[0689] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

[0690] The ISVD of item 40, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.

[0691] The ISVD of item 40 or 41, in which

[0692] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 242, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0693] or in which

[0694] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in which

[0695] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237 - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68; or in which

[0696] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69; or in which

[0697] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 244, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0698] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 245, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0699] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 246, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0700] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 247, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0701] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 248, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in which

[0702] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 249, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in which

[0703] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0704] or in which

[0705] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69;

[0706] or in which

[0707] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;

[0708] or in which

[0709] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 238, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;

[0710] or in which

[0711] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 251, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;

[0712] or in which

[0713] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 252, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67.

[0714] The ISVD of any one of items 40 to 42, which amino acid sequence

[0715] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 1-33, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;

[0716] and in which:ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[0717] 44. The ISVD of any one of item 30 to 43, wherein the ISVD forms an interaction site with the CD19 protein as defined in any one of items 20-27.

[0718] 45. The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[0719] 46. The ISVD of any one of the previous items, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 1-33 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 1-33.

[0720] 47. The ISVD of any one of the previous items, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 1-33.

[0721] 48. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of 10-7to 10-11moles / litre or less, and preferably 10-8to 10-11moles / litre or less, such as more preferably 10-9to 10-10moles / litre, even more preferably wherein the ISVD specifically binds to human CD19 with a KDof about 10-10moles / litre, as determined by SPR.

[0722] 49. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 on B-cells with a EC50 of 10-7to 10-11M or less, and preferably 10-8to 10-11M or less such as more preferably 10-8to 10-10M, even more preferably wherein the ISVD specifically binds to human CD19 with a EC50 of about 3.1 xlO’9M, 2.8xl09M, 3.1xl0'9M, 2.3xl0'9M, 4.8xl09M, or 8.7xl0-9M, as determined by FACS assay on PBMCs or DLBCL cells expressing human CD19.50. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 40-fold difference in affinity (KD).

[0723] 51. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10-7to 10-11moles / litre or less, and preferably 10-7to 10-10moles / litre or less such as more preferably 10-8to 10-9moles / litre, even more preferably wherein the ISVD specifically binds to cyno CD19 with a KDof about 3.8x10-9moles / litre moles / litre, as determined by SPR.

[0724] 52. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[0725] 53. The polypeptide or construct of item 52, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[0726] 54. The polypeptide or construct of item 52, in which said one or more linkers are one or more amino acid sequences.

[0727] 55. The polypeptide or construct of any item 52 or 53, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[0728] 56. The polypeptide or construct of item 55, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[0729] 57. The polypeptide or construct of any one of items 52 to 56, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[0730] 58. The polypeptide or construct of any one of items 52 to 57, which is a multivalent construct.The polypeptide or construct of any one of items 52 to 58, which is a multispecific construct.

[0731] The polypeptide or construct of any one of items 52 to 59, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[0732] The polypeptide or construct of any one of items 52 to 60, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or a NK-cell.

[0733] The polypeptide or construct of item 61, wherein said polypeptide or constructs directs the T-cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[0734] The polypeptide or construct of item 61 or 62, wherein said polypeptide induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[0735] The polypeptide or construct of item 60 or 61, wherein said antigen is selected from T-cell receptor, CD3, CD16a, NKp46, and NKp30.

[0736] The polypeptide or construct of any one of items 52 to 64, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti-CD3 scFv.

[0737] The polypeptide or construct of any one of items 52 to 59, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[0738] The polypeptide or construct of item 66, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins orfragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

[0739] The polypeptide or construct of item 66 or 67, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[0740] The polypeptide or construct of any one of items 66 to 67, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[0741] The polypeptide or construct of items 69, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[0742] The polypeptide or construct of any one of items 69 to 70, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[0743] The polypeptide or construct of item71, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0744] CDR1 (AbM numbering) has an amino acid sequence selected from:

[0745] a) the amino acid sequence of SEQ ID NO: 158;

[0746] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[0747] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[0748] and

[0749] CDR2 (AbM numbering) has an amino acid sequence selected from:d) the amino acid sequence of SEQ ID NO: 160;

[0750] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160;

[0751] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[0752] and

[0753] CDR3 (AbM numbering) has an amino acid sequence selected from:

[0754] g) the amino acid sequence of SEQ ID NO: 162;

[0755] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162;

[0756] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[0757] The polypeptide or construct of item 72, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[0758] The polypeptide or construct of item 73, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB23002 (SEQ ID NO: 156).

[0759] The polypeptide or construct of any one of items 52 to 74, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[0760] The polypeptide or construct of any of items 52 to 75, further comprising a C-terminal extension.

[0761] The polypeptide or construct of item 76, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).A nucleic acid that encodes an ISVD of any one of items 1 to 51, or a polypeptide of any one of items 52 to 77.

[0762] The nucleic acid of item 78, that is in the form of a genetic construct.

[0763] A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 51, or a polypeptide of any one of items 52 to 77; and / or that comprises the nucleic acid of any one of items 78 or 79.

[0764] A method for producing an ISVD of any one of items 1 to 51, or a polypeptide of any one of items 52 to 77, at least comprising the steps of:

[0765] i) expressing, in a suitable (non human) host or host cell or in another suitable expression system, a nucleic acid of item 78 or 79;

[0766] optionally followed by:

[0767] ii) isolating and / or purifying the ISVD of any one of items 1 to 51, or the polypeptide of any one of items 52 to 77.

[0768] A method for producing an ISVD of any one of items 1 to 51 or a polypeptide of any one of items 52 to 77, said method at least comprising the steps of:

[0769] i) cultivating and / or maintaining a (non-human) host or host cell according to item 69 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 51, or at least one polypeptide of any one of items 52 to 77

[0770] optionally followed by:

[0771] ii) isolating and / or purifying the ISVD of any one of items 1 to 51, or polypeptide of any one of items 52 to 77.

[0772] A composition comprising at least one ISVD of any one of items Ito 51, at least one polypeptide or construct of any one of items 52 to 77, or at least one nucleic acid of items 78 or 79.

[0773] The composition of item 83, which is a pharmaceutical composition.The composition of item 83 or 84, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[0774] The ISVD of any one of items 1 to 51, the polypeptide or construct of any one of items 52 to 77, or the composition of any one of items 83 to 85, for use as a medicament.

[0775] The ISVD of any one of items 1 to 51, the polypeptide or construct of any one of items 52 to 77 or the composition of any one of items 83 to 85, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[0776] The ISVD of any one of items 1 to 51, the polypeptide or construct of any one of items 52 to 77, or the composition of any one of items 83 to 85, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[0777] The ISVD of any one of items 1 to 51, the polypeptide or construct of any one of items 52 to 77, or the composition of any one of items 83 to 85, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[0778] Use of the ISVD of any one of items 1 to 51, a polypeptide or construct of any one of items 52 to 77, or a composition of any one of items 83 to 85 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[0779] The ISVD, polypeptide or construct, composition for use according to item 89 or the use according to item 90, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of items 1 to 51, a polypeptide or construct of any one of items 52 to 77, or a composition of any one of items 83 to 85.

[0780] The method of item 92, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 51, a polypeptide or construct of any one of items 52 to 77, or a composition of any one of items 83 to 85.

[0781] The method of item 92 or 93, for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 51, a polypeptide or construct of any one of items 52 to 77, or a composition of any one of items 83 to 85.

[0782] The ISVD of any one of items 1 to 51, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 1.

[0783] The ISVD of any one of items 1 to 51 or 95, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 1.

[0784] Embodiment 3 (A0289046C04 family)

[0785] An immunoglobulin single variable domain (ISVD) specifically binding to human CD19, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human CD19, wherein at least one amino acid residue, located in at least one of the CDRs, is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19 when numbered in accordance with SEQ ID NO: 214:

[0786] C97-W111;

[0787] Q186; and / orC200-P211.

[0788] The ISVD of item 1, wherein the at least one amino acid residue in at least one, preferably in each amino acids stretch of human CD19 is selected from:

[0789] • From stretch C97-W111: C97, P99, A106, W107, Q108, P109 and Will;

[0790] • Q186;

[0791] • From stretch C200-P211: C200, G201, V202, D205, S206, V207, S208, R209, G210, and P211;

[0792] when numbered in accordance with SEQ ID NO: 214.

[0793] The ISVD of item 1 or item 2, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or preferably all of the following amino acid residues in stretch C97-W111 of human CD19, when numbered in accordance with SEQ ID NO: 214: C97, P99, A106, W107, Q108, P109 and Will.

[0794] The ISVD of any one of the preceding items, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with Q186 of human CD19 when numbered in accordance with SEQ ID NO: 214.

[0795] The ISVD of any one of the preceding items, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, or preferably all of the following amino acid residues in stretch C200-P211 of human CD19, when numbered in accordance with SEQ ID NO: 214: C200, G201, V202, D205, S206, V207, S208, R209, G210, and P211.

[0796] The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least one amino acid of the CD19 protein selected from Q108, V202, D205 and S206 when numbered in accordance with SEQ ID NO.: 214.

[0797] The immunoglobulin single variable domain (ISVD) of item 1, that interacts with at least two amino acids of the CD19 protein selected from Q108, V202, D205 and S206.8. The ISVD of any one of the preceding items, wherein at least one amino acid residue is capable of forming hydrogen bonds with at least one, or all of the following amino acid residues of human CD19, when numbered in accordance with SEQ ID NO: 214: Q108, V202, D205 and S206.

[0798] 9. The ISVD of any one of the preceding items, wherein:

[0799] the amino acid residue at position Y98 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with V202 in human CD19; and / or

[0800] the amino acid residue at position S31 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with S206 and / or D205 in human CD19, the amino acid residue at position R95 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q108 in human CD19,

[0801] when numbered in accordance with SEQ ID NO: 214.

[0802] 10. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least one amino of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

[0803] 11. The immunoglobulin single variable domain (ISVD) of any one of the preceding items, that interacts with at least two amino acids, optionally, at least five amino acids, at least ten amino acids, at least fifteen amino acids of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211, further optionally that interacts with the amino acids of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

[0804] 12. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with following amino acids of the CD19 protein: Q108, V202, D205 and S206.

[0805] 13. The immunoglobulin single variable domain (ISVD) of any one of the previous items, that interacts with the following amino acids of the CD19 protein: P99, P109, Q186, G201, V207, S208, R209, G210 and P211, optionally that interacts with following amino acids of the CD19 protein: C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.An immunoglobulin single variable domain (ISVD) specifically binding to human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), and that comprises at least one amino acid residue selected from the group consisting of: S31, Y98 and R95 (Kabat numbering), optionally at least two, further optionally, that comprises the amino acid residues selected from the group consisting of: S31, Y98 and R95 (Kabat numbering), even further optionally that interacts with the CD19 protein as defined in items 1-6, preferably wherein:

[0806] Y98 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with V202 in human CD19; and / or

[0807] S31 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with S206 and / or D205 in human CD19; and / or

[0808] R95 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q108 in human CD19;

[0809] when numbered in accordance with SEQ. ID NO: 214.

[0810] The immunoglobulin single variable domain (ISVD) of item 14, that comprises S31 (Kabat numbering) in CDR1 (Abm definition) and / or that comprises L52a and S53 (Kabat numbering) in CDR2 (Abm definition).

[0811] The immunoglobulin single variable domain (ISVD) of item 14 or 15, that comprises R95, P96, V97, Y98 and M99 (Kabat numbering) in CDR3 (Abm definition).

[0812] The immunoglobulin single variable domain (ISVD) of any one of items 14 to 16, that comprises S31 (Kabat numbering) in CDR1 (Abm definition), L52a and S53 (Kabat numbering) in CDR2 (Abm definition) and R95, P96, V97, Y98 and M99 (Kabat numbering) in CDR3 (Abm definition).

[0813] The immunoglobulin single variable domain (ISVD) according to any one of items 14 to 17, that comprises S31, R95 and Y98 (Kabat numbering), wherein S31, R95 and Y98 form an interaction site with at least one amino acid selected from the group consisting of Q108, V202, D205 and S206 of the CD19 protein.19. The immunoglobulin single variable domain (ISVD) of item 18, wherein the interaction site is formed by at least two, at least three, or all amino acids selected from the group consisting of Q108, V202, D205 and S206 of the CD19 protein.

[0814] 20. The immunoglobulin single variable domain (ISVD) of any one of items 14 to 19, that comprises S31, R95 and Y98 (Kabat numbering), wherein S31, R95 and Y98 form an interaction site, preferably an hydrogen bond, with Q108, V202, D205 and S206 of the CD19 protein as follows:

[0815] o S31 (Kabat numbering) interacts with D205 and S206 in CD19; o R95 in (Kabat numbering) interacts with Q108 in CD19; and o Y98 (Kabat numbering) interacts with Y202 in CD19.

[0816] 21. The immunoglobulin single variable domain (ISVD) of any one of items 14 to 20, in which F29, 530, S31, L52a, S53, R95, P96, V97, Y98 and M99 (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

[0817] 22. The immunoglobulin single variable domain (ISVD) of item 21, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen amino acids of the CD19 protein selected C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

[0818] 23. The immunoglobulin single variable domain (ISVD) of item 21 or 22, that comprise F29, S30, 531, L52a, S53, R95, P96, V97, Y98 and M99 (Kabat numbering), in which F29, S30, S31, L52a, S53, R95, P96, V97, Y98 and M99 form the interaction site with following amino acids of the CD19 protein: C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

[0819] 24. The ISVD of any one of the preceding items, wherein two amino acids are considered to interact when the distance between them is 4.0 A or less.

[0820] 25. The ISVD of any one of the preceding items, wherein the interacting amino acid residue(s) in the ISVD and in human CD19 are identified by cryo-EM by:

[0821] Mixing CD19 recombinant protein, the ISVD and an anti-VHH Fab at a molar ratio of 1:2:1 in 20 mM Hepes (pH 7.4), 150 mM NaCI;Diluting the protein complex to 0.5 mg / mL in buffer containing 150 mM NaCI and 20 mM Hepes (pH 7.4);

[0822] Applying the protein complex to glow-discharged Ultrafoil Rl.2 / 1.3 grids, blotting for 4 seconds under 100% humidity and 4°C, plunge-freezing in liquid-ethane cooled by liquid nitrogen;

[0823] Collecting cryo-EM data using a cryo-transmission electron microscope, optionally at a pixel size of ~ 0.59 A in movie mode yielding a cumulative dose of ~50 e“ / A2; and Processing the collected data,

[0824] preferably as described in Example 3.

[0825] The immunoglobulin single variable domain (ISVD) according to any one of the previous items, wherein

[0826] CDR1 (AbM definition) consists of an amino acid sequence X1X2X3FSSX4X5X6X7 (SEQ. ID NO: 297); wherein the amino acid residue:

[0827] ■ Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as G;

[0828] ■ X2 is selected from any amino acid, preferably X2 is selected from F, Y and W, such as F;

[0829] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, and Q, such as T;

[0830] ■ X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;

[0831] ■ X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as A;

[0832] ■ Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as M;

[0833] ■ X7is selected from any amino acid, preferably X7is selected from G, A, V, L, I, M and P, such as A;

[0834] and

[0835] CDR2 (AbM definition) consists of an amino acid sequence XIX2X3LSX4X5XSX7X8(SEQ ID NO: 298); wherein the amino acid residue:

[0836] ■ Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;■ X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as I;

[0837] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, and Q, such as S;

[0838] ■ X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as G;

[0839] ■ X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as G;

[0840] ■ Xs is selected from any amino acid, preferably Xs is selected from S, T, C, N, and Q, such as S;

[0841] ■ X7is selected from any amino acid, preferably X7is selected from G, A, V, L, I, M and P, such as V;

[0842] ■ Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;

[0843] and

[0844] CDR3 (AbM definition) consists of an amino acid sequence RPVYMXiX2X3X4X5XgX7XgXg (SEQ. ID NO: 301); wherein the amino acid residue:

[0845] ■ Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;

[0846] ■ X2 is selected from any amino acid, preferably X2 is selected from F, Y and W, such as W;

[0847] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;

[0848] ■ X4is selected from any amino acid, preferably X4is selected from E and D, such as E;

[0849] ■ X5is selected from any amino acid, preferably X5is selected from K, R and H, such as R;

[0850] ■ Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;

[0851] ■ X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as F;

[0852] ■ Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;■ Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y.

