Antibodies that bind to FOLR1 and methods of use

Abstract

The invention provides antibodies that bind to FolR1, particularly pH responsive anti-FolR1 antibodies and methods of using the same.

Description

[0001] ANTIBODIES THAT BIND TO FOLR1 AND METHODS OF USE

[0002] TECHNICAL FIELD

[0003] The present invention relates to antibodies that bind to FolRl, particularly pH responsive antibodies that bind to FolRl, pH responsive T cell bispecifics (TCBs) containing the pH responsive antibodies that bind to FolRl and methods of using them, e.g. for preferential binding to folate receptor 1 (FolRl) at acidic pH as compared to neutral pH and / or preferential activation of T cells at acidic pH as compared to neutral pH. In addition, the present invention relates to polynucleotides encoding such antibodies, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the antibodies, and to methods of using them in the treatment of disease.

[0004] BACKGROUND

[0005] FolRl is expressed on epithelial tumor cells of various origins, e.g., ovarian cancer, lung cancer, breast cancer, renal cancer, colorectal cancer and endometrial cancer. Several approaches to target FolRl with therapeutic antibodies, such as farletuzumab, antibody drug conjugates, or adoptive T cell therapy for imaging of tumors have been described (Kandalaft et al., J Transl Med. 2012 Aug 3 ; 10: 157. doi: 10.1186 / 1479-5876-10-157; van Dam et al., Nat Med. 2011 Sep 18;17(10):1315-9. doi: 10.1038 / nm.2472; Cliftonet al., Hum Vaccin. 2011 Feb;7(2): 183-90. Epub 2011 Feb 1; Kelemen et al., Int J Cancer. 2006 Jul 15; 119(2):243-50; Vaitilingam et al., J Nucl Med. 2012 Jul;53(7); Teng et al., 2012 Aug;9(8):901-8. doi:

[0006] 10.1517 / 17425247.2012.694863. Epub 2012 Jun 5). Some attempts have been made to target folate receptor-positive tumors with constructs that target the folate receptor and CD3 (Kranz et al., Proc Natl Acad Sci U S A. Sep 26, 1995; 92(20): 9057-9061; Roy et al., Adv Drug Deliv Rev. 2004 Apr 29;56(8): 1219-31; Huiting Cui et al Biol Chem. Aug 17, 2012; 287(34): 28206- 28214; Larners et al., Int. J. Cancer. 60(4):450 (1995); Thompson et al., MAbs. 2009 Jul- Aug; l(4):348-56. Epub 2009 Jul 19; Mezzanzanca et al., Int. J. Cancer, 41, 609-615 (1988).

[0007] CD3 has been extensively explored as a drug target. Monoclonal antibodies targeting CD3 have been used as immunosuppressant therapies in autoimmune diseases such as type I diabetes, or in the treatment of transplant rejection. The CD3 antibody muromonab-CD3 (OKT3) was the first monoclonal antibody ever approved for clinical use in humans, in 1985. WO20 16 / 079076 describes T cell activating bispecific antigen binding molecules targeting CD3 and FolRl, thus binding CD3 on the one hand and a tumor cell antigen on the other hand. The simultaneous binding of such an antibody to both of its targets will force a temporary interaction between target cell and T cell, causing activation of any cytotoxic T cell and subsequent lysis of the target cell.

[0008] The approaches taken so far with regard to CD3 bispecific antibodies have many disadvantages, such as lack of tumor specificity resulting in on target - off tumor toxicity, limited T cell infiltration in the tumor microenvironment and impact on T cell effector function levels (doi: 10.3390 / cancersl3020287).

[0009] To maximize tumor specificity is a primary goal in cancer therapy. One approach to obtain this is by making use of the acidic tumor cell surface and acidic tumor microenvironment. (Warburg, O., Posener, K., & Negelein, E. (1924) Uber den Stoffwechsel der Carcinomzelle. Naturwissenschaften, 12(50), 1131-1137). (Krahling, H. et al. The glycocalyx maintains a cell surface pH nanoenvironment crucial for integrin-mediated migration of human melanoma cells. 2009; doi.org / 10.1007 / s00424-009-0694-7).

[0010] Given the tremendous therapeutic potential of pH responsive antibodies, particularly bispecific antibodies for the activation of T cells, there is a need for pH responsive FolRl and pH responsive bispecific CD3 / FolRl antibodies.

[0011] In addition, pH responsive antibodies are also a valuable tool for imaging purposes and the measuring of acidification. Rohani et al used a labeled pH-responsive peptide to mark acidic regions within tumors (doi: 10.1158 / 0008-5472. CAN-18-1604). Methods like PET, MRI or optical methods have been tried to get an accurate impression of the extracellular pH (pHe). Reviewed by Zhang and colleagues (Zhang 2010; doi: 10.2967 / jnumed.109.068981).

[0012] Reshetnyak et al. combined the pH-sensitive folding and transmembrane insertion of pH (low) insertion peptide (pHLIP) with a pH sensitive dye to measure the local pH on the surface of a tumor cell. They conclude that the pH at the surfaces of highly metastatic cells within tumors has been measured to be about 6.1-6.4, compared to 6.7-6.9 in nonmetastatic tumors (doi / 10.1073 / pnas.1608247113).

[0013] Several approaches have been tried to harness the acidic tumor microenvironment for therapeutic applications. Sulea and coworkers applied a method of dual-pH histidine-scanning mutagenesis for pH selectivity optimization (Sulea et al. doi.org / 10.1080 / 19420862.2019.1682866). Binding selectivity toward acidic pH was improved by as much as 25 fold relative to a parental anti- Her2 antibody, albeit with an overall lowered affinity. Indeed, pH engineering of antibodies generally results in affinity loss. To retain initial affinity or obtain higher affinity binders at the desired acidic pH conditions, while decreasing binding at neutral pH levels is therefore a tremendous engineering effort and challenge.

[0014] SUMMARY

[0015] The invention provides antibodies that bind to FolRl, including multispecific (e.g. bispecific) antibodies, and methods of using the same. The antibodies according to the invention bind to FolRl in a pH dependent manner. The (multispecific) antibodies provided can thus increase tumor specificity.

[0016] In one aspect, the invention provides an antibody that binds to FolRl, wherein the antibody binds to FolRl at neutral pH with a first KD and at an acidic pH with a second KD, wherein the first KD is greater than the second KD and the first KD and the second KD are measured by surface plasmon resonance (SPR) at 25 °C.

[0017] In a certain aspect, the acidic pH ranges from 6.0 to 6.6 and the neutral pH ranges from 7.0 to 7.4, particularly the acidic pH is 6.5 or 6.1 and the neutral pH is 7.0 or 7.4 more particularly the acidic pH is 6.5 and the neutral pH is 7.4.

[0018] In a certain aspect, the first KD is greater than the second KD by a factor of at least 2, at least 5, at least 8, at least 10, at least 11, at least 13, at least 16, at least 23, at least 31, at least 40, at least 60, at least 74 or at least 195 or more.

[0019] In a certain aspect, the first KD is greater than the second KD by a factor of at least 2, at least 5, at least 8, at least 10, at least 11, at least 13, at least 16, at least 23, at least 31, at least 40, at least 60, at least 74 or at least 195 or more and the second KD is equal to 47nM or less at pH 6.5 and the first KD is equal to 46 nM or more at pH 7.4.

[0020] In a certain aspect, the first KD is greater than the second KD by a factor ranging from 2 to 195 particularly from 5 to 195.

[0021] In a certain aspect, the antibody is a monoclonal antibody. In a certain aspect, the antibody is a human antibody.

[0022] In a certain aspect, the antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of X2YYX3H SEQ ID NO:88, (b) CDR-H2 comprising the amino acid sequence of X4INPX5X6GX7TX8YAQKFQG (SEQ ID NO:89), and (c) CDR-H3 comprising the amino acid sequence of GDX9X10X11LDY (SEQ ID NO:90), and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of RSSQSLLHX12NGYX13YLD (SEQ ID NO:86), (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of MQALQGX14X15X16T (SEQ ID NO:87), wherein X2 is S, T or E, X3 is M or I, X4 is I or V, X5 is S or R, X6 is D or G, X7 is R, S, or N, X8 is S, R, N or T, X9 is F or Y, X10 is D or E, XI 1 is A, G or S, X12 is A or S, X13 N or H, X14 is P or L, X15 is Y or A and XI 6 is N or D, optionally wherein when XI 5 is Y XI 6 is N and when XI 5 is A XI 6 is D.

[0023] In a certain aspect, the antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 44, 49, 54, and 58, (b) CDR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 45, 50, 55, 59, 62, and 66, and (c) CDR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 46, 51, 60, 63, 78, 81, and 84, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 36, and 40, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR- L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 37, and 41.

[0024] In a certain aspect, the antibody comprises

[0025] A) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25; B) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0026] C) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0027] D) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:78, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0028] E) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0029] G) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:50, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:51, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0030] H) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0031] I) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:54, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:55, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0032] J) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of (SEQ ID NO: 19), (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:62, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:63, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0033] K) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:66, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25; L) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0034] M) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:81, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37; or

[0035] N) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:84, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37.