[0853] The immunoglobulin single variable domain (ISVD) according to any one of the previous items, wherein

[0854] CDR1 (Kabat definition) consists of an amino acid sequence SX1X2X3X4 (SEQ ID NO: 302); wherein the amino acid residue:

[0855] ■ Xi is selected from any amino acid, preferably Xi is selected from F, Y and W, such as Y;

[0856] ■ X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as A;

[0857] ■ X3 is selected from any amino acid, preferably X3 is selected from G, A, V, L, I, M and P, such as M;

[0858] ■ X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as A;

[0859] and

[0860] CDR2 (Kabat definition) consists of an amino acid sequence XiX2X3LSX4X5X6X7X8XgXioXiiXi2Xi3Xi4Xi5 (SEQ ID NO: V); wherein the amino acid residue:

[0861] ■ Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;

[0862] ■ X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as I;

[0863] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, and Q, such as S;

[0864] ■ X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as G;

[0865] ■ X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as G;

[0866] ■ Xg is selected from any amino acid, preferably Xg is selected from S, T, C, N, and Q, such as S;

[0867] ■ X7is selected from any amino acid, preferably X7is selected from G, A, V, L, I, M and P, such as V;■ Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;

[0868] ■ Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y;

[0869] ■ Xio is selected from any amino acid, preferably Xw is selected from G, A, V, L, I, M, K, R, H and P, such as A or R;

[0870] ■ Xn is selected from any amino acid, preferably Xu is selected from E and D, such as D;

[0871] ■ X12 is selected from any amino acid, preferably Xu is selected from S, T, C, N, and Q, such as S;

[0872] ■ X13 is selected from any amino acid, preferably X13 is selected from G, A, V, L, I, M and P, such as V;

[0873] ■ XMis selected from any amino acid, preferably XMis selected from K, R and H, such as K;

[0874] ■ X15 is selected from any amino acid, preferably Xi5is selected from G, A, V, L, I, M and P, such as G;

[0875] and

[0876] CDR3 (Kabat definition) consists of an amino acid sequence RPVYMXiX2X3X4X5XsX7XgXg (SEQ. ID NO: 301); wherein the amino acid residue:

[0877] ■ Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;

[0878] ■ X2 is selected from any amino acid, preferably X2 is selected from F, Y and W, such as W;

[0879] ■ X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;

[0880] ■ X4is selected from any amino acid, preferably X4is selected from E and D, such as E;

[0881] ■ X5is selected from any amino acid, preferably X5is selected from K, R and H, such as R;

[0882] ■ Xg is selected from any amino acid, preferably Xs is selected from E and D, such as D;

[0883] ■ X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as F;■ Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;

[0884] ■ Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y.

[0885] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0886] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[0887] a) the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);

[0888] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136); and

[0889] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);

[0890] and

[0891] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[0892] d) the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137);

[0893] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137); and

[0894] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137);

[0895] and

[0896] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[0897] g) the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V;

[0898] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V; and

[0899] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V.

[0900] The ISVD of item 28 in which:CDR1 (AbM definition) consists of the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);

[0901] CDR2 (AbM definition) consists of the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137); and

[0902] CDR3 (AbM definition) consists of the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V.

[0903] 30. The ISVD of items 28 or 29, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 116-134.

[0904] 31. The ISVD of items 28 to 30, in which

[0905] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0906] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0907] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 154;

[0908] or in which

[0909] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0910] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0911] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 152;

[0912] or in which

[0913] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0914] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0915] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 153;

[0916] or in which

[0917] - CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,

[0918] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,

[0919] - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 155.An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[0920] - CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[0921] a) the amino acid sequence of SYAMA (SEQ ID NO: 272);

[0922] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYAMA (SEQ ID NO: 272); and

[0923] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SYAMA (SEQ ID NO: 272);

[0924] and

[0925] - CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[0926] d) the amino acid sequence of VISLSGGSVDYXDSVKG (SEQ ID NO: 300); wherein the amino acid residue X is selected from R and A;

[0927] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VISLSGGSVDYXDSVKG (SEQ ID NO: 300); wherein the amino acid residue X is selected from R and A; and

[0928] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VISLSGGSVDYXDSVKG (SEQ ID NO: 300); wherein the amino acid residue X is selected from R and A;

[0929] and

[0930] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[0931] g) the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V;

[0932] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V; and

[0933] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V.

[0934] The ISVD of item 32, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequenceidentity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 116-134.

[0935] 34. The ISVD of item 32 or 33, in which

[0936] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: il, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 154;

[0937] or in which

[0938] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 274, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 154;

[0939] or in which

[0940] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 152;

[0941] or in which

[0942] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 153;

[0943] or in which

[0944] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 155;

[0945] or in which

[0946] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 274, - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 152.

[0947] 35. The ISVD of any one of items 32 to 34, which amino acid sequencei) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 116-134, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which:

[0948] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[0949] 36. The ISVD of any one of item 28 to 35, wherein the ISVD forms an interaction site with the CD19 protein as defined in any one of items 18-23.

[0950] 37. The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[0951] 38. The ISVD of any one of the previous items, which is chosen from the group consisting of SEQ ID NOs: 116-134 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 116-134.

[0952] 39. The ISVD of any one of the previous items, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 116-134.

[0953] 40. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'8to 1011moles / litre or less, such as more preferably 10'8to IO10moles / litre, even more preferably wherein the ISVD specifically binds to human CD19 with a KDof about 8xl0-9moles / litre, as determined by SPR.

[0954] 41. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 on B-cells with a EC50 of 10-7to 10-11M or less, and preferably 10-8to 10-11M or less such as more preferably 10-8to 10-10M, even more preferably wherein the ISVD specifically binds to human CD19 with a EC50 of about 3.4 xlO’9M, 2.4xl0'9M, 4.3xl0'9M, 2.5xl0'9M, 5.8xl09M,or 8.8xl0-9M, as determined by FACS assay on PBMCs or DLBCL cells expressing human CD19.

[0955] 42. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as 2-fold difference in affinity (KD).

[0956] 43. The ISVD of any one of the previous items,, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less, such as more preferably 5xl0-8to 10'9moles / litre, even more preferably wherein the ISVD specifically binds to cyno CD19 with a KDof about 1.2xl0-8moles / litre, as determined by SPR.

[0957] 44. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[0958] 45. The polypeptide or construct of item 44, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[0959] 46. The polypeptide or construct of item 44, in which said one or more linkers are one or more amino acid sequences.

[0960] 47. The polypeptide or construct of any item 44 or 45, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[0961] 48. The polypeptide or construct of item 47, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[0962] 49. The polypeptide or construct of any one of items 44 to 48, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.The polypeptide or construct of any one of items 44 to 49, which is a multivalent construct.

[0963] The polypeptide or construct of any one of items 44 to 50, which is a multispecific construct.

[0964] The polypeptide or construct of any one of items 44 to 51, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[0965] The polypeptide or construct of any one of items 44 to 52, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or a NK-cell.

[0966] The polypeptide or construct of item 53, wherein said polypeptide or constructs directs the T-cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[0967] The polypeptide or construct of item 53 or 54, wherein said polypeptide induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[0968] The polypeptide or construct of item 52 to 55, wherein said antigen is selected from T-cell receptor, CD3, CD16a, NKp46, and NKp30.

[0969] The polypeptide or construct of any one of items 44 to 56, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti-CD3 scFv.

[0970] The polypeptide or construct of any one of items 44 to 51, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[0971] The polypeptide or construct of item 58, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life ischosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

[0972] 60. The polypeptide or construct of item 58 or 59, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[0973] 61. The polypeptide or construct of item 58 or 59, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[0974] 62. The polypeptide or construct of items 61, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[0975] 63. The polypeptide or construct of any one of items 61 to 62, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[0976] 64. The polypeptide or construct of item 63, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0977] CDR1 (AbM numbering) has an amino acid sequence selected from:

[0978] a) the amino acid sequence of SEQ ID NO: 158;

[0979] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[0980] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[0981] andCDR2 (AbM numbering) has an amino acid sequence selected from:

[0982] d) the amino acid sequence of SEQ ID NO: 160;

[0983] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; and

[0984] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[0985] and

[0986] CDR3 (AbM numbering) has an amino acid sequence selected from:

[0987] g) the amino acid sequence of SEQ ID NO: 162;

[0988] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[0989] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[0990] 65. The polypeptide or construct of item 64, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[0991] 66. The polypeptide or construct of any one o items 63 to 65, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB23002 (SEQ ID NO: 156).

[0992] 67. The polypeptide or construct of any one of items 44 to 66, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[0993] 68. The polypeptide or construct of any of items 44 to 67, further comprising a C-terminal extension.

[0994] 69. The polypeptide or construct of item 68, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).70. A nucleic acid that encodes an ISVD of any one of items 1 to 43, or a polypeptide of any one of items 44 to 69.

[0995] 71. The nucleic acid of item 70, that is in the form of a genetic construct.

[0996] 72. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 43, or a polypeptide of any one of items 44 to 69; and / or that comprises the nucleic acid of any one of items 70 or 71.

[0997] 73. A method for producing an ISVD of any one of items 1 to 43, or a polypeptide of any one of items 44 to 69, at least comprising the steps of:

[0998] i) expressing, in a suitable (non-human) host or host cell or in another suitable expression system, a nucleic acid of item 70 or 71;

[0999] optionally followed by:

[1000] ii) isolating and / or purifying the ISVD of any one of items 1 to 43, or the polypeptide of any one of items 44 to 69.

[1001] 74. A method for producing an ISVD of any one of items 1 to 43 or a polypeptide of any one of items 44 to 69, said method at least comprising the steps of:

[1002] i) cultivating and / or maintaining a (non-human) host or host cell according to item 69 under conditions that are such that said (non-human host) or host cell expresses and / or produces at least one ISVD of any one of items 1 to 43, or at least one polypeptide of any one of items 44 to 69

[1003] optionally followed by:

[1004] ii) isolating and / or purifying the ISVD of any one of items 1 to 43, or polypeptide of any one of items 44 to 69.

[1005] 75. A composition comprising at least one ISVD of any one of items Ito 43, at least one polypeptide or construct of any one of items 44 to 69, or at least one nucleic acid of items 70 or 71.

[1006] 76. The composition of item 75, which is a pharmaceutical composition.The composition of item 75 or 76, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[1007] The ISVD of any one of items 1 to 43, the polypeptide or construct of any one of items 44 to 69, or the composition of any one of items 75 to 77, for use as a medicament.

[1008] The ISVD of any one of items 1 to 43, the polypeptide or construct of any one of items 44 to 69 or the composition of any one of items 75 to 77, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[1009] The ISVD of any one of items 1 to 43, the polypeptide or construct of any one of items 44 to 69, or the composition of any one of items 75 to 77, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[1010] The ISVD of any one of items 1 to 43, the polypeptide or construct of any one of items 44 to 69, or the composition of any one of items 75 to 77, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[1011] Use of the ISVD of any one of items 1 to 43, a polypeptide or construct of any one of items 44 to 69, or a composition of any one of items 75 to 77 for the manufacture of a medicament for thetreatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[1012] The ISVD, polypeptide or construct, composition for use according to item 81 or the use according to item 82, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of items 1 to 43, a polypeptide or construct of any one of items 44 to 69, or a composition of any one of items 75 to 77.

[1013] The method of item 84, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 43, a polypeptide or construct of any one of items 44 to 69, or a composition of any one of items 75 to 77.

[1014] The method of item 84 or 85, for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 43, a polypeptide or construct of any one of items 44 to 69, or a composition of any one of items 75 to 77.

[1015] The ISVD of any one of items 1 to 43, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 116.

[1016] The ISVD of any one of items 1 to 43 or 87, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 116.

[1017] Embodiment 4 (A0289036F06)

[1018] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1019] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[1020] a) the amino acid sequence of GRTFSSYVAA (SEQ ID NO: 304);

[1021] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTFSSYVAA (SEQ ID NO: 304);

[1022] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTFSSYVAA (SEQ ID NO: 304);and

[1023] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[1024] d) the amino acid sequence AASLSGGTTD (SEQ ID NO: 305);

[1025] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AASLSGGTTD (SEQ ID NO: 305);

[1026] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence AASLSGGTTD (SEQ ID NO: 305);

[1027] and

[1028] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[1029] g) the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306);

[1030] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306);

[1031] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306).

[1032] The ISVD of item 1, in which:

[1033] - CDR1 (AbM definition) consists of an amino acid sequence of GRTFSSYVAA (SEQ ID NO:

[1034] 304);

[1035] - CDR2 (AbM definition) consists of the amino acid sequence AASLSGGTTD (SEQ ID NO:

[1036] 305); and

[1037] - CDR3 (AbM definition) consists of an amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306).

[1038] The ISVD of any one of item 1 or 1, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NO: 200.

[1039] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[1040] a) the amino acid sequence of SYVAA (SEQ ID NO: 310);

[1041] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYVAA (SEQ ID NO: 310); and

[1042] c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SYVAA (SEQ ID NO: 310);

[1043] and

[1044] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[1045] d) the amino acid sequence of AASLSGGTTDYADSVKG (SEQ ID NO: 311);

[1046] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AASLSGGTTDYADSVKG (SEQ ID NO: 311); and

[1047] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of AASLSGGTTDYADSVKG (SEQ ID NO: 311);

[1048] and

[1049] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[1050] g) the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306);

[1051] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306); and

[1052] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of RPVYLKYTYHDYDF (SEQ ID NO: 306).

[1053] The ISVD of item 4, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NO: 200.

[1054] The ISVD of item 4 or 5, in which:

[1055] CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 310, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 311, and CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 306.7. The ISVD of any one of the previous items, which amino acid sequence

[1056] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 200, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;

[1057] and in which:

[1058] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[1059] 8. The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[1060] 9. The ISVD of any one of the previous items, which is chosen from the group consisting of SEQ ID NO: 200 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 200.

[1061] 10. The ISVD of any one of the previous items, in which the amino acid sequence is SEQ ID NO: 200.

[1062] 11. The ISVD of any one of the previous items, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

[1063] 12. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less, such as more preferably 10'7to IO-9moles / litre, even more preferably wherein the ISVD specifically binds to human CD19 with a KDof about 1.7xl0-8moles / litre, as determined by SPR.

[1064] 13. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD),preferably less than 10-fold difference in affinity (KD), such as a 3-fold difference in affinity (KD).

[1065] 14. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less such as more preferably 10'7to 10'9moles / litre, even more preferably wherein the ISVD specifically binds to cyno CD19 with a KDof about 5.1xl0-8moles / litre moles / litre, as determined by SPR.

[1066] 15. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[1067] 16. The polypeptide or construct of item 15, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[1068] 17. The polypeptide or construct of item 15, in which said one or more linkers are one or more amino acid sequences.