[0036] In one aspect, the invention provides an antibody that binds to FolRl, wherein the antibody comprises

[0037] A) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25; B) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0038] C) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0039] D) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:78, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0040] E) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0041] G) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:50, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:51, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0042] H) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0043] I) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:54, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:55, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0044] J) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of (SEQ ID NO: 19), (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:62, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:63, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;

[0045] K) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:66, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25; L) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;

[0046] M) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:81, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37; or

[0047] N) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:84, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37.

[0048] In a certain aspect, the antibody further comprising a light chain variable domain framework FR1 sequence of SEQ ID NO:91, FR2 sequence of SEQ ID NO:92, FR3 sequence of SEQ ID NO:93, FR4 sequence of SEQ ID NO:94, and / or a heavy chain variable domain framework FR1 sequence of SEQ ID NO:95 or SEQ ID NO:96, FR2 sequence of SEQ ID NO:97, FR3 sequence of SEQ ID NO:98, and FR4 sequence of SEQ ID NO:99.

[0049] In a certain aspect, the antibody comprises a VH comprising an amino acid sequence of QVQLVQSGAEVKKPGASVKVSCKASGYTFX17X2YYX3HWVRQAPGQGLEWMGX4I NPX5X6GX7TX8YAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGDX9X1 0X11LDYWGQGTLVTVSS (SEQ ID NO: 107), and / or a VL comprising an amino acid sequence of

[0050] DIVMTQSPLSLPVTPGEPASISCRSSQSLLHX12NGYX13YLDWYLQKPGQSPQLLIYL GSNRASGVPDRF SGSGSGTDFTLKISRVEAED VGVYYCMQ ALQGX 14X 15X16TFGQG TKVEIK (SEQ ID NO: 108), wherein X2 is S, T or E, X3 is M or I, X4 is I or V, X5 is S or R, X6 is D or G, X7 is R, S, or N, X8 is S, R, N or T, X9 is F or Y, X10 is D or E, XI 1 is A, G or S, X12 is A or S, X13 N or H, X14 is P or L, X15 is Y or A, X16 is N or D and X17 is T or S, optionally wherein when XI 5 is Y XI 6 is N and when XI 5 is A XI 6 is D.

[0051] In a certain aspect, the antibody comprises

[0052] A) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

[0053] B) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

[0054] C) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 60, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

[0055] D) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 79, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;

[0056] E) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38; G) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 52, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

[0057] H) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;

[0058] I) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 56, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

[0059] J) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 64, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

[0060] K) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 67, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;

[0061] L) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 76, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38; M) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 82, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38; or

[0062] N) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 85, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38.

[0063] In a certain aspect, the antibody comprises

[0064] A) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0065] B) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0066] C) a VH comprising an amino acid sequence of SEQ ID NO: 60, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0067] D) a VH comprising an amino acid sequence of SEQ ID NO: 79, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;

[0068] E) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;

[0069] G) a VH comprising an amino acid sequence of SEQ ID NO: 52, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0070] H) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;

[0071] I) a VH comprising an amino acid sequence of SEQ ID NO: 56, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26; J) a VH comprising an amino acid sequence of SEQ ID NO: 64, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0072] K) a VH comprising an amino acid sequence of SEQ ID NO: 67, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0073] L) a VH comprising an amino acid sequence of SEQ ID NO: 76, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;

[0074] M) a VH comprising an amino acid sequence of SEQ ID NO: 82, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38; or

[0075] N) a VH comprising an amino acid sequence of SEQ ID NO: 85, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38.

[0076] In one aspect, the invention provides an antibody that binds to FolRl, wherein the antibody comprises

[0077] A) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0078] B) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0079] C) a VH comprising an amino acid sequence of SEQ ID NO: 60, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0080] D) a VH comprising an amino acid sequence of SEQ ID NO: 79, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;

[0081] E) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;

[0082] G) a VH comprising an amino acid sequence of SEQ ID NO: 52, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0083] H) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38; I) a VH comprising an amino acid sequence of SEQ ID NO: 56, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0084] J) a VH comprising an amino acid sequence of SEQ ID NO: 64, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0085] K) a VH comprising an amino acid sequence of SEQ ID NO: 67, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;

[0086] L) a VH comprising an amino acid sequence of SEQ ID NO: 76, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;

[0087] M) a VH comprising an amino acid sequence of SEQ ID NO: 82, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38; or

[0088] N) a VH comprising an amino acid sequence of SEQ ID NO: 85, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38.

[0089] In a certain aspect, the antibody is an antibody fragment that binds FolRl.

[0090] In a certain aspect, the antibody fragment is a Fab molecule.

[0091] In a certain aspect, the antibody is a full length IgGi antibody.

[0092] In a certain aspect, the antibody comprises an Fc domain composed of a first and a second subunit.

[0093] In a certain aspect, the antibody comprises an Fc domain composed of a first and a second subunit, wherein the Fc domain is a human IgGi Fc domain.