[1069] 18. The polypeptide or construct of item 15 or 16, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[1070] 19. The polypeptide or construct of item 18, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[1071] 20. The polypeptide or construct of any one of items 15 to 19, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[1072] 21. The polypeptide or construct of any one of items 15 to 20, which is a multivalent construct.

[1073] 22. The polypeptide or construct of any one of items 15 to 21, which is a multispecific construct.The polypeptide or construct of any one of items 15 to 22, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[1074] The polypeptide or construct of any one of items 15 to 23, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or NK-cell.

[1075] The polypeptide or construct of item 24, wherein said polypeptide or constructs directs the T-cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[1076] The polypeptide or construct of item 24 or 25, wherein said polypeptide or construct induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[1077] The polypeptide or construct of items 24 or 25, wherein said antigen is selected from CD3, T-cell receptor, CD16a, NKp2, and NKp46.

[1078] The polypeptide or construct of any one of items 15 to 27, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti-CD3 scFv.

[1079] The polypeptide or construct of any one of items 15 to 22, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[1080] The polypeptide or construct of item 29, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.31. The polypeptide or construct of item 29 or 30, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[1081] 32. The polypeptide or construct of any one of items 29 or 30, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1082] 33. The polypeptide or construct of items 32, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1083] 34. The polypeptide or construct of any one of items 32 to 33, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[1084] 35. The polypeptide or construct of item 36, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[1085] CDR1 (AbM numbering) has an amino acid sequence selected from:

[1086] a) the amino acid sequence of SEQ ID NO: 158;

[1087] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[1088] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[1089] and

[1090] CDR2 (AbM numbering) has an amino acid sequence selected from:

[1091] d) the amino acid sequence of SEQ ID NO: 160;

[1092] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[1093] and

[1094] CDR3 (AbM numbering) has an amino acid sequence selected from:

[1095] g) the amino acid sequence of SEQ ID NO: 162;

[1096] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[1097] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[1098] 36. The polypeptide or construct of item 35, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[1099] 37. The polypeptide or construct of item 34 to 36, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB2202 (SEQ ID NO: 156).

[1100] 38. The polypeptide or construct of any one of items 15 to 37, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[1101] 39. The polypeptide or construct of any one of items 15 to 38, further comprising a C-terminal extension.

[1102] 40. The polypeptide or construct of item 39, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

[1103] 41. A nucleic acid that encodes an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40.42. The nucleic acid according to item 41, that is in the form of a genetic construct.

[1104] 43. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40; and / or that comprises the nucleic acid of item 41 or 42.

[1105] 44. A method for producing an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40, at least comprising the steps of:

[1106] i) expressing, in a suitable (non-human) host cell or host cell or in another suitable expression system, a nucleic acid of item 41 or 42;

[1107] optionally followed by:

[1108] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or the polypeptide of any one of items 15 to 40.

[1109] 45. A method for producing an ISVD of any one of items 1 to 14 or a polypeptide of any one of items 15 to 40, said method at least comprising the steps of:

[1110] i) cultivating and / or maintaining a (non-human) host or host cell according to item 46 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 14, or at least one polypeptide of any one of items 18 to 43

[1111] optionally followed by:

[1112] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or polypeptide of any one of items 15 to 40.

[1113] 46. A composition comprising at least one ISVD of any one of items 1 to 14, at least one polypeptide or construct of any one of items 15 to 40, or at least one nucleic acid of item 41 or 42.

[1114] 47. The composition according to item 46, which is a pharmaceutical composition.

[1115] 48. The composition of item 46 or 47 which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / oradjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[1116] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use as a medicament.

[1117] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[1118] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[1119] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[1120] Use of the ISVD of any one of it items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[1121] The ISVD, polypeptide or construct, or composition for use according to item 52 or the use according to item 53, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

[1122] A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceuticallyactive amount of an ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48.

[1123] The method according to item 55, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1124] The method of item 55 or 56 for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1125] The ISVD of any one of items 1 to 14, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 200.

[1126] The ISVD of any one of items 1 to 14 or 58, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 200.

[1127] Embodiment 5 (A0289046F07)

[1128] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1129] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[1130] a) the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[1131] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[1132] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[1133] and

[1134] CDR2 (AbM definition) consists of an amino acid sequence selected from:d) the amino acid sequence VSSLSGGTSD (SEQ ID NO: 356);

[1135] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VSSLSGGTSD (SEQ ID NO: 356);

[1136] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence VSSLSGGTSD (SEQ ID NO: 356);

[1137] and

[1138] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[1139] g) the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[1140] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[1141] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363).

[1142] The ISVD of item 1, in which:

[1143] - CDR1 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 362;

[1144] - CDR2 (AbM definition) consists of the amino acid sequence SEQ ID NO: 356; and - CDR3 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 363.

[1145] The ISVD of any one of item 1 or 1, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NO: 202.

[1146] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1147] CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[1148] a) the amino acid sequence of SYAMA (SEQ ID NO: 272);

[1149] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYAMA (SEQ ID NO: 272); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SYAMA (SEQ ID NO: 272);

[1150] and

[1151] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[1152] d) the amino acid sequence of VSSLSGGTSDYADSVKG (SEQ ID NO: 364); e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSSLSGGTSDYADSVKG (SEQ ID NO: 364); and

[1153] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSSLSGGTSDYADSVKG (SEQ ID NO: 364);

[1154] and

[1155] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[1156] g) the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[1157] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363); and

[1158] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363).

[1159] 5. The ISVD of item 4, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NO: 202.

[1160] 6. The ISVD of item 4 or 5, in which:

[1161] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 272, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 364, and - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 363.

[1162] 7. The ISVD of any one of the previous items, which amino acid sequence

[1163] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 202, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;and in which:

[1164] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[1165] 8. The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[1166] 9. The ISVD of any one of the previous items, which is chosen from the group consisting of SEQ ID NO: 202 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 202.

[1167] 10. The ISVD of any one of the previous items, in which the amino acid sequence is SEQ ID NO: 202.

[1168] 11. The ISVD of any one of the previous items, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

[1169] 12. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less such, as more preferably 10'8to 10'9moles / litre, even more preferably with a KDof about 9.8xl0-9moles / litre, as determined by SPR.

[1170] 13. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as a 3-fold difference in affinity (KD).

[1171] 14. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / l itre or less, such as more preferably IO-7to IO-9moles / litre, even more preferably with a KDof about 1.9xl0-8moles / litre, as determined by SPR.

[1172] 15. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[1173] 16. The polypeptide or construct of item 15, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[1174] 17. The polypeptide or construct of item 15, in which said one or more linkers are one or more amino acid sequences.

[1175] 18. The polypeptide or construct of item 15 or 16, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[1176] 19. The polypeptide or construct of item 18, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[1177] 20. The polypeptide or construct of any one of items 15 to 19, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[1178] 21. The polypeptide or construct of any one of items 15 to 20, which is a multivalent construct.

[1179] 22. The polypeptide or construct of any one of items 15 to 21, which is a multispecific construct.

[1180] 23. The polypeptide or construct of any one of items 15 to 22, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[1181] 24. The polypeptide or construct of any one of items 15 to 23, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or NK-cell.25. The polypeptide or construct of item 24, wherein said polypeptide or constructs directs the T- cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[1182] 26. The polypeptide or construct of item 24 or 25, wherein said polypeptide or construct induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[1183] 27. The polypeptide or construct of items 24 or 25, wherein said antigen is selected from CD3, T- cell receptor, CD16a, NKp2, and NKp46.

[1184] 28. The polypeptide or construct of any one of items 15 to 27, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti- CD3 scFv.

[1185] 29. The polypeptide or construct of any one of items 15 to 22, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[1186] 30. The polypeptide or construct of item 29, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

[1187] 31. The polypeptide or construct of item 29 or 30, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[1188] 32. The polypeptide or construct of any one of items 29 or 30, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct withincreased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1189] The polypeptide or construct of items 32, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1190] The polypeptide or construct of any one of items 32 to 33, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[1191] The polypeptide or construct of item 36, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[1192] CDR1 (AbM numbering) has an amino acid sequence selected from:

[1193] a) the amino acid sequence of SEQ ID NO: 158;

[1194] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[1195] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[1196] and

[1197] CDR2 (AbM numbering) has an amino acid sequence selected from:

[1198] d) the amino acid sequence of SEQ ID NO: 160;

[1199] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; and

[1200] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[1201] and

[1202] CDR3 (AbM numbering) has an amino acid sequence selected from:

[1203] g) the amino acid sequence of SEQ ID NO: 162;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[1204] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[1205] 36. The polypeptide or construct of item 35, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[1206] 37. The polypeptide or construct of items 34 to 36, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB2202 (SEQ ID NO: 156).

[1207] 38. The polypeptide or construct of any one of items 15 to 37, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[1208] 39. The polypeptide or construct of any one of items 15 to 38, further comprising a C-terminal extension.

[1209] 40. The polypeptide or construct of item 39, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

[1210] 41. A nucleic acid that encodes an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40.

[1211] 42. The nucleic acid according to item 41, that is in the form of a genetic construct.

[1212] 43. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40; and / or that comprises the nucleic acid of item 41 or 42.44. A method for producing an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40, at least comprising the steps of:

[1213] i) expressing, in a suitable (non-human) host cell or host cell or in another suitable expression system, a nucleic acid of item 41 or 42;

[1214] optionally followed by:

[1215] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or the polypeptide of any one of items 15 to 40.

[1216] 45. A method for producing an ISVD of any one of items 1 to 14 or a polypeptide of any one of items 15 to 40, said method at least comprising the steps of:

[1217] i) cultivating and / or maintaining a (non-human) host or host cell according to item 46 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 14, or at least one polypeptide of any one of items 18 to 43

[1218] optionally followed by:

[1219] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or polypeptide of any one of items 15 to 40.

[1220] 46. A composition comprising at least one ISVD of any one of items 1 to 14, at least one polypeptide or construct of any one of items 15 to 40, or at least one nucleic acid of item 41 or 42.

[1221] 47. The composition according to item 46, which is a pharmaceutical composition.

[1222] 48. The composition of item 46 or 47 which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[1223] 49. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use as a medicament.The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[1224] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[1225] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[1226] Use of the ISVD of any one of it items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[1227] The ISVD, polypeptide or construct, or composition for use according to item 52 or the use according to item 53, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

[1228] A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48.

[1229] The method according to item 55, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically activeamount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1230] The method of item 55 or 56 for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1231] The ISVD of any one of items 1 to 14, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 202.

[1232] The ISVD of any one of items 1 to 14 or 58, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 202.

[1233] Embodiment 6 (A0289038C06)

[1234] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1235] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[1236] a) the amino acid sequence of GLTFAGYSVG (SEQ ID NO: 324);

[1237] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFAGYSVG (SEQ ID NO: 324);

[1238] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GLTFAGYSVG (SEQ ID NO: 324);

[1239] and

[1240] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[1241] d) the amino acid sequence VITRGGDYRY (SEQ ID NO: 325);

[1242] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VITRGGDYRY (SEQ ID NO: 325);

[1243] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VITRGGDYRY (SEQ ID NO: 325);

[1244] andCDR3 (AbM definition) consists of an amino acid sequence selected from:

[1245] g) the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326);

[1246] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326);

[1247] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326).

[1248] 2. The ISVD of item 1, in which:

[1249] - CDR1 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 324;

[1250] - CDR2 (AbM definition) consists of the amino acid sequence SEQ ID NO: 325; and - CDR3 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 326.

[1251] 3. The ISVD of any one of item 1 or 1, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NO: 197.

[1252] 4. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1253] CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[1254] a) the amino acid sequence of GYSVG (SEQ ID NO: 327);

[1255] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GYSVG (SEQ ID NO: 327); and

[1256] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GYSVG (SEQ ID NO: 327);

[1257] and

[1258] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[1259] d) the amino acid sequence of VITRGGDYRYFAESVQG (SEQ ID NO: 328); e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VITRGGDYRYFAESVQG (SEQ ID NO: 328); andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VITRGGDYRYFAESVQG (SEQ ID NO: 328);

[1260] and

[1261] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[1262] g) the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326);

[1263] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326); and

[1264] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GTMTYAIRETRAYNY (SEQ ID NO: 326).

[1265] The ISVD of item 4, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NO: 197.

[1266] The ISVD of item 4 or 5, in which:

[1267] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 327, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 328, and - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 326.

[1268] The ISVD of any one of the previous items, which amino acid sequence

[1269] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 197, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;

[1270] and in which:

[1271] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.8. The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[1272] 9. The ISVD of any one of the previous items, which is chosen from the group consisting of SEQ ID NO: 197 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 197.

[1273] 10. The ISVD of any one of the previous items, in which the amino acid sequence is SEQ ID NO: 197.

[1274] 11. The ISVD of any one of the previous items, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

[1275] 12. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of 10-7to 10-11moles / litre or less, and preferably 10-8to 10-11moles / litre or less, such as more preferably 10-9to 10-10moles / litre, even more preferably with a KDof about 1.4x10-10moles / litre, as determined by SPR.

[1276] 13. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as a 3-fold difference in affinity (KD).

[1277] 14. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less such as more preferably 10'7to 10'9moles / litre, even more preferably with a KDof about 1.8xl0-8moles / litre, as determined by SPR.

[1278] 15. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.16. The polypeptide or construct of item 15, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[1279] 17. The polypeptide or construct of item 15, in which said one or more linkers are one or more amino acid sequences.

[1280] 18. The polypeptide or construct of item 15 or 16, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[1281] 19. The polypeptide or construct of item 18, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[1282] 20. The polypeptide or construct of any one of items 15 to 19, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[1283] 21. The polypeptide or construct of any one of items 15 to 20, which is a multivalent construct.

[1284] 22. The polypeptide or construct of any one of items 15 to 21, which is a multispecific construct.

[1285] 23. The polypeptide or construct of any one of items 15 to 22, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[1286] 24. The polypeptide or construct of any one of items 15 to 23, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or NK-cell.

[1287] 25. The polypeptide or construct of item 24, wherein said polypeptide or constructs directs the T- cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[1288] 26. The polypeptide or construct of item 24 or 25, wherein said polypeptide or construct induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting saidpolypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[1289] The polypeptide or construct of items 24 or 25, wherein said antigen is selected from CD3, T-cell receptor, CD16a, NKp2, and NKp46.

[1290] The polypeptide or construct of any one of items 15 to 27, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti-CD3 scFv.

[1291] The polypeptide or construct of any one of items 15 to 22, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[1292] The polypeptide or construct of item 29, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

[1293] The polypeptide or construct of item 29 or 30, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[1294] The polypeptide or construct of any one of items 29 or 30, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1295] The polypeptide or construct of items 32, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domainantibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1296] The polypeptide or construct of any one of items 32 to 33, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[1297] The polypeptide or construct of item 36, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[1298] CDR1 (AbM numbering) has an amino acid sequence selected from:

[1299] a) the amino acid sequence of SEQ ID NO: 158;

[1300] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[1301] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[1302] and

[1303] CDR2 (AbM numbering) has an amino acid sequence selected from:

[1304] d) the amino acid sequence of SEQ ID NO: 160;

[1305] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; and

[1306] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[1307] and

[1308] CDR3 (AbM numbering) has an amino acid sequence selected from:

[1309] g) the amino acid sequence of SEQ ID NO: 162;

[1310] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[1311] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.36. The polypeptide or construct of item 35, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[1312] 37. The polypeptide or construct of items 34 to 36, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB2202 (SEQ ID NO: 156).

[1313] 38. The polypeptide or construct of any one of items 15 to 37, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[1314] 39. The polypeptide or construct of any one of items 15 to 38, further comprising a C-terminal extension.

[1315] 40. The polypeptide or construct of item 39, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

[1316] 41. A nucleic acid that encodes an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40.

[1317] 42. The nucleic acid according to item 41, that is in the form of a genetic construct.

[1318] 43. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40; and / or that comprises the nucleic acid of item 41 or 42.

[1319] 44. A method for producing an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40, at least comprising the steps of:

[1320] i) expressing, in a suitable (non-human) host cell or host cell or in another suitable expression system, a nucleic acid of item 41 or 42;optionally followed by:

[1321] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or the polypeptide of any one of items 15 to 40.

[1322] 45. A method for producing an ISVD of any one of items 1 to 14 or a polypeptide of any one of items 15 to 40, said method at least comprising the steps of:

[1323] i) cultivating and / or maintaining a (non-human) host or host cell according to item 46 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 14, or at least one polypeptide of any one of items 18 to 43

[1324] optionally followed by:

[1325] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or polypeptide of any one of items 15 to 40.

[1326] 46. A composition comprising at least one ISVD of any one of items 1 to 14, at least one polypeptide or construct of any one of items 15 to 40, or at least one nucleic acid of item 41 or 42.

[1327] 47. The composition according to item 46, which is a pharmaceutical composition.

[1328] 48. The composition of item 46 or 47 which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[1329] 49. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use as a medicament.

[1330] 50. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[1331] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[1332] Use of the ISVD of any one of it items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[1333] The ISVD, polypeptide or construct, or composition for use according to item 52 or the use according to item 53, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

[1334] A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48.

[1335] The method according to item 55, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1336] The method of item 55 or 56 for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmunedisorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1337] 58. The ISVD of any one of items 1 to 14, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 197.

[1338] 59. The ISVD of any one of items 1 to 14 or 58, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 197.

[1339] 3.7 Embodiment 7 (A0289044A08)

[1340] 1. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1341] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[1342] a) the amino acid sequence of GRTLSSYTTG (SEQ ID NO: 333);

[1343] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTLSSYTTG (SEQ ID NO: 333);

[1344] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTLSSYTTG (SEQ ID NO: 333);

[1345] and

[1346] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[1347] d) the amino acid sequence AITKNGPYLY (SEQ ID NO: 334);

[1348] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AITKNGPYLY (SEQ ID NO: 334);

[1349] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AITKNGPYLY (SEQ ID NO: 334);

[1350] and

[1351] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[1352] g) the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335);

[1353] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335);i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335).

[1354] The ISVD of item 1, in which:

[1355] - CDR1 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 333;

[1356] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 334; and - CDR3 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 335.

[1357] The ISVD of any one of item 1 or 2, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NO: 198.

[1358] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1359] CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[1360] a) the amino acid sequence of SYTTG (SEQ ID NO: 336);

[1361] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYTTG (SEQ ID NO: 336); and

[1362] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SYTTG (SEQ ID NO: 336);

[1363] and

[1364] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[1365] d) the amino acid sequence of AITKNGPYLYYKDSVRG (SEQ ID NO: 337);

[1366] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AITKNGPYLYYKDSVRG (SEQ ID NO: 337); and

[1367] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AITKNGPYLYYKDSVRG (SEQ ID NO: 337);

[1368] and

[1369] CDR3 (Kabat definition) consists of an amino acid sequence selected from:g) the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335);

[1370] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335); and

[1371] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SDAQYDIRNREKYYY (SEQ ID NO: 335).

[1372] The ISVD of item 4, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NO: 198.

[1373] The ISVD of item 4 or 5, in which:

[1374] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 336, - CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 337, and - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 335.

[1375] The ISVD of any one of the previous items, which amino acid sequence

[1376] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 198, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;

[1377] and in which:

[1378] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[1379] The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[1380] The ISVD of any one of the previous items, which is chosen from the group consisting of SEQ ID NO: 198 or from the group consisting of amino acid sequences that have more than 80%,preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 198.

[1381] 10. The ISVD of any one of the previous items, in which the amino acid sequence is SEQ ID NO: 198.

[1382] 11. The ISVD of any one of the previous items, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

[1383] 12. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of 10-7to 10-11moles / litre or less, and preferably 10-8to 10-10moles / litre or less, such as more preferably 10-9to 10-10moles / litre, even more preferably with a KDof about 8.2x10-10moles / litre, as determined by SPR.

[1384] 13. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as a 3-fold difference in affinity (KD).

[1385] 14. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10-7to 10-11moles / litre or less, and preferably 10-8to 10-10moles / litre or less, such as more preferably 10-8to 10-9moles / litre, even more preferably with a KDof about 2.5x10-9moles / litre, as determined by SPR.

[1386] 15. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[1387] 16. The polypeptide or construct of item 15, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[1388] 17. The polypeptide or construct of item 15, in which said one or more linkers are one or more amino acid sequences.18. The polypeptide or construct of item 15 or 16, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[1389] 19. The polypeptide or construct of item 18, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[1390] 20. The polypeptide or construct of any one of items 15 to 19, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[1391] 21. The polypeptide or construct of any one of items 15 to 20, which is a multivalent construct.

[1392] 22. The polypeptide or construct of any one of items 15 to 21, which is a multispecific construct.

[1393] 23. The polypeptide or construct of any one of items 15 to 22, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[1394] 24. The polypeptide or construct of any one of items 15 to 23, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or NK-cell.

[1395] 25. The polypeptide or construct of item 24, wherein said polypeptide or constructs directs the T- cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[1396] 26. The polypeptide or construct of item 24 or 25, wherein said polypeptide or construct induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[1397] 27. The polypeptide or construct of items 24 or 25, wherein said antigen is selected from CD3, T- cell receptor, CD16a, NKp2, and NKp46.28. The polypeptide or construct of any one of items 15 to 27, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti- CD3 scFv.

[1398] 29. The polypeptide or construct of any one of items 15 to 22, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[1399] 30. The polypeptide or construct of item 29, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

[1400] 31. The polypeptide or construct of item 29 or 30, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[1401] 32. The polypeptide or construct of any one of items 29 or 30, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1402] 33. The polypeptide or construct of items 32, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1403] 34. The polypeptide or construct of any one of items 32 to 33, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.35. The polypeptide or construct of item 36, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[1404] CDR1 (AbM numbering) has an amino acid sequence selected from:

[1405] a) the amino acid sequence of SEQ ID NO: 158;

[1406] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[1407] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[1408] and

[1409] CDR2 (AbM numbering) has an amino acid sequence selected from:

[1410] d) the amino acid sequence of SEQ ID NO: 160;

[1411] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; and

[1412] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[1413] and

[1414] CDR3 (AbM numbering) has an amino acid sequence selected from:

[1415] g) the amino acid sequence of SEQ ID NO: 162;

[1416] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[1417] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[1418] 36. The polypeptide or construct of item 35, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[1419] 37. The polypeptide or construct of items 34 to 36, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB2202 (SEQ ID NO: 156).38. The polypeptide or construct of any one of items 15 to 37, wherein said linker is chosen from the group consisting of SEQ. ID NOs: 179 to 195.

[1420] 39. The polypeptide or construct of any one of items 15 to 38, further comprising a C-terminal extension.

[1421] 40. The polypeptide or construct of item 39, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

[1422] 41. A nucleic acid that encodes an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40.

[1423] 42. The nucleic acid according to item 41, that is in the form of a genetic construct.

[1424] 43. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40; and / or that comprises the nucleic acid of item 41 or 42.

[1425] 44. A method for producing an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40, at least comprising the steps of:

[1426] i) expressing, in a suitable (non-human) host cell or host cell or in another suitable expression system, a nucleic acid of item 41 or 42;

[1427] optionally followed by:

[1428] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or the polypeptide of any one of items 15 to 40.

[1429] 45. A method for producing an ISVD of any one of items 1 to 14 or a polypeptide of any one of items 15 to 40, said method at least comprising the steps of:i) cultivating and / or maintaining a (non-human) host or host cell according to item 46 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 14, or at least one polypeptide of any one of items 18 to 43

[1430] optionally followed by:

[1431] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or polypeptide of any one of items 15 to 40.

[1432] 46. A composition comprising at least one ISVD of any one of items 1 to 14, at least one polypeptide or construct of any one of items 15 to 40, or at least one nucleic acid of item 41 or 42.

[1433] 47. The composition according to item 46, which is a pharmaceutical composition.

[1434] 48. The composition of item 46 or 47 which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[1435] 49. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use as a medicament.

[1436] 50. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[1437] 51. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[1438] 52. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / ortreatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[1439] Use of the ISVD of any one of it items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[1440] The ISVD, polypeptide or construct, or composition for use according to item 52 or the use according to item 53, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

[1441] A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48.

[1442] The method according to item 55, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1443] The method of item 55 or 56 for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1444] The ISVD of any one of items 1 to 14, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 198.59. The ISVD of any one of items 1 to 14 or 58, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 198.

[1445] 3.5 Embodiment 5 (A0289046F07)

[1446] 1. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1447] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[1448] a) the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[1449] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[1450] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GRTMSSYAMA (SEQ ID NO: 362);

[1451] and

[1452] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[1453] d) the amino acid sequence VSSLSGGTSD (SEQ ID NO: 356);

[1454] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VSSLSGGTSD (SEQ ID NO: 356);

[1455] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VSSLSGGTSD (SEQ ID NO: 356);

[1456] and

[1457] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[1458] g) the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[1459] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[1460] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363).

[1461] 2. The ISVD of item 1, in which:

[1462] - CDR1 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 315;

[1463] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 316; and - CDR3 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 317.The ISVD of any one of item 1 or 2, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NO: 202.

[1464] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1465] CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[1466] a) the amino acid sequence of SYAMA (SEQ ID NO: 272);

[1467] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYAMA (SEQ ID NO: 272); and

[1468] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SYAMA (SEQ ID NO: 272);

[1469] and

[1470] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[1471] d) the amino acid sequence of VSSLSGGTSDYADSVKG (SEQ ID NO: 364);

[1472] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSSLSGGTSDYADSVKG (SEQ ID NO: 364); and

[1473] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSSLSGGTSDYADSVKG (SEQ ID NO: 364);

[1474] and

[1475] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[1476] g) the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363);

[1477] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363); and

[1478] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYIRYSIRDYDI (SEQ ID NO: 363).

[1479] The ISVD of item 4, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% aminoacid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NO: 202.

[1480] 6. The ISVD of item 4 or 5, in which:

[1481] – CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 272,– CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 364, and– CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 363.

[1482] 7. The ISVD of any one of the previous items, which amino acid sequence

[1483] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 202, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;

[1484] and in which:

[1485] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[1486] 8. The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[1487] 9. The ISVD of any one of the previous items, which is chosen from the group consisting of SEQ ID NO: 202 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 202.

[1488] 10. The ISVD of any one of the previous items, in which the amino acid sequence is SEQ ID NO: 202.

[1489] 11. The ISVD of any one of the previous items, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.12. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of IO-7to 1011moles / litre or less, and preferably IO-7to IO10moles / litre or less, such as more preferably IO-8to 1010moles / litre, even more preferably with a KDof about 1.6xl0-9moles / litre, as determined by SPR.

[1490] 13. The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as a 3-fold difference in affinity (KD).

[1491] 14. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less, such as more preferably 10'7to 10'9moles / litre, even more preferably with a KDof about 6xl0-8moles / litre, as determined by SPR.

[1492] 15. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[1493] 16. The polypeptide or construct of item 15, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[1494] 17. The polypeptide or construct of item 15, in which said one or more linkers are one or more amino acid sequences.

[1495] 18. The polypeptide or construct of item 15 or 16, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[1496] 19. The polypeptide or construct of item 18, in which said one or more other groups, residues, moieties or binding units are ISVDs.20. The polypeptide or construct of any one of items 15 to 19, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[1497] 21. The polypeptide or construct of any one of items 15 to 20, which is a multivalent construct.

[1498] 22. The polypeptide or construct of any one of items 15 to 21, which is a multispecific construct.

[1499] 23. The polypeptide or construct of any one of items 15 to 22, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[1500] 24. The polypeptide or construct of any one of items 15 to 23, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or NK-cell.

[1501] 25. The polypeptide or construct of item 24, wherein said polypeptide or constructs directs the T- cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[1502] 26. The polypeptide or construct of item 24 or 25, wherein said polypeptide or construct induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[1503] 27. The polypeptide or construct of items 24 or 25, wherein said antigen is selected from CD3, T- cell receptor, CD16a, NKp2, and NKp46.

[1504] 28. The polypeptide or construct of any one of items 15 to 27, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti- CD3 scFv.

[1505] 29. The polypeptide or construct of any one of items 15 to 22, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.The polypeptide or construct of item 29, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

[1506] The polypeptide or construct of item 29 or 30, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[1507] The polypeptide or construct of any one of items 29 or 30, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1508] The polypeptide or construct of items 32, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1509] The polypeptide or construct of any one of items 32 to 33, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[1510] The polypeptide or construct of item 36, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[1511] CDR1 (AbM numbering) has an amino acid sequence selected from:

[1512] a) the amino acid sequence of SEQ ID NO: 158;

[1513] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[1514] and

[1515] CDR2 (AbM numbering) has an amino acid sequence selected from:

[1516] d) the amino acid sequence of SEQ ID NO: 160;

[1517] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; and

[1518] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[1519] and

[1520] CDR3 (AbM numbering) has an amino acid sequence selected from:

[1521] g) the amino acid sequence of SEQ ID NO: 162;

[1522] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[1523] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[1524] The polypeptide or construct of item 35, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[1525] The polypeptide or construct of items 34 to 36, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB2202 (SEQ ID NO: 156).

[1526] The polypeptide or construct of any one of items 15 to 37, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[1527] The polypeptide or construct of any one of items 15 to 38, further comprising a C-terminal extension.

[1528] The polypeptide or construct of item 39, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

[1529] 41. A nucleic acid that encodes an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40.

[1530] 42. The nucleic acid according to item 41, that is in the form of a genetic construct.

[1531] 43. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40; and / or that comprises the nucleic acid of item 41 or 42.

[1532] 44. A method for producing an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40, at least comprising the steps of:

[1533] i) expressing, in a suitable (non-human) host cell or host cell or in another suitable expression system, a nucleic acid of item 41 or 42;

[1534] optionally followed by:

[1535] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or the polypeptide of any one of items 15 to 40.

[1536] 45. A method for producing an ISVD of any one of items 1 to 14 or a polypeptide of any one of items 15 to 40, said method at least comprising the steps of:

[1537] i) cultivating and / or maintaining a (non-human) host or host cell according to item 46 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 14, or at least one polypeptide of any one of items 18 to 43

[1538] optionally followed by:

[1539] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or polypeptide of any one of items 15 to 40.46. A composition comprising at least one ISVD of any one of items 1 to 14, at least one polypeptide or construct of any one of items 15 to 40, or at least one nucleic acid of item 41 or 42.

[1540] 47. The composition according to item 46, which is a pharmaceutical composition.

[1541] 48. The composition of item 46 or 47 which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[1542] 49. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use as a medicament.

[1543] 50. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[1544] 51. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[1545] 52. The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[1546] 53. Use of the ISVD of any one of it items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.54. The ISVD, polypeptide or construct, or composition for use according to item 52 or the use according to item 53, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

[1547] 55. A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48.