[0094] In a certain aspect, the antibody is multispecific.

[0095] In a certain aspect, the antibody is a bispecific antibody comprising at least one domain that binds to CD3 and at least one domain that binds to FolRl.

[0096] In a certain aspect, the domain that binds to CD3 is a Fab molecule wherein the variable domains VL and VH or the constant domains CL and CHI, particularly the variable domains VL and VH, of the Fab light chain and the Fab heavy chain are replaced by each other. In a certain aspect, the domain that binds to FolRl is a Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0097] In a certain aspect, the Fab molecule is a conventional Fab molecule.

[0098] In a certain aspect, the domain that binds to CD3 and the domain that binds to FolRl are fused to each other, optionally via a peptide linker.

[0099] In a certain aspect, the antibody comprises a domain that binds to CD3 and a domain that binds to FolRl, wherein the domain that binds to CD3 and the domain that binds to FolRl are each a Fab molecule and either (i) the domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3, or (ii) the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N- terminus of the Fab heavy chain of the domain that binds to FolRl.

[0100] In a certain aspect, the antibody comprises a domain that binds to CD3 and a first domain that binds to FolRl, optionally a second domain that binds to FolRl, wherein the domain that binds to CD3 and the domain that binds to FolRl are each a Fab molecule and the antibody comprises an Fc domain composed of a first and a second subunit; and wherein either (i) the first domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3 and the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, or (ii) the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N- terminus of the Fab heavy chain of the first domain that binds to FolRl and the first domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain; and the second domain that binds to FolRl, where present, is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain. In a certain aspect, the Fc domain is an IgG Fc domain, particularly an IgGi Fc domain, more particularly a human IgGl Fc domain.

[0101] In a certain aspect, the Fc domain is a human Fc domain.

[0102] In a certain aspect, the Fc comprises a modification promoting the association of the first and the second subunit of the Fc domain.

[0103] In a certain aspect, the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor and / or effector function.

[0104] In a certain aspect, the antibody comprises an Fc region derived from a human IgGi Fc region and comprising the substitutions L234A, L235A and P329G (LALA-PG).

[0105] In one aspect, the invention provides an immunoconjugate comprising the antibody and a cytotoxic agent.

[0106] In one aspect, the invention provides an isolated nucleic acid encoding the antibody.

[0107] In one aspect, the invention provides a host cell comprising the nucleic acid.

[0108] In one aspect, the invention provides a method of producing an antibody that binds to FolRl comprising culturing the host cell of under conditions suitable for the expression of the antibody.

[0109] In a certain aspect, the method, further comprises recovering the antibody from the host cell.

[0110] In one aspect the invention provides an antibody produced by the method according to the invention.

[0111] In one aspect, the invention provides a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier.

[0112] In a certain aspect, the antibody or the pharmaceutical composition are for use as a medicament.

[0113] In a certain aspect, the antibody or the pharmaceutical composition are for use in treating cancer.

[0114] Also provided is the use of an antibody or pharmaceutical composition according to the invention in the manufacture of a medicament for treatment of cancer. Also provided is the use of the antibody or the pharmaceutical composition according to the invention in the manufacture of a medicament for pH dependent T-cell redirection and pH dependent T-cell mediated cancer cell killing.

[0115] The invention also provides a method of treating an individual having cancer comprising administering to the individual an effective amount of the antibody or the pharmaceutical composition according to the invention.

[0116] The invention also provides a method of pH dependent T-cell redirection and T-cell mediated cancer cell killing in an individual comprising administering to the individual an effective amount of the antibody or pharmaceutical composition according to the invention to redirect T cells and mediate T-cells to kill cancer cells in a pH dependent manner.

[0117] BRIEF DESCRIPTION OF THE FIGURES

[0118] Figure 1 A-E relates to the cell surface binding to human FolRl endogenously expressed on HeLa cells of pH engineered antibodies that bind to FolRl as bivalent IgGs. As shown, all the tested clones led to dose dependent binding to the human FolRl, pH engineered clones (P1AF7023, P1AF7206, P1AF7015, P1AF7016) (FIG 1 B-E) showed higher binding at acidic pH 6.5 as compared to neutral pH of 7.4. FIG 1 (A) represents the previously described FolRl binder 16D5 (Pl AD2897) (see W02016079076A1 incorporated herein by reference) that was used as a non-pH responsive control IgG. The FolRl binder 16D5 is also referred to as FolRl ID FV000670 throughout this application. Depicted are technical average values from duplicates; error bars indicate standard deviation (SD).

[0119] Figure 2 A-H relates to the cell surface binding to human FolRl endogenously expressed on T47D cells of selected pH engineered variants of P018.394 (P1AF7016) tested as bivalent IgGs. As shown, all the tested clones led to dose dependent binding to human FolRl. pH responsive parental clone P018.394 (P1AF7016) (Fig 2 B) and its pH engineered derivatives (P1AI2373, P1AH5969, P1AI2378, P1AI2380, P1AI2381, P1AH5980) (fig 2 C-H) showed higher binding at acidic pH 6.5 as compared to neutral pH of 7.4. All of the derivative clones showed further reduction in binding at pH 7.4 as compared to the parental clone P018.394 (P1AF7016) (Fig 2 B). A previously described FolRl binder 16D5 (P1AD2897) was used as a non-pH responsive control IgG (Fig 2 A). Depicted are average values from technical duplicates; error bars indicate SD. Figure 3 A-H relates to activation of anti-P329G Chimeric Antigen Receptor Jurkat (a-P329G CAR-J) reporter cells with human FolRl expressing Hela cells used as target cells, with different concentrations of non-pH responsive (Pl AD2897, 16D5) (FIG 3 A) and pH responsive (FIG 3 B-H) human IgGi antibodies that bind to FolRl with P329G mutation in the Fc portion (P329G IgG) (P1AI2378, P1AI2373, P1AH5861, P1AF7016, P1AH5980, P1AH5969, P1AH5963). pH engineered clones show higher activation at acidic pH of 6.5 as compared to activation at neutral pH 7.4. Results show relative luminescence emitted by reporter cells 6 hours after treatment with antibodies that bind to FolRl in assay media set to pH 6.5 and 7.4. Depicted are average values of technical duplicates; error bars indicate SD.

[0120] Figure 4 A-D schematic illustration of T cell bispecifics (TCBs) formats used in the experiments: All tested TCB antibody molecules were produced as (A) “2+1 IgG CrossFab, inverted”, (B) “2+1 IgG CrossFab, classical”, (C) “1+1 head to tail (HtoT) CrossFab, inverted” or (D) “1+1 head to tail (HtoT) CrossFab, classical” formats with VH (black, lined) / VL (gray, lined) exchange in CD3 binder and charge modifications in target human FolRl binder CHI XC- (dark gray) / Cl XC+ (light gray), where XC- = 147E, 213E; XC+ = 123R, 124K EE. A-D Components for the assembly of the TCBs: heavy chain variable domain (black) and light chain variable domain (white) of anti-human FolRl Fab molecule with charge modifications in CHI XC- (dark gray) and CL XC+ (light gray), heavy chain (VH) variable domain (black, lined) and light chain (VL) variable domain (gray, lined) of anti-human CD3 crossover Fab molecule with inverted CHI XMab (black, dotted) and CL XMab (gray, dotted), heavy chain with knob and PG LALA mutations in Fc region (dark gray, black outline) and heavy chain with hole and PG LALA mutations in Fc region (light gray, black outline).

[0121] Figure 5 A-F relates to the cell surface binding to human FolRl endogenously expressed on T47D cells of selected pH engineered variants of P018.394 tested as 2+1 TCB (monovalent anti -human CD3 and pH responsive bivalent anti -human FolRl). As shown, all the tested clones show dose dependent binding to the FolRl. pH engineered clones (P1AI5834, P1AI2991, P1AI2992, P1AI2993, P1AI2994) (FIG 5 B-F) showed higher binding at acidic pH 6.5 as compared to neutral pH of 7.4. The previously described FolRl binder 16D5 was used as a nonpH responsive control 2+1 TCB (Pl AD4200) (FIG 5 A). Depicted are technical average values from duplicates; error bars indicate SD. Figure 6 A-F relates to the cell surface binding to human FolRl endogenously expressed on T47D cells of selected pH engineered variants of P018.394 tested as 1+1 TCB (monovalent anti-human CD3 and pH dependent monovalent anti-human FolRl). As shown, all the tested clones show dose dependent binding to FolRl. pH engineered clones (P1AI3010, P1AI3011, P1AI3008, P1AI3012, P1AI5836) (FIG 6 B-F) showed higher binding at acidic pH 6.5 as compared to neutral pH of 7.4. The previously described FolRl binder 16D5 was used as a nonpH responsive control in the 1+1 format (Pl AI3009) (FIG 6 A). Depicted are technical average values from duplicates; error bars indicate SD.