[1548] 56. The method according to item 55, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1549] 57. The method of item 55 or 56 for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1550] 58. The ISVD of any one of items 1 to 14, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 202.

[1551] 59. The ISVD of any one of items 1 to 14 or 58, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 202.

[1552] 3.6 Embodiment 6 (A0289038C06)

[1553] 1. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1554] CDR1 (AbM definition) consists of an amino acid sequence selected from:a) the amino acid sequence of GLTFDNYAMG (SEQ ID NO: 341);

[1555] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFDNYAMG (SEQ ID NO: 341);

[1556] c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of GLTFDNYAMG (SEQ ID NO: 341);

[1557] and

[1558] CDR2 (AbM definition) consists of an amino acid sequence selected from:

[1559] d) the amino acid sequence TISAAGHRTI (SEQ ID NO: 342);

[1560] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TISAAGHRTI (SEQ ID NO: 342);

[1561] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence TISAAGHRTI (SEQ ID NO: 342);

[1562] and

[1563] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[1564] g) the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343);

[1565] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343);

[1566] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343).

[1567] The ISVD of item 1, in which:

[1568] - CDR1 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 341;

[1569] - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 342; and - CDR3 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 343.

[1570] The ISVD of any one of item 1 or 1, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NO: 199.An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1571] CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[1572] a) the amino acid sequence of NYAMG (SEQ ID NO: 344);

[1573] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of NYAMG (SEQ ID NO: 344); and

[1574] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of NYAMG (SEQ ID NO: 344);

[1575] and

[1576] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[1577] d) the amino acid sequence of TISAAGHRTIFTNSVRG (SEQ ID NO: 345);

[1578] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TISAAGHRTIFTNSVRG (SEQ ID NO: 345); and

[1579] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of TISAAGHRTIFTNSVRG (SEQ ID NO: 345);

[1580] and

[1581] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[1582] g) the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343);

[1583] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343); and

[1584] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SPSQYGSMGKSAYDY (SEQ ID NO: 343).

[1585] The ISVD of item 4, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NO: 199.

[1586] The ISVD of item 4 or 5, in which:

[1587] - CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 344,- CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 345, and - CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 343.

[1588] The ISVD of any one of the previous items, which amino acid sequence

[1589] i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 199, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;

[1590] and in which:

[1591] ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

[1592] The ISVD of any one of the previous items, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

[1593] The ISVD of any one of the previous items, which is chosen from the group consisting of SEQ ID NO: 199 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 199.

[1594] The ISVD of any one of the previous items, in which the amino acid sequence is SEQ ID NO: 199.

[1595] The ISVD of any one of the previous items, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

[1596] The ISVD of any one of the previous items, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of IO-7to 1011moles / litre or less, and preferably IO-7to IO10moles / litre or less, such as more preferably IO-8to 1010moles / litre, even more preferably with a KDof about 1.4x10-10moles / litre, as determined by SPR.

[1597] The ISVD of any one of the previous items, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as a 3-fold difference in affinity (KD).

[1598] 14. The ISVD of any one of the previous items, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less, such as more preferably 5xl0-8to 10'9moles / litre, even more preferably with a KDof about 3.9xl0-8moles / litre, as determined by SPR.

[1599] 15. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to anyone of the previous items, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

[1600] 16. The polypeptide or construct of item 15, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

[1601] 17. The polypeptide or construct of item 15, in which said one or more linkers are one or more amino acid sequences.

[1602] 18. The polypeptide or construct of item 15 or 16, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

[1603] 19. The polypeptide or construct of item 18, in which said one or more other groups, residues, moieties or binding units are ISVDs.

[1604] 20. The polypeptide or construct of any one of items 15 to 19, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

[1605] 21. The polypeptide or construct of any one of items 15 to 20, which is a multivalent construct.

[1606] 22. The polypeptide or construct of any one of items 15 to 21, which is a multispecific construct.The polypeptide or construct of any one of items 15 to 22, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

[1607] The polypeptide or construct of any one of items 15 to 23, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or NK-cell.

[1608] The polypeptide or construct of item 24, wherein said polypeptide or constructs directs the T-cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

[1609] The polypeptide or construct of item 24 or 25, wherein said polypeptide or construct induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

[1610] The polypeptide or construct of items 24 or 25, wherein said antigen is selected from CD3, T-cell receptor, CD16a, NKp2, and NKp46.

[1611] The polypeptide or construct of any one of items 15 to 27, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti-CD3 scFv.

[1612] The polypeptide or construct of any one of items 15 to 22, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

[1613] The polypeptide or construct of item 29, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.31. The polypeptide or construct of item 29 or 30, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

[1614] 32. The polypeptide or construct of any one of items 29 or 30, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1615] 33. The polypeptide or construct of items 32, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

[1616] 34. The polypeptide or construct of any one of items 32 to 33, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

[1617] 35. The polypeptide or construct of item 36, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[1618] CDR1 (AbM numbering) has an amino acid sequence selected from:

[1619] a) the amino acid sequence of SEQ ID NO: 158;

[1620] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; and

[1621] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;

[1622] and

[1623] CDR2 (AbM numbering) has an amino acid sequence selected from:

[1624] d) the amino acid sequence of SEQ ID NO: 160;

[1625] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;

[1626] and

[1627] CDR3 (AbM numbering) has an amino acid sequence selected from:

[1628] g) the amino acid sequence of SEQ ID NO: 162;

[1629] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; and

[1630] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

[1631] 36. The polypeptide or construct of item 35, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

[1632] 37. The polypeptide or construct of items 34 to 36, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB2202 (SEQ ID NO: 156).

[1633] 38. The polypeptide or construct of any one of items 15 to 37, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

[1634] 39. The polypeptide or construct of any one of items 15 to 38, further comprising a C-terminal extension.

[1635] 40. The polypeptide or construct of item 39, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

[1636] 41. A nucleic acid that encodes an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40.42. The nucleic acid according to item 41, that is in the form of a genetic construct.

[1637] 43. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40; and / or that comprises the nucleic acid of item 41 or 42.

[1638] 44. A method for producing an ISVD of any one of items 1 to 14, or a polypeptide of any one of items 15 to 40, at least comprising the steps of:

[1639] i) expressing, in a suitable (non-human) host cell or host cell or in another suitable expression system, a nucleic acid of item 41 or 42;

[1640] optionally followed by:

[1641] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or the polypeptide of any one of items 15 to 40.

[1642] 45. A method for producing an ISVD of any one of items 1 to 14 or a polypeptide of any one of items 15 to 40, said method at least comprising the steps of:

[1643] i) cultivating and / or maintaining a (non-human) host or host cell according to item 46 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD of any one of items 1 to 14, or at least one polypeptide of any one of items 18 to 43

[1644] optionally followed by:

[1645] ii) isolating and / or purifying the ISVD of any one of items 1 to 14, or polypeptide of any one of items 15 to 40.

[1646] 46. A composition comprising at least one ISVD of any one of items 1 to 14, at least one polypeptide or construct of any one of items 15 to 40, or at least one nucleic acid of item 41 or 42.

[1647] 47. The composition according to item 46, which is a pharmaceutical composition.

[1648] 48. The composition of item 46 or 47 which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / oradjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[1649] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use as a medicament.

[1650] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

[1651] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40, or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

[1652] The ISVD of any one of items 1 to 14, the polypeptide or construct of any one of items 15 to 40 or the composition of any one of items 46 to 48, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

[1653] Use of the ISVD of any one of it items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

[1654] The ISVD, polypeptide or construct, or composition for use according to item 52 or the use according to item 53, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

[1655] A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceuticallyactive amount of an ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or a composition of any one of items 46 to 48.

[1656] The method according to item 55, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1657] The method of item 55 or 56 for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of items 1 to 14, a polypeptide or construct of any one of items 15 to 40, or composition of any one of items 46 to 48.

[1658] The ISVD of any one of items 1 to 14, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 199.

[1659] The ISVD of any one of items 1 to 14 or 58, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 199.

[1660] Embodiment 10 (A0289044A12)

[1661] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1662] CDR1 (AbM definition) consists of an amino acid sequence selected from:

[1663] a) the amino acid sequence of GSRLSFTTMG (SEQ ID NO: 351);

[1664] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GSRLSFTTMG (SEQ ID NO: 351);

[1665] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GSRLSFTTMG (SEQ ID NO: 351);

[1666] and

[1667] CDR2 (AbM definition) consists of an amino acid sequence selected from:d) the amino acid sequence YITESGSTA (SEQ ID NO: 352);

[1668] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence YITESGSTA (SEQ ID NO: 352);

[1669] f) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence YITESGSTA (SEQ ID NO: 352);

[1670] and

[1671] CDR3 (AbM definition) consists of an amino acid sequence selected from:

[1672] g) the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353);

[1673] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353);

[1674] i) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353).

[1675] The ISVD of item 1, in which:

[1676] - CDR1 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 351;

[1677] - CDR2 (AbM definition) consists of the amino acid sequence SEQ ID NO: 352; and - CDR3 (AbM definition) consists of an amino acid sequence of SEQ ID NO: 353.

[1678] The ISVD of any one of item 1 or 1, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NO: 201.

[1679] An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:

[1680] CDR1 (Kabat definition) consists of an amino acid sequence selected from:

[1681] a) the amino acid sequence of FTTMG (SEQ ID NO: 354);

[1682] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of FTTMG (SEQ ID NO: 354); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of FTTMG (SEQ ID NO: 354);

[1683] and

[1684] CDR2 (Kabat definition) consists of an amino acid sequence selected from:

[1685] d) the amino acid sequence of YITESGSTAYTASVKD (SEQ ID NO: 355);

[1686] e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of YITESGSTAYTASVKD (SEQ ID NO: 355); and

[1687] f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of YITESGSTAYTASVKD (SEQ ID NO: 355);

[1688] and

[1689] CDR3 (Kabat definition) consists of an amino acid sequence selected from:

[1690] g) the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353);

[1691] h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353); and

[1692] i) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VIMMGGSGTY (SEQ ID NO: 353).

[1693] 5. The ISVD of item 4, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NO: 201.

[1694] 6. The ISVD of item 4 or 5, i...

Claims

1. 8 CLAIMS1. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human CD19, wherein at least one amino acid residue is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19 when numbered in accordance with SEQ ID NO: 214:Q98-W111;W124-D128;W159-K161;S185-Q186; and / orC200-V207.

2. The ISVD of claim 1, wherein the at least one amino acid residue in at least one, preferably in each amino acids stretch of human CD19 is selected from:From stretch Q98-W111: Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109 and Will;From stretch W124-D128: W124, N125 and D128;From stretch W159-K161: W159 and K161;From stretch S185-Q186: S185 and Q186;From stretch C200-V207: C200, G201, V202, P204, D205, S206 and V207, when numbered in accordance with SEQ ID NO: 214.

3. The ISVD of claim 1 or claim 2, wherein at least one amino acid residue is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or preferably all of the following amino acid residues in stretch Q98-W111 of human CD19, when numbered in accordance with SEQ ID NO: 214: Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109 and Will.

4. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of interacting with at least one, at least two, or preferably all of the following amino acid residues in stretch W124-D128 of human CD19, when numbered in accordance with SEQ ID NO: 214: W124, N125 and D128.

5. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of interacting with at least one, or preferably all of the following amino acid residues in stretch W159-K161 of human CD19, when numbered in accordance with SEQ ID NO: 214: W159 and K161.

6. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of interacting with at least one, or preferably all of the following amino acid residues in stretch S185-Q186 of human CD19, when numbered in accordance with SEQ ID NO: 214: S185 and Q186.

7. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, or preferably all of the following amino acid residues in stretch C200-V207 of human CD19, when numbered in accordance with SEQ ID NO: 214: C200, G201, V202, P204, D205, S206 and V207.

8. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least one amino acid of the CD19 protein selected from E104, Q98, P99, Q108, S185 and Q186, when numbered in accordance with SEQ ID NO.: 214.

9. The immunoglobulin single variable domain (ISVD) of claim 8, that interacts with at least two amino acids, optionally, at least three amino acids, at least four amino acids, at least five amino acids, or preferably all amino acids of the CD19 protein selected from E104, Q98, P99, Q108, S185 and Q186.

10. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of forming a salt bridge with E104 of human CD19, when numbered in accordance with SEQ ID NO: 214.

11. The ISVD of any one of the preceding claims, wherein:the amino acid residue at position R73 (Kabat numbering) is capable of interacting, preferably by forming a salt bridge, with E104 in human CD19,when numbered in accordance with SEQ ID NO: 214;12. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of forming hydrogen bonds with at least one, or all of the following amino acid residues of human CD19, when numbered in accordance with SEQ ID NO: 214: Q98, P99, E104, Q108, S185 and Q186.

13. The ISVD of any one of the preceding claims, wherein:the amino acid residue at position Y100 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with S185 in human CD19; and / orthe amino acid residue at position F98 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q186 in human CD19,the amino acid residue at position T53 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q108 in human CD19,the amino acid residue at position R73 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q98 and / or P99 in human CD19, the amino acid residue at position R96 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N125 N-acetylglucosamine in human CD19, when numbered in accordance with SEQ ID NO: 214.

14. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least one amino acid of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

15. The immunoglobulin single variable domain (ISVD) of claim 14, that interacts with at least two amino acids, optionally, at least five amino acids, at least ten amino acids, at least twenty amino acids of theCD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

16. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with the following amino acids of the CD19 protein: Q98, P99, Q108, S185 and Q186.

17. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with the following amino acid of the CD19 protein: E104.

18. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with the following amino acids of the CD19 protein: Q98, P99, E104, Q108, S185 and Q186.

19. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with the following amino acids of the CD19 protein: K105, A106, W107, P109, W111, W124, N125, W159, K161, C200, V202, P204, D205, S206 and V207, optionally that interacts with the following amino acids of the CD19 protein Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

20. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), and that comprises at least one amino acid residue selected from the group consisting of: T53, R73, R96, F98 and Y100 (Kabat numbering), optionally at least two, at least three, at least four, further optionally, that comprises the amino acid residues selected from the group consisting of: T53, R73, R96, F98 and Y100 (Kabat numbering), even further optionally that interacts with the CD19 protein as defined in claims 1-8, preferably wherein:R73 (Kabat numbering) in the ISVD interacts, preferably by forming a salt bridge, with E104 in human CD19, and / orY100 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with S185 in human CD19; and / orF98 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q186 in human CD19; and / orT53 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q108 in human CD19; and / orR73 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q98 and / or P99 in human CD19; and / orR96 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with N125 N-acetylglucosamine in human CD19,when numbered in accordance with SEQ. ID NO: 214.

21. The immunoglobulin single variable domain (ISVD) of claim 20, that comprises D27, F29, G30, and T31 (Kabat numbering) in CDR1 (Abm definition).

22. The immunoglobulin single variable domain (ISVD) of claim 20 or 21, that comprises T52, W52a, T53, A54 and L56 (Kabat numbering) in CDR2 (Abm definition).

23. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 22, that comprises F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).

24. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 23, that comprises R96, F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).

25. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 24, that comprises D27, F29, G30, and T31 (Kabat numbering) in CDR1 (Abm definition), T52, W52a, T53, A54 and L56 (Kabat numbering) in CDR2 (Abm definition) and F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).

26. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 25, that comprises D27, F29, G30, and T31 (Kabat numbering) in CDR1 (Abm definition), T52, W52a, T53, A54 and L56 (Kabat numbering) in CDR2 (Abm definition) and R96, F98, Y100 and H100b (Kabat numbering) in CDR3 (Abm definition).

27. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that comprises R73.

28. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that comprises K71, V74 and / or N76.

29. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 28, that comprises T53, R73, F98 and Y100 (Kabat numbering), wherein T53, R73, F98 and Y100 form an interaction site, preferably a salt bridge or an hydrogen bound, with at least one amino acid selected from the group consisting of Q108, Q98 and P99, Q186 and S185 of the CD19 protein.

30. The immunoglobulin single variable domain (ISVD) of claim 29, wherein the interaction site is formed by at least two, at least three, at least four, at least five amino acids selected from the group consisting of Q108, Q98 and P99, Q186 and S185 of the CD19 protein.

31. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 28, that comprises T53, R73, R96, F98 and Y100 (Kabat numbering), wherein T53, R73, R96, F98 and Y100 form an interaction site, preferably a salt bridge or an hydrogen bound, with at least one residue selected from the group consisting of E104, Q108, Q98, P99, N-acetyl glucosamine on N125, Q186, and S185 of the CD19 protein.

32. The immunoglobulin single variable domain (ISVD) of claim 31, wherein the interaction site is formed by at least two, at least three, at least four, at least five, at least six, or all residues selected from the group consisting of E104, Q108, Q98 and P99, N-acetyl glucosamine on N125, Q186, and S185 of the CD19 protein.

33. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 32, that comprises T53, R73, F98 and Y100 (Kabat numbering), wherein T53, R73, F98 and Y100 form an interaction site, preferably an hydrogen bound, with Q108, Q98 and P99, Q186 and S185 of the CD19 protein as follows:o Y100 (Kabat numbering) interacts with S185 in CD19o F98 (Kabat numbering) interacts with Q186 in CD19;o T53 (Kabat numbering) interacts with Q108 in CD19;o R73 (Kabat numbering) interacts with Q98 in CD19; ando R73 (Kabat numbering) interacts with P99 in CD19.

34. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 33, that comprises T53, R73, R96, F98 and Y100 (Kabat numbering), wherein T53, R73, R96, F98 and Y100 form an interaction site, preferably an hydrogen bound, with Q108, Q98 and P99, N- acetylglucosamine of N125, Q186 and S185 of the CD19 protein as follows:o Y100 (Kabat numbering) interacts with S185 in CD19o F98 (Kabat numbering) interacts with Q186 in CD19;o T53 (Kabat numbering) interacts with Q108 in CD19;o R73 (Kabat numbering) interacts with Q98 in CD19;o R73 (Kabat numbering) interacts with P99 in CD19; ando R96 (Kabat numbering) interacts with N-acetyl glucosamine on N125 in CD19.

35. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 33, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, F98, Y100 and H100b (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

36. The immunoglobulin single variable domain (ISVD) of claim 35, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen, at least twenty amino acids of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

37. The immunoglobulin single variable domain (ISVD) of claim 35 or 36, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, F98, Y100 and H100b (Kabat numbering) form the interaction site with following amino acids of the CD19 protein: Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

38. The immunoglobulin single variable domain (ISVD) of any one of claims 20 to 34, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, R96, F98, Y100 and H100b (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

39. The immunoglobulin single variable domain (ISVD) of claim 38, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen, at least twenty amino acids of the CD19 protein selected from Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C200, G201, V202, P204, D205, S206 and V207.

40. The immunoglobulin single variable domain (ISVD) of claim 38 or 39, in which D27, F29, G30, T31, T52, W52a, T53, A54, L56, K71, R73, V74, N76, R96, F98, Y100 and H100b (Kabat numbering) form the interaction site with following amino acids of the CD19 protein: Q98, P99,G100, P1O1, E104, K105, A106, W107, Q108, P109, W111, W124, N125, D128, W159, K161, S185, Q186, C2OO, G2O1, V2O2, P204, D205, S206 and V207.

41. The ISVD of any one of the preceding claims, wherein two amino acids are considered to interact when the distance between them is 4.0 A or less.

42. The ISVD of any one of the preceding claims, wherein the interacting amino acid residue(s) in the ISVD and in human CD19 are identified by cryo-EM by:Mixing CD19 recombinant protein, the ISVD and an anti-VHH Fab at a molar ratio of 1:2:1 in 20 mM Hepes (pH 7.4), 150 mM NaCI;Diluting the protein complex to 0.5 mg / mL in buffer containing 150 mM NaCI and 20 mM Hepes (pH 7.4);Applying the protein complex to glow-discharged Ultrafoil Rl.2 / 1.3 grids, blotting for 4 seconds under 100% humidity and 4°C, plunge-freezing in liquid-ethane cooled by liquid nitrogen;Collecting cryo-EM data using a cryo-transmission electron microscope, optionally at a pixel size of ~ 0.59 A in movie mode yielding a cumulative dose of ~50 e“ / A2; and Processing the collected data,preferably as described in Example 3.

43. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, wherein CDR1 (AbM definition) consists of an amino acid sequence X1DX2FGTX3X4X5X6 (SEQ. ID NO:203); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as G;X2 is selected from any amino acid, preferably X2 is selected from S, T, C, N, Q, such as T;X3 is selected from any amino acid, preferably X3 is selected from K, R and H, such as K;X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as A;X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as M;Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as G;and- CDR2 (AbM definition) consists of an amino acid sequence X1X2TWTAX3LX4X5 (SEQ ID NO:204); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as A;X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as I;X3 is selected from any amino acid, preferably X3 is selected from G, A, V, L, I, M and P, such as G;X4is selected from any amino acid, preferably X4is selected from S, T, C, N, Q, such as T;X5is selected from any amino acid, preferably X5is selected from F, Y and W, such as Y;and- CDR3 (AbM definition) consists of an amino acid sequence X1X2X3FX4YX5HX6X7X8X9X10X11X12X13X14X15X16 (SEQ ID NO: 205); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as R;X2 is selected from any amino acid, preferably X2 is selected from K, R and H, such as R;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as T;X4is selected from any amino acid, preferably X4is selected from S, T, C, N, Q, such as S;X5is selected from any amino acid, preferably X5is selected from E and D, such as E;Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as P;X7is selected from any amino acid, preferably X7is selected from S, T, C, N, Q, such as N;Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y;Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y;Xio is selected from any amino acid, preferably X10 is selected from S, T, C, N, Q, such as T;Xn is selected from any amino acid, preferably Xn is selected from G, A, V, L, I, M, K, R, H and P, such as A, P, or R;X12 is selected from any amino acid, preferably X12 is selected from S, T, C, N, Q, such as S;X13 is selected from any amino acid, preferably X13 is selected from G, A, V, L, I, M and P, such as A;XMis selected from any amino acid, preferably X14is selected from F, Y and W, such as Y;X15 is selected from any amino acid, preferably X15 is selected from K, R and H, such as H;Xis is selected from any amino acid, preferably Xis is selected from F, Y and W, such as F.

44. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (AbM definition) consists of an amino acid sequence selected from:a) the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97);andCDR2 (AbM definition) consists of an amino acid sequence selected from:d) the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99);e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99); andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99);andCDR3 (AbM definition) consists of an amino acid sequence selected from:g) the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R; andi) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R.

45. The ISVD of claim 44, in which:CDR1 (AbM definition) consists of an amino acid sequence of GDTFGTKAMG (SEQ ID NO: 97);CDR2 (AbM definition) consists of the amino acid sequence of AITWTAGLTY (SEQ ID NO: 99); andCDR3 (AbM definition) consists of an amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R.

46. The ISVD of any one of claim 44 or 45, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of an ISVD with the amino acid sequence selected from SEQ ID NOs: 71-95.

47. The ISVD of any one of claims 44 to 46, in which- CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 113; or in which- CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 114; or in which- CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 97, - CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 99, - CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 115.

48. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (Kabat definition) consists of an amino acid sequence selected from:a) the amino acid sequence of TKAMG (SEQ ID NO: 255);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TKAMG (SEQ ID NO: 255); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of TKAMG (SEQ ID NO: 255);CDR2 (Kabat definition) consists of an amino acid sequence selected from:d) the amino acid sequence of AITWTAGLTYX1ADSX2KG (SEQ ID NO: 287); wherein the amino acid residue Xi is selected from L and Y; and wherein the amino acid residue X2 is selected from A and V, preferably A;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AITWTAGLTYX1ADSX2KG (SEQ ID NO: 287); wherein the amino acid residue Xi is selected from L and Y; and wherein the amino acid residue X2 is selected from A and V, preferably A; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AITWTAGLTYX1ADSX2KG (SEQ ID NO: 287); wherein the amino acid residue Xi is selected from L and Y; and wherein the amino acid residue X2 is selected from A and V, preferably A;andCDR3 (Kabat definition) consists of an amino acid sequence selected from:g) the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R, preferably A;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R, preferably A; andi) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of RRTFSYEHPNYYTXSAYHF (SEQ ID NO: 206); wherein the amino acid residue X is selected from A, P, and R, preferably A.

49. The ISVD of claim 48, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 71-95.

50. The ISVD of claim 48 or 49, in which:CDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 258, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 260, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 259, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 261, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 113; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 261, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 114;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 260, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 114; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 261, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 115; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 255, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 260, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 115.

51. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that comprises R73.

52. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that comprises K71, V74 and / or N76.

53. The ISVD of any one of the previous claims, which amino acid sequencei) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 71-95, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;and in which:ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

54. The ISVD of any one of claim 44 to 53, wherein the ISVD forms an interaction site with the CD19 protein as defined in any one of claims 29-40.

55. The ISVD of any one of the previous claims, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody.

56. The ISVD of any one of the previous claims, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 71-95 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 71-95.

57. The ISVD of any one of the previous claims, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 71-95.

58. The ISVD of any one of the previous claims, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

59. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of IO-7to 1011moles / litre or less, and preferably IO-8to IO10moles / litre or less, such as more preferably IO-9to IO10moles / litre, even more preferably wherein the ISVD specifically binds to human CD19 with a KDof about 5.5xlO10moles / litre, as determined by SPR.

60. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human CD19 on B-cells with a EC50 of 10'7to 1011M or less, and preferably 10'7to IO10M or less, such as more preferably 10'8to IO10M, even more preferably wherein the ISVD specifically binds to human CD19 with a EC50 of about 6.1xlO’9M, 3.9xlO'9IVI, 4.6xlO'9IVI, or 1.1X10’9M, as determined by FACS assay on PBMCs or DLBCLs expressing human CD19.

61. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as a 8-fold difference in affinity (KD).

62. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less such as more preferably 10'8to 10'9moles / litre, even more preferablywherein the ISVD specifically binds to cyno CD19 with a KDof about 4.4xl0-9moles / litre moles / litre, as determined by SPR.

63. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human CD19, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19 when numbered in accordance with SEQ ID NO: 214:L78;C97-P109;Q186;C200-P211; and / orD232.

64. The ISVD of claim 63, wherein the at least one amino acid residue in at least one, preferably in each, amino acids stretch of human CD19 is selected from:L78;From stretch C97-P109: C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, and P109;Q186;From stretch C200-P211: C200, G201, V202, P204, D205, S206, V207, S208, R209, G210 and P211; andD232;when numbered in accordance with SEQ ID NO: 214.

65. The ISVD of claim 63 or claim 64, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or preferably all of the following amino acid residues in stretch C97-P109 of human CD19, when numbered in accordance with SEQ ID NO: 214: C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, and P109.

66. The ISVD of any one of the preceding claims, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with Q186 of human CD19, when numbered in accordance with SEQ ID NO: 214.

67. The ISVD of any one of the preceding claims, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with D232 of human CD19, when numbered in accordance with SEQ ID NO: 214.

68. The ISVD of any one of the preceding claims, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with L78 of human CD19, when numbered in accordance with SEQ ID NO: 214.

69. The ISVD of any one of the preceding claims, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or preferably all of the following amino acid residues in stretch C200- P211 of human CD19 when numbered in accordance with SEQ ID NO: 214: C200, G201, V202, P204, D205, S206, V207, S208, R209, G210 and P211.

70. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least one amino acid of the CD19 protein selected from P99, Q108 and S208 when numbered in accordance with SEQ ID NO.: 214.

71. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least two amino acids of the CD19 protein selected from P99, Q108 and S208, further optionally, that interacts with the amino acids of the CD19 protein selected from P99, Q108 and S208.

72. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of forming hydrogen bonds with at least one, or all of the following amino acid residues of human CD19, when numbered in accordance with SEQ ID NO: 214: P99, Q108 and S208.

73. The ISVD of any one of the preceding claims, wherein:the amino acid residue at position R100 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with P99 in human CD19; and / orthe amino acid residue at position S99 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q108 in human CD19,the amino acid residue at position NIOOa (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with S208 in human CD19,when numbered in accordance with SEQ. ID NO: 214.

74. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least one amino of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

75. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least two amino acids, optionally, at least five amino acids, at least ten amino acids, at least twenty amino acids of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

76. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with following amino acids of the CD19 protein: P99, Q108 and S208.

77. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with the following amino acids of the CD19 protein: G100, P101, K105, A106, W107, P109, C200, G201, V202, P204, D205, S206, V207, R209, G210, P211 and D232, optionally that interacts with following amino acids of the CD19 protein: L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

78. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), and that comprises at least one amino acid residue selected from the group consisting of: S99, NIOOa and RIOOc (Kabat numbering), optionally at least two, further optionally, that comprises the amino acidresidues selected from the group consisting of: S99, NIOOa and RIOOc (Kabat numbering), even further optionally that interacts with the CD19 protein as defined in claims 63-77, preferably wherein:RIOOc (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with P99 in human CD19; and / orS99 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q108 in human CD19; and / orNIOOa (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with S208 in human CD19;when numbered in accordance with SEQ. ID NO: 214.

79. The immunoglobulin single variable domain (ISVD) of claim 78, that comprises N53, Y55, Y58, G59, E60 and S63, (Kabat numbering) in CDR2 (Kabat definition).

80. The immunoglobulin single variable domain (ISVD) of claim 78 or 79, that comprises R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering) in CDR3 (Kabat definition).

81. The immunoglobulin single variable domain (ISVD) of any one of claims 78 to 80, that comprises N53, Y55, Y58, G59, E60 and S63, (Kabat numbering) in CDR2 (Kabat definition) and R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering) in CDR3 (Kabat definition).

82. The immunoglobulin single variable domain (ISVD) according to any one of claims 78 to 81, that comprises S99, NIOOa and RIOOc (Kabat numbering), wherein S99, NIOOa and RIOOc form an interaction site with at least one amino acid selected from the group consisting of Q108, S208 and P99 of the CD19 protein.

83. The immunoglobulin single variable domain (ISVD) of claim 82, wherein the interaction site is formed by at least two, at least three amino acids selected from the group consisting of Q108, S208 and P99 of the CD19 protein.

84. The immunoglobulin single variable domain (ISVD) of any one of claims 78 to 83, that comprises S99, NIOOa and RIOOc (Kabat numbering), wherein S99, NIOOa and RIOOc form aninteraction site, preferably an hydrogen bound, with Q108, S208 and P99 of the CD19 protein as follows:o RIOOc (Kabat numbering) interacts with P99 in CD19;o S99 in (Kabat numbering) interacts with Q108 in CD19; and o NIOOa (Kabat numbering) interacts with S208 in CD19.