[0122] Figure 7 A-G relates to Jurkat NF AT reporter cell activation after 6h of incubation, as determined by luminescence. The latter is induced upon simultaneous binding of the 2+1 TCBs that bind to FolRl to FolRl expressing tumor cells T47D and to the CD3 expressing Jurkat NF AT reporter cells. As shown, tested constructs show dose dependent increase in signal and pH responsive TCBs that bind to FolRl (P1AG7578, P1AI2993, P1AI2991, P1AI2992, P1AI5834, P1AA0917) (FIG 7 B-F) led to higher activation at acidic pH 6.5 as compared to neutral pH 7.4. Control TCB with non pH responsive CD3 and FolRl binder showed equivalent activation at acidic and neutral pH (Pl AF2092) (FIG 7 A) and TCB with a non binding target DP47 (P1AA0917) showed minimal / no activation (FIG 7G). Depicted are technical average values from duplicates; error bars indicate SD.

[0123] Figure 8 A-G relates to Jurkat NF AT reporter cell activation after 6h of incubation, as determined by luminescence. The latter is induced upon simultaneous binding of the 1+1 TCBs that bind to FolRl to FolRl expressing tumor cells T47D and to the CD3 expressing Jurkat NF AT reporter cells. As shown, tested constructs show dose dependent increase in signal and pH responsive TCBs that bind to FolRl (P1AI3008, P1AI3010, P1AI3011, P1AI5836, P1AI3012, P1AA0917) (FIG 8 B-G) led to higher activation at acidic pH 6.5 as compared to neutral pH 7.4. Control TCB with non pH responsive CD3 and FolRl binder showed equivalent activation at acidic and neutral pH (P1AI3009) (FIG 8 A) and a 2+1 TCB (P1AA0917) with the non binding target DP47 showed minimal / no activation (FIG 8G). Depicted are average values from technical duplicates; error bars indicate SD.

[0124] Figure 9 A-F relates to tumor cell killing induced by pH responsive 2+1 TCBs that bind to FolRl in FolRl and Red Fluorescent Protein (RFP) reporter expressing T47D cells. As shown, pH responsive TCBs that bind to FolRl P1AG7578, P1AI2991, P1AI2992, P1AI2993, P1AI5834 (FIG 9 B-F) led to higher tumor killing at acidic pH 6.5 as compared to neutral pH 7.4. Shown are average of technical replicates n=3, error bars indicate standard error of mean SEM.

[0125] Figure 10 A-D relates to tumor cell killing induced by pH responsive 1+1 TCBs that bind to FolRl in FolRl and RFP reporter expressing T47D cells. As shown, pH responsive TCBs that bind to FolRl P1AI3008, P1AI5836, P1AI3011 (FIG 10 B-D) led to higher tumor killing at acidic pH 6.5 as compared to neutral pH 7.4. Shown are average of technical replicates n=3, error bars indicate standard error of mean SEM.

[0126] Figure 11 relates to tumor growth inhibition curves of breast Patient Derived Xenograft (PDX) BC004 model in humanized mice with the P018.394 1+1 TCB that binds to FolRl Pl AG7640 (0.38 mg / kg), 2+1 TCB that binds to P1AG7578 (0.5 mg / kg) or vehicle, n=10. Each point represents the mean tumor volume + / - SD. Vertical lines represent therapy administration.

[0127] Figure 12 relates to tumor growth inhibition curves of the breast patient derived xenograft BC004 model in humanized mice with) with 2+1 TCB that binds to FolRl P1AI2991 (1.5 mg / kg), orvehicle, (n=13). Each point represents the mean tumor volume + / - SD. Vertical lines represent therapy administration.

[0128] Figure 13 Normalized affinity to FolRl upon protein stress. All clones P1AF7016, P1AH5969, Pl AH5963, Pl AI2378 retained at least 87% of their binding level as compared to the untreated samples with the exception of Pl AH5980, which only retained 65% of binding when incubated at 40°C and pH 6.0.

[0129] Figure 14 A-C relates to the cell surface binding to human FolRl endogenously expressed on T47D cells of selected DG aspartate deamidation mitigation mutants variants of P1AH5980 tested as IgG. As shown, the two tested clones P1AK2574 and P1AK2576 (FIG 14 B and C) showed higher binding at acidic pH 6.5 as compared to neutral pH of 7.4. The construct Pl AD2897 with the previously described FolRl binder 16D5 was used as a non-pH responsive control IgG (FIG 14 A). Depicted are technical average values from duplicates; error bars indicate SD. Figure 15 A-Z Exemplary configurations of the (multispecific) antibodies of the invention. (A, D) Illustration of the “1+1 CrossMab” molecule. (B, E) Illustration of the “2+1 IgG Crossfab” molecule with alternative order of Crossfab and Fab components (“inverted”). (C, F) Illustration of the “2+1 IgG Crossfab” molecule. (G, K) Illustration of the “1+1 IgG Crossfab” molecule with alternative order of Crossfab and Fab components (“inverted”). (H, L) Illustration of the “1+1 IgG Crossfab” molecule. (I, M) Illustration of the “2+1 IgG Crossfab” molecule with two CrossFabs. (J, N) Illustration of the “2+1 IgG Crossfab” molecule with two CrossFabs and alternative order of Crossfab and Fab components (“inverted”). (O, S) Illustration of the “Fab -Crossfab” molecule. (P, T) Illustration of the “Crossfab-Fab” molecule. (Q, U) Illustration of the “(Fab)2-Crossfab” molecule. (R, V) Illustration of the “Crossfab- (Fab)?” molecule. (W, Y) Illustration of the “Fab-(Crossfab)2” molecule. (X, Z) Illustration of the “(Crossfab)2-Fab” molecule. Black dot: optional modification in the Fc domain promoting heterodimerization. ++, — : amino acids of opposite charges optionally introduced in the CHI and CL domains. Crossfab molecules are depicted as comprising an exchange of VH and VL regions, but may - in aspects wherein no charge modifications are introduced in CHI and CL domains - alternatively comprise an exchange of the CHI and CL domains.