85. The immunoglobulin single variable domain (ISVD) of any one of claims 78 to 84, in which N53, Y55, Y58, G59, E60, S63, R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

86. The immunoglobulin single variable domain (ISVD) of claim 85, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen, at least twenty amino acids of the CD19 protein selected from L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

87. The immunoglobulin single variable domain (ISVD) of claim 85 or 86, that comprise N53, Y55, Y58, G59, E60, S63, R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg (Kabat numbering), in which N53, Y55, Y58, G59, E60, S63, R97, 198, S99, Y100, NIOOa, VlOOb, RIOOc, DIOOd, DIOOe and FlOOg form the interaction site with following amino acids of the CD19 protein: L78, C97, Q98, P99, G100, P101, E104, K105, A106, W107, Q108, P109, Q186, C200, G201, V202, P204, D205, S206, V207, S208, R209, G210, P211 and D232.

88. The ISVD of any one of the preceding claims, wherein two amino acids are considered to interact when the distance between them is 4.0 A or less.

89. The ISVD of any one of the preceding claims, wherein the interacting amino acid residue(s) in the ISVD and in human CD19 are identified by cryo-EM by:Mixing CD19 recombinant protein, the ISVD and an anti-VHH Fab at a molar ratio of 1:2:1 in 20 mM Hepes (pH 7.4), 150 mM NaCI;Diluting the protein complex to 0.5 mg / mL in buffer containing 150 mM NaCI and 20 mM Hepes (pH 7.4);Applying the protein complex to glow-discharged Ultrafoil Rl.2 / 1.3 grids, blotting for 4 seconds under 100% humidity and 4°C, plunge-freezing in liquid-ethane cooled by liquid nitrogen;Collecting cryo-EM data using a cryo-transmission electron microscope, optionally at a pixel size of ~ 0.59 A in movie mode yielding a cumulative dose of ~50 e“ / A2; and Processing the collected data,preferably as described in Example 3.

90. The immunoglobulin single variable domain (ISVD) according to anyone of the previous claims, whereinCDR2 (AbM definition) consists of an amino acid sequence X1X2X3X4NX5YX6X7 (SEQ ID NO: 210); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;X2 is selected from any amino acid, preferably X2 is selected from S, T, C, N, Q, such as S;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as T;X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M, K, R, H, T and P, such as G, A, R, T, and K;Xs is selected from any amino acid, preferably Xs is selected from S, T, C, N, Q, such as T;X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as Y;andCDR3 (AbM definition) consists of an amino acid sequence X1X2RISYNVRDDX3FX4X5X6 (SEQ ID NO: 211); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;X2 is selected from any amino acid, preferably X2 is selected from F, Y, S, T, C, N, Q and W, such as F, Q, and S;Xa is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;X5is selected from any amino acid, preferably X5is selected from E and D, such as D;Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as L.

91. The immunoglobulin single variable domain (ISVD) according to any one of claims 78 to 90, whereinCDR2 (Kabat definition) consists of an amino acid sequence XIX2X3X4NX5YX6X7YGEX8X9SXIO(SEQ ID NO: 212); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;X2is selected from any amino acid, preferably X2is selected from S, T, C, N, Q, such as S;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as T;X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as W;X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M, K, R, H, T and P, such as G, A, R, T, and K;Xs is selected from any amino acid, preferably Xs is selected from S, T, C, N, Q, such as T;X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as Y;Xg is selected from any amino acid, preferably Xg is selected from G, A, V, L, I, M, K, R, H, P, S, T, C, N, Q, such as G, K, A and S;Xg is selected from any amino acid, preferably Xg is selected from G, A, V, L, I, M and P, such as V;X10 is selected from any amino acid, preferably Xw is selected from G, A, V, L, I, M and P, such as G;andCDR3 (Kabat definition) consists of an amino acid sequence X1X2RISYNVRDDX3FX4X5X6 (SEQ ID NO: 213); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;X2 is selected from any amino acid, preferably X2 is selected from F, Y, S, T, C, N, Q and W, such as F, Q, and S;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;X5is selected from any amino acid, preferably X5is selected from E and D, such as D;Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as L.

92. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR2 (AbM definition) consists of an amino acid sequence selected from:a) the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;andCDR3 (AbM definition) consists of an amino acid sequence selected from:d) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

93. The ISVD of claim 92, in which the amino acid sequences of the CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.

94. The ISVD of claim 92 or 93, in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 43, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 46, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 44, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45,CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69;or in whichCDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68.

95. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR2 (Kabat definition) consists of an amino acid sequence selected from:a) the amino acid sequence of VSTWNX1YTYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2 is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S and wherein the amino acid residue X5is selected from K and S;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNX1YTYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2 is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSTWNX1YTYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2 is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S;andCDR3 (Kabat definition) consists of an amino acid sequence selected from:d) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from X is F, Q, and S; the amino acid residue X2 is selected from F, Q, and S;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

96. The ISVD of claim 95, in which the amino acid sequences of the CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.

97. The ISVD of claim 95 or 96, in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 242, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 244, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 245, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 246, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 247,CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 248, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 249, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 251, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 252, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67.

98. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (AbM definition) consists of an amino acid sequence selected from:a) the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;andCDR2 (AbM definition) consists of an amino acid sequence selected from:d) the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K;andCDR3 (AbM definition) consists of an amino acid sequence selected from:g) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; andi) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

99. The ISVD of claim 98 in which:CDR1 (AbM definition) consists of the amino acid sequence of GLFLSXYTLA (SEQ ID NO: 209); wherein the amino acid residue X is selected from Y and D;CDR2 (AbM definition) consists of the amino acid sequence of VSTWNXYTY (SEQ ID NO: 207); wherein the amino acid residue X is selected from G, A, R, T, and K; andCDR3 (AbM definition) consists of the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

100. The ISVD of claim 98 or 100, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90%amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.

101. The ISVD of any one of claims 99 to 100, in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 43, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 46, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 44, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 69;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 37, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 42, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 38, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 45, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 68.

102. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (Kabat definition) consists of an amino acid sequence selected from:a) the amino acid sequence of XYTLA (SEQ ID NO: 289); wherein the amino acid residue Xis selected from Y and D;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of XYTLA (SEQ ID NO: 289); wherein the amino acid residue X is selected from Y and D; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of XYTLA (SEQ ID NO: 289); wherein the amino acid residue X is selected from Y and D;andCDR2 (Kabat definition) consists of an amino acid sequence selected from:d) the amino acid sequence of VSTWNX1ITYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S;and wherein the amino acid residue X5is selected from K and S;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VSTWNX1ITYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S; andf) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of VSTWNX1ITYYX2X3X4VX5G (SEQ ID NO: 288); wherein the amino acid residue Xi is selected from G, A, R, T, and K; wherein the amino acid residue X2is selected from G and A; wherein the amino acid residue X3 is selected from E and D; wherein the amino acid residue X4is selected from G, K, A and S; and wherein the amino acid residue X5is selected from K and S;andCDR3 (Kabat definition) consists of an amino acid sequence selected from:g) the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from X is F, Q, and S; wherein the amino acid residue X2is selected from F, Q, and S;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S; andi) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of KXRISYNVRDDSFYDL (SEQ ID NO: 208); wherein the amino acid residue X is selected from F, Q, and S.

103. The ISVD of claim 102, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-33.

104. The ISVD of claim 102 or 103, in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 242, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237,CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237 CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 243, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 244, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 245, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 246, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 247, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 248, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67; or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 249, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 69;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 238, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 250, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 68;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 251, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 237, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 252, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 67.

105. The ISVD of any one of claims 102 to 104, which amino acid sequencei) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 1-33, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded;and in which:ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

106. The ISVD of any one of claim 92 to 105, wherein the ISVD forms an interaction site with the CD19 protein as defined in any one of claims 82-89.

107. The ISVD of any one of the previous claims, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

108. The ISVD of any one of the previous claims, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 1-33 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 1-33.

109. The ISVD of any one of the previous claims, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 1-33.

109. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'8to 1011moles / litre or less, such as more preferably 10'9to IO10moles / litre, even more preferably wherein the ISVD specifically binds to human CD19 with a KDof about IO10moles / litre, as determined by SPR.

110. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human CD19 on B-cells with a EC50 of 10'7to 1011M or less, and preferably 10'8to 1011M or less such as more preferably 10'8to IO10M, even more preferably wherein the ISVD specifically binds to human CD19 with a EC50 of about 3.1 xlO9M, 2.8xl09M, 3.1xl09M, 2.3xlO9M, 4.8xl09M, or 8.7xl0-9M, as determined by FACS assay on PBMCs or DLBCL cells expressing human CD19.

111. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 40-fold difference in affinity (KD).

112. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of IO-7to 1011moles / litre or less, and preferably IO-7to IO10moles / litre or less such as more preferably IO-8to IO-9moles / litre, even more preferably wherein the ISVD specifically binds to cyno CD19 with a KDof about 3.8xl0-9moles / litre moles / litre, as determined by SPR.

113. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human CD19, wherein at least one amino acid residue, located in at least one of the CDRs, is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following amino acids (stretches) of human CD19 when numbered in accordance with SEQ ID NO: 214:C97-W111;Q186; and / orC200-P211.

114. The ISVD of claim 113, wherein the at least one amino acid residue in at least one, preferably in each amino acid stretch of human CD19 is selected from:From stretch C97-W111: C97, P99, A106, W107, Q108, P109 and Will;Q186;From stretch C200-P211: C200, G201, V202, D205, S206, V207, S208, R209, G210, - and P211;when numbered in accordance with SEQ ID NO: 214.

115. The ISVD of claim 113 or claim 114, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or preferably all of the following amino acid residues in stretch C97-W111 of human CD19, when numbered in accordance with SEQ ID NO: 214: C97, P99, A106, W107, Q108, P109 and Will.

116. The ISVD of any one of the preceding claims, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with Q186 of human CD19 when numbered in accordance with SEQ ID NO: 214.

117. The ISVD of any one of the preceding claims, wherein at least one amino acid residue, preferably located in at least one of the CDRs, is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, or preferably all of the following amino acid residues in stretch C200-P211 of human CD19, when numbered in accordance with SEQ ID NO: 214: C200, G201, V202, D205, S206, V207, S208, R209, G210, and P211.

118. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least one amino acid of the CD19 protein selected from Q108, V202, D205 and S206 when numbered in accordance with SEQ ID NO.: 214.

119. The immunoglobulin single variable domain (ISVD) of claim 113, that interacts with at least two amino acids of the CD19 protein selected from Q108, V202, D205 and S206.

120. The ISVD of any one of the preceding claims, wherein at least one amino acid residue is capable of forming hydrogen bonds with at least one, or all of the following amino acid residues of human CD19, when numbered in accordance with SEQ ID NO: 214: Q108, V202, D205 and S206.

121. The ISVD of any one of the preceding claims, wherein:the amino acid residue at position Y98 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with V202 in human CD19; and / orthe amino acid residue at position S31 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with S206 and / or D205 in human CD19, the amino acid residue at position R95 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Q108 in human CD19,when numbered in accordance with SEQ ID NO: 214.

122. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least one amino of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

123. The immunoglobulin single variable domain (ISVD) of any one of the preceding claims, that interacts with at least two amino acids, optionally, at least five amino acids, at least ten amino acids, at least fifteen amino acids of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211, further optionally that interacts with the amino acids of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

124. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with following amino acids of the CD19 protein: Q108, V202, D205 and S206.

125. The immunoglobulin single variable domain (ISVD) of any one of the previous claims, that interacts with the following amino acids of the CD19 protein: P99, P109, Q186, G201, V207, S208, R209, G210 and P211, optionally that interacts with following amino acids of the CD19 protein: C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

126. An immunoglobulin single variable domain (ISVD) specifically binding to human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), and that comprises at least one amino acid residue selected from the group consisting of: S31, Y98 and R95 (Kabat numbering), optionally at least two, further optionally, that comprises the amino acid residues selected from the group consisting of: S31, Y98 and R95 (Kabat numbering), even further optionally that interacts with the CD19 protein as defined in claims 113-118, preferably wherein:Y98 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with V202 in human CD19; and / orS31 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with S206 and / or D205 in human CD19; and / orR95 (Kabat numbering) in the ISVD interacts, preferably by forming a hydrogen bond, with Q108 in human CD19;when numbered in accordance with SEQ. ID NO: 214.

127. The immunoglobulin single variable domain (ISVD) of claim 126, that comprises S31 (Kabat numbering) in CDR1 (Abm definition) and / or that comprises L52a and S53 (Kabat numbering) in CDR2 (Abm definition).

128. The immunoglobulin single variable domain (ISVD) of claim 126 or 127, that comprises R95, P96, V97, Y98 and M99 (Kabat numbering) in CDR3 (Abm definition).

129. The immunoglobulin single variable domain (ISVD) of any one of claims 126 to 128, that comprises S31 (Kabat numbering) in CDR1 (Abm definition), L52a and S53 (Kabat numbering) in CDR2 (Abm definition) and R95, P96, V97, Y98 and M99 (Kabat numbering) in CDR3 (Abm definition).

130. The immunoglobulin single variable domain (ISVD) according to any one of claims 126 to 129, that comprises S31, R95 and Y98 (Kabat numbering), wherein S31, R95 and Y98 form an interaction site with at least one amino acid selected from the group consisting of Q108, V202, D205 and S206 of the CD19 protein.

131. The immunoglobulin single variable domain (ISVD) of claim 130, wherein the interaction site is formed by at least two, at least three, or all amino acids selected from the group consisting of Q108, V202, D205 and S206 of the CD19 protein.

132. The immunoglobulin single variable domain (ISVD) of any one of claims 126 to 131, that comprises S31, R95 and Y98 (Kabat numbering), wherein S31, R95 and Y98 form an interaction site, preferably an hydrogen bond, with Q108, V202, D205 and S206 of the CD19 protein as follows:o S31 (Kabat numbering) interacts with D205 and S206 in CD19; o R95 in (Kabat numbering) interacts with Q108 in CD19; and o Y98 (Kabat numbering) interacts with Y202 in CD19.

133. The immunoglobulin single variable domain (ISVD) of any one of claims 126 to 132, in which F29, S30, S31, L52a, S53, R95, P96, V97, Y98 and M99 (Kabat numbering) form the interaction site with at least one amino acid of the CD19 protein selected from C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

134. The immunoglobulin single variable domain (ISVD) of claim 133, wherein the interaction site is formed by at least two, at least five, at least ten, at least fifteen amino acids of the CD19 protein selected C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

135. The immunoglobulin single variable domain (ISVD) of claim 133 or 134, that comprise F29, S30, S31, L52a, S53, R95, P96, V97, Y98 and M99 (Kabat numbering), in which F29, S30, S31, L52a, S53, R95, P96, V97, Y98 and M99 form the interaction site with following amino acids of the CD19 protein: C97, P99, A106, W107, Q108, P109, Will, Q186, C200, G201, V202, D205, S206, V207, S208, R209, G210 and P211.

136. The ISVD of any one of the preceding claims, wherein two amino acids are considered to interact when the distance between them is 4.0 A or less.

137. The ISVD of any one of the preceding claims, wherein the interacting amino acid residue(s) in the ISVD and in human CD19 are identified by cryo-EM by:Mixing CD19 recombinant protein, the ISVD and an anti-VHH Fab at a molar ratio of 1:2:1 in 20 mM Hepes (pH 7.4), 150 mM NaCI;Diluting the protein complex to 0.5 mg / mL in buffer containing 150 mM NaCI and 20 mM Hepes (pH 7.4);Applying the protein complex to glow-discharged Ultrafoil Rl.2 / 1.3 grids, blotting for 4 seconds under 100% humidity and 4°C, plunge-freezing in liquid-ethane cooled by liquid nitrogen;Collecting cryo-EM data using a cryo-transmission electron microscope, optionally at a pixel size of ~ 0.59 A in movie mode yielding a cumulative dose of ~50 e“ / A2; and Processing the collected data,preferably as described in Example 3.