[0130] Figure 16 A-G Schematic illustration of 2+1 TCB inverted (A) or classical formats (B) with their respective chains (C-G). (A) “2+1 IgG CrossFab, inverted” and (B) “2+1 IgG CrossFab, classical” used with VH (black, lined) / VL (gray, lined) exchange (Xmab) and charge modifications in CHI XC- (dark gray) / Cl XC+ (light gray), where XC- = 147E, 213E; XC+ = 123R, 124K EE. (C-G) Components for the assembly of the TCBs: heavy chain variable domain (black) and light chain variable domain (white) of anti-human FolRl Fab molecule with charge modifications in CHI XC- (dark gray) and CL XC+ (light gray), heavy chain (VH) variable domain (black, lined) and light chain (VL) variable domain (gray, lined) of anti-human CD3 crossover Fab molecule with inverted CHI XMab (black, dotted) and CL XMab (gray, dotted), heavy chain with knob and PG LALA mutations in Fc region (dark gray, black outline) and heavy chain with hole and PG LALA mutations in Fc region (light gray, black outline). (C) Chain A. (D) Chain B. (E) Chain H. (F) Chain K inverted. (G) Chain K classical.

[0131] Figure 17 A-G Schematic illustration of 1+1 TCB inverted (A) or classical formats (B) with their respective chains (C-G)

[0132] (A) “1+1 head to tail (HtoT) CrossFab, inverted” or (B) “1+1 head to tail (HtoT) CrossFab, classical” formats used with VH (black, lined) / VL (gray, lined) exchange (Xmab) and charge modifications in CHI XC- (dark gray) / Cl XC+ (light gray), where XC- = 147E, 213E; XC+ = 123R, 124K EE. (C-G) Components for the assembly of the TCBs: heavy chain variable domain (black) and light chain variable domain (white) of anti-human FolRl Fab molecule with charge modifications in CHI XC- (dark gray) and CL XC+ (light gray), heavy chain (VH) variable domain (black, lined) and light chain (VL) variable domain (gray, lined) of anti-human CD3 crossover Fab molecule with inverted CHI XMab (black, dotted) and CL XMab (gray, dotted), heavy chain with knob and PG LALA mutations in Fc region (dark gray, black outline) and heavy chain with hole and PG LALA mutations in Fc region (light gray, black outline). (C) Chain A. (D) Chain B. (E) Chain H. (F) Chain K inverted. (G) Chain K classical.

[0133] DETAILED DESCRIPTION

[0134] I. DEFINITIONS

[0135] Terms are used herein as generally used in the art, unless otherwise defined in the following.

[0136] Use of the terms “first” or “second” is not intended to confer a specific order or orientation of the moiety unless explicitly so stated.

[0137] The terms “anti-CD3 antibody” and “an antibody that binds to CD3” refer to an antibody that is capable of binding CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD3. In one aspect, the extent of binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than 10% of the binding of the antibody to CD3 as measured, e.g., by surface plasmon resonance (SPR) at 25°C. In certain aspects, an antibody that binds to CD3 has a dissociation constant (KD) of < 1 pM, < 500 nM, < 200 nM, or < 100 nM. An antibody is said to “specifically bind” to CD3 when the antibody has a KD of 1 pM or less, as measured, e.g., by SPR at 25°C. In certain aspects, an anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0138] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary methods for measuring binding affinity are described in the following.

[0139] An “affinity matured” antibody refers to an antibody with one or more alterations in one or more complementary determining regions (CDRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.

[0140] “Reduced binding”, for example reduced binding to an Fc receptor, refers to a decrease in affinity for the respective interaction, as measured for example by SPR. For clarity, the term also includes reduction of the affinity to zero (or below the detection limit of the analytic method), i.e. complete abolishment of the interaction. Conversely, “increased binding” refers to an increase in binding affinity (lower absolute value for KD measurement) for the respective interaction.

[0141] The terms “anti-FolRl antibody” and “an antibody that binds to FolRl” refer to an antibody that is capable of binding FolRl with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting FolRl. The terms “anti -FolRl antibody” and “an antibody that binds to FolRl” include pH responsive antibodies. The term “pH responsive antibody” as used in the current application refers to an antibody with preferential binding at acidic pH as compared to neutral pH. “Acidic pH” refers to a pH lower than 7.0 particularly to a pH ranging from 6.0 to 6.6 and more particularly the acidic pH refers to pH 6.1 and / or pH 6.5. “Neutral pH” refers to a pH ranging from 7.0 to 7.4, particularly to pH 7.4. An antibody is said to “preferentially bind” to FolRl at acidic pH as compared to neutral pH or have “preferential binding” at acidic pH as compared to neutral pH, when the antibody binds to FolRl at neutral pH 7.4 with a first KD and at acidic pH 6.5 with a second KD, wherein the first KD is greater than the second KD as measured by SPR at 25°C. In certain aspects the first KD at pH 7.4 is greater than the second KD at pH 6.5 by a factor of at least 2 as measured by SPR at 25°C. In a further aspect, the first KD at pH 7.4 is greater than the second KD at pH 6.5 by a factor of at least 2, at least 5, at least 8, at least 10, at least 11, at least 13, at least 16, at least 23, at least 31, at least 40, at least 60, at least 74 or at least 195 or more as measured by SPR at 25°C, particularly wherein the second KD is equal to 47nM or less at pH 6.5 and the first KD is equal to 46 nM or more at pH 7.4 as measured by SPR at 25°C. In one aspect, the extent of binding of an antibody that binds to FolRl to an unrelated, non-FolRl protein is less than about 10% of the binding of the antibody to FolRl as measured, e.g., by surface plasmon resonance (SPR) at 25°C. An antibody is said to “specifically bind” to FolRl when the antibody has a KD of IpM or less at pH 6.5 as measured by SPR at 25°C. In certain aspects, an antibody that binds to FolRl binds to an epitope of FolRl that is conserved among FolRl from different species.

[0142] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired antigen-binding activity.

[0143] An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, and scFab); single domain antibodies (dAbs); and multispecific antibodies formed from antibody fragments. For a review of certain antibody fragments, see Holliger and Hudson, Nature Biotechnology 23: 1126-1136 (2005).

[0144] The term “chimeric” antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0145] The term “immunoglobulin molecule” herein refers to a protein having the structure of a naturally occurring antibody. For example, immunoglobulins of the IgG class are heterotetrameric glycoproteins of about 150,000 daltons, composed of two light chains and two heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable domain (VH), also called a variable heavy domain or a heavy chain variable region, followed by three constant domains (CHI, CH2, and CH3), also called a heavy chain constant region. Similarly, from N- to C-terminus, each light chain has a variable domain (VL), also called a variable light domain or a light chain variable region, followed by a constant light (CL) domain, also called a light chain constant region. The heavy chain of an immunoglobulin may be assigned to one of five types, called a (IgA), 5 (IgD), a (IgE), y (IgG), or p (IgM), some of which may be further divided into subtypes, e.g. yi (IgGi), 72 (IgG2), 73 (IgGs), 74 (IgG4), ai (IgAi) and 012 (IgA2). The light chain of an immunoglobulin may be assigned to one of two types, called kappa (K) and lambda (X), based on the amino acid sequence of its constant domain. An immunoglobulin essentially consists of two Fab molecules and an Fc domain, linked via the immunoglobulin hinge region.

[0146] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, IgG?, IgG?, IgG4, IgAi, and IgA?. In certain aspects, the antibody is of the IgGi isotype. In certain aspects, the antibody is of the IgGi isotype with the P329G, L234A and L235A mutation to reduce Fc- region effector function. In other aspects, the antibody is of the IgG? isotype. In certain aspects, the antibody is of the IgG4isotype with the S228P mutation in the hinge region to improve stability of IgG4antibody. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, a, y, and p, respectively. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (X), based on the amino acid sequence of its constant domain.

[0147] A “Fab molecule” refers to a protein consisting of the VH and CHI domain of the heavy chain (the “Fab heavy chain”) and the VL and CL domain of the light chain (the “Fab light chain”) of an immunoglobulin.

[0148] By a “crossover” Fab molecule (also termed “Crossfab”) is meant a Fab molecule wherein the variable domains or the constant domains of the Fab heavy and light chain are exchanged (i.e. replaced by each other), i.e. the crossover Fab molecule comprises a peptide chain composed of the light chain variable domain VL and the heavy chain constant