138. The immunoglobulin single variable domain (ISVD) according to anyone of the previous claims, whereinCDR1 (AbM definition) consists of an amino acid sequence X1X2X3FSSX4X5X6X7 (SEQ. ID NO: 297); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as G;X2 is selected from any amino acid, preferably X2 is selected from F, Y and W, such as F;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, and Q, such as T;X4is selected from any amino acid, preferably X4is selected from F, Y and W, such as Y;X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as A;Xs is selected from any amino acid, preferably Xs is selected from G, A, V, L, I, M and P, such as M;X7is selected from any amino acid, preferably X7is selected from G, A, V, L, I, M and P, such as A;andCDR2 (AbM definition) consists of an amino acid sequence XIX2X3LSX4X5XSX7X8(SEQ ID NO: 298); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as I;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, and Q, such as S;X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as G;X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as G;Xs is selected from any amino acid, preferably Xs is selected from S, T, C, N, and Q, such as S;X7is selected from any amino acid, preferably X7is selected from G, A, V, L, I, M and P, such as V;Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;andCDR3 (AbM definition) consists of an amino acid sequence RPVYMX1X2X3X4X5X6X7X8X9 (SEQ. ID NO: 301); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;X2 is selected from any amino acid, preferably X2 is selected from F, Y and W, such as W;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;X4is selected from any amino acid, preferably X4is selected from E and D, such as E;X5is selected from any amino acid, preferably X5is selected from K, R and H, such as R;Xs is selected from any amino acid, preferably Xs is selected from E and D, such as D;X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as F;Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y.

139. The immunoglobulin single variable domain (ISVD) according to anyone of the previous claims, whereinCDR1 (Kabat definition) consists of an amino acid sequence SX1X2X3X4 (SEQ ID NO: 302); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from F, Y and W, such as Y;X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as A;X3 is selected from any amino acid, preferably X3 is selected from G, A, V, L, I, M and P, such as M;X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as A;andCDR2 (Kabat definition) consists of an amino acid sequence XiX2X3LSX4X5X6X7XgXgXioXiiXi2Xi3Xi4Xi5 (SEQ ID NO: V); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from G, A, V, L, I, M and P, such as V;X2 is selected from any amino acid, preferably X2 is selected from G, A, V, L, I, M and P, such as I;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, and Q, such as S;X4is selected from any amino acid, preferably X4is selected from G, A, V, L, I, M and P, such as G;X5is selected from any amino acid, preferably X5is selected from G, A, V, L, I, M and P, such as G;Xs is selected from any amino acid, preferably Xs is selected from S, T, C, N, and Q, such as S;X7is selected from any amino acid, preferably X7is selected from G, A, V, L, I, M and P, such as V;Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y;X10 is selected from any amino acid, preferably Xw is selected from G, A, V, L, I, M, K, R, H and P, such as A or R;Xn is selected from any amino acid, preferably X12 is selected from E and D, such as D;X12 is selected from any amino acid, preferably X12 is selected from S, T, C, N, and Q, such as S;X13 is selected from any amino acid, preferably X13 is selected from G, A, V, L, I, M and P, such as V;XMis selected from any amino acid, preferably XMis selected from K, R and H, such as K;X15 is selected from any amino acid, preferably X15 is selected from G, A, V, L, I, M and P, such as G;andCDR3 (Kabat definition) consists of an amino acid sequence RPVYMXiX2X3X4X5X6X7XgXg (SEQ. ID NO: 301); wherein the amino acid residue:Xi is selected from any amino acid, preferably Xi is selected from K, R and H, such as K;X2 is selected from any amino acid, preferably X2 is selected from F, Y and W, such as W;X3 is selected from any amino acid, preferably X3 is selected from S, T, C, N, Q, such as S;X4is selected from any amino acid, preferably X4is selected from E and D, such as E;X5is selected from any amino acid, preferably X5is selected from K, R and H, such as R;Xs is selected from any amino acid, preferably Xs is selected from E and D, such as D;X7is selected from any amino acid, preferably X7is selected from F, Y and W, such as F;Xg is selected from any amino acid, preferably Xg is selected from E and D, such as D;Xg is selected from any amino acid, preferably Xg is selected from F, Y and W, such as Y.

140. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (AbM definition) consists of an amino acid sequence selected from:a) the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);andCDR2 (AbM definition) consists of an amino acid sequence selected from:d) the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137);e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137); andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137);andCDR3 (AbM definition) consists of an amino acid sequence selected from:g) the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V; andi) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V.

141. The ISVD of claim 140 in which:CDR1 (AbM definition) consists of the amino acid sequence of GFTFSSYAMA (SEQ ID NO: 136);CDR2 (AbM definition) consists of the amino acid sequence of VISLSGGSVD (SEQ ID NO: 137); andCDR3 (AbM definition) consists of the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V.

142. The ISVD of claims 140 or 141, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 116-134.

143. The ISVD of claims 140 to 142, in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 154;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 152;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 153;or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 136,CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 137,CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 155.

144. An immunoglobulin single variable domain (ISVD) specifically binding human CD19 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (Kabat definition) consists of an amino acid sequence selected from:a) the amino acid sequence of SYAMA (SEQ ID NO: 272);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYAMA (SEQ ID NO: 272); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SYAMA (SEQ ID NO: 272);andCDR2 (Kabat definition) consists of an amino acid sequence selected from:d) the amino acid sequence of VISLSGGSVDYXDSVKG (SEQ ID NO: 300); wherein the amino acid residue X is selected from R and A;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VISLSGGSVDYXDSVKG (SEQ ID NO: 300); wherein the amino acid residue X is selected from R and A; andf) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VISLSGGSVDYXDSVKG (SEQ ID NO: 300); wherein the amino acid residue X is selected from R and A;andCDR3 (Kabat definition) consists of an amino acid sequence selected from:g) the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V; andi) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of RPVYXKWSERDFDY (SEQ ID NO: 299); wherein the amino acid residue X is selected from M, I, L and V.

145. The ISVD of claim 144, in which the amino acid sequences of the CDR1, CDR2 and CDR3 (Kabat definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR1, CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 116-134.

146. The ISVD of claim 144 or 145, in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: il, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 154;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 274, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 154;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 152;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 153;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: Til, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 275, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 155;or in whichCDR1 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: il, CDR2 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 274, CDR3 (Kabat definition) consists of the amino acid sequence of SEQ ID NO: 152.

147. The ISVD of any one of claims 144 to 146, which amino acid sequencei) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 116-134, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which:ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1.

148. The ISVD of any one of claim 144 to 147, wherein the ISVD forms an interaction site with the CD19 protein as defined in any one of claims 130-135.

149. The ISVD of any one of the previous claims, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from heavy chain antibody.

150. The ISVD of any one of the previous claims, which is chosen from the group consisting of SEQ ID NOs: 116-134 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 116-134.

151. The ISVD of any one of the previous claims, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 116-134.

152. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human CD19 with a dissociation constant (KD) of IO-7to 1011moles / litre or less, and preferably IO-8to 1011moles / litre or less, such as more preferably IO-8to IO10moles / litre, even more preferablywherein the ISVD specifically binds to human CD19 with a KDof about 8xl0-9moles / litre, as determined by SPR.

153. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human CD19 on B-cells with a EC50 of 10-7to 10-11M or less, and preferably 10-8to 10-11M or less such as more preferably 10-8to 10-10M, even more preferably wherein the ISVD specifically binds to human CD19 with a EC50 of about 3.4 xlO’9M, 2.4xl0'9M, 4.3xl0'9M, 2.5xl0'9M, 5.8xl09M, or 8.8xl0-9M, as determined by FACS assay on PBMCs or DLBCL cells expressing human CD19.

154. The ISVD of any one of the previous claims, wherein the ISVD specifically binds to human and cyno CD19, optionally wherein the ISVD binds to human CD19 and cyno CD19 with less than 500, less than 400, less than 300, less than 200, less than 100-fold difference in affinity (KD), preferably less than 10-fold difference in affinity (KD), such as 2-fold difference in affinity (KD).

155. The ISVD of any one of the previous claims,, wherein the ISVD specifically binds to cyno CD19 with a dissociation constant (KD) of 10'7to 1011moles / litre or less, and preferably 10'7to IO10moles / litre or less, such as more preferably 5xl0-8to 10'9moles / litre, even more preferably wherein the ISVD specifically binds to cyno CD19 with a KDof about 1.2xl0-8moles / litre, as determined by SPR.

156. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of the previous claims, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

157. The polypeptide or construct of claim 156, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

158. The polypeptide or construct of claim 156, in which said one or more linkers are one or more amino acid sequences.

159. The polypeptide or construct of any claim 156 or 157, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

160. The polypeptide or construct of claim 159, in which said one or more other groups, residues, moieties or binding units are ISVDs.

161. The polypeptide or construct of any one of claims 156 to 160, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

162. The polypeptide or construct of any one of claims 156 to 161, which is a multivalent construct.

163. The polypeptide or construct of any one of claims 156 to 162, which is a multispecific construct.

164. The polypeptide or construct of any one of claims 156 to 163, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on an immune cell.

165. The polypeptide or construct of any one of claims 156 to 164, wherein said group, residue, moiety or binding unit is capable of specifically binding to an antigen on a T-cell or a NK-cell.

166. The polypeptide or construct of claim 165, wherein said polypeptide or constructs directs the T-cell or NK-cell to the target cell, preferably a B-cell, such as a B cell lymphoma cell, expressing CD19.

167. The polypeptide or construct of claim 165 or 166, wherein said polypeptide induces T-cell or NK-cell activation, wherein said T-cell or NK-cell activation depends on presenting said polypeptide bound to CD19 on a target cell, preferably a B-cell, such as a B cell lymphoma cell, to a T-cell or NK-cell.

168. The polypeptide or construct of claim 164 to 167, wherein said antigen is selected from T-cell receptor, CD3, CD16a, NKp46, and NKp30.

169. The polypeptide or construct of any one of claims 156 to 168, in which said one or more other groups, residues, moieties or binding units is an anti-T-cell receptor ISVD, anti-CD3 Fab or anti- CD3 scFv.

170. The polypeptide or construct of any one of claims 156 to 163, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

171. The polypeptide or construct of claim 170, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

172. The polypeptide or construct of claim 170 or 171, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

173. The polypeptide or construct of claim 170 or 171, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

174. The polypeptide or construct of claims 173, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

175. The polypeptide or construct of any one of claims 173 to 174, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

176. The polypeptide or construct of claim 175, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:CDR1 (AbM numbering) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 158;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 158; andc) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 158;andCDR2 (AbM numbering) has an amino acid sequence selected from:d) the amino acid sequence of SEQ ID NO: 160;e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 160; andf) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 160;andCDR3 (AbM numbering) has an amino acid sequence selected from:g) the amino acid sequence of SEQ ID NO: 162;h) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 162; andi) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 162.

177. The polypeptide or construct of claim 176, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 158, CDR2 consists of the amino acid sequence of SEQ ID NO: 160, and CDR3 consists of the amino acid sequence of SEQ ID NO: 162.

178. The polypeptide or construct of any one o claims 175 to 177, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 164), ALB23 (SEQ ID NO: 165), ALBX00001 (SEQ ID NO: 178) and ALB23002 (SEQ ID NO: 156).

179. The polypeptide or construct of any one of claims 156 to 178, wherein said linker is chosen from the group consisting of SEQ ID NOs: 179 to 195.

180. The polypeptide or construct of any of claims 156 to 179, further comprising a C-terminal extension.

181. The polypeptide or construct of claim 180, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

182. A nucleic acid that encodes an ISVD of any one of claims 1 to 155, or a polypeptide of any one of claims 156 to 180.

183. The nucleic acid of claim 182, that is in the form of a genetic construct.

184. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD of any one of claims 1 to 155, or a polypeptide of any one of claims 156 to 180; and / or that comprises the nucleic acid of any one of claims 182 or 183.

185. A method for producing an ISVD of any one of claims 1 to 155, or a polypeptide of any one of claims 156 to 180, at least comprising the steps of:i) expressing, in a suitable (non-human) host or host cell or in another suitable expression system, a nucleic acid of claim 182 or 183;optionally followed by:ii) isolating and / or purifying the ISVD of any one of claims 1 to 155, or the polypeptide of any one of claims 156 to 180.

186. A method for producing an ISVD of any one of claims 1 to 155 or a polypeptide of any one of claims 156 to 180, said method at least comprising the steps of:i) cultivating and / or maintaining a (non-human) host or host cell according to claim 69 under conditions that are such that said (non-human host) or host cell expresses and / or produces at least one ISVD of any one of claims 1 to 155, or at least one polypeptide of any one of claims 156 to 180optionally followed by:ii) isolating and / or purifying the ISVD of any one of claims 1 to 155, or polypeptide of any one of claims 156 to 180.

187. A composition comprising at least one ISVD of any one of claims 1 to 155, at least one polypeptide or construct of any one of claims 156 to 180, or at least one nucleic acid of claims 182 or 183.

188. The composition of claim 187, which is a pharmaceutical composition.

189. The composition of claim 187 or 188, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

190. The ISVD of any one of claims 1 to 155, the polypeptide or construct of any one of claims 156 to 180, or the composition of any one of claims 187 to 189, for use as a medicament.

191. The ISVD of any one of claims 1 to 155, the polypeptide or construct of any one of claims 156 to 180 or the composition of any one of claims 187 to 189, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

192. The ISVD of any one of claims 1 to 155, the polypeptide or construct of any one of claims 156 to 180, or the composition of any one of claims 187 to 189, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with CD19 and / or with cells that express CD19.

193. The ISVD of any one of claims 1 to 155, the polypeptide or construct of any one of claims 156 to 180, or the composition of any one of claims 187 to 189, for use in the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disorder.

194. Use of the ISVD of any one of claims 1 to 155, a polypeptide or construct of any one of claims 156 to 180, or a composition of any one of claims 187 to 189 for the manufacture of a medicament for the treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease.

195. The ISVD, polypeptide or construct, composition for use according to claim 193 or the use according to claim 194, wherein the cancer is a B-cell malignancies, such as diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukaemia (ALL) and / or wherein the autoimmune disorder is systemic lupus erythematosus (SLE).

196. A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD of any one of claims 1 to 155, a polypeptide or construct of any one of claims 156 to 180, or a composition of any one of claims 187 to 189.

197. The method of claim 196, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with CD19 and / or with cells that express CD19, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of claims 1 to 155, a polypeptide or construct of any one of claims 156 to 180, or a composition of any one of claims 187 to 189.

198. The method of claim 196 or 197, for the diagnosis, prevention and / or treatment of a proliferative disease, such as cancer, an immunological disease, an infectious disease or an autoimmune disease, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD of any one of claims 1 to 155, a polypeptide or construct of any one of claims 156 to 180, or a composition of any one of claims 187 to 189.

199. The ISVD of any one of claims 1 to 155, wherein the ISVD blocks the binding to human CD19 by an ISVD having SEQ ID NO: 1, 71, or 116.

200. The ISVD of any one of claims 1 to 155 or 87, wherein the ISVD binds to the same epitope on human CD19 as an ISVD having SEQ ID NO: 1, 71, or 116.

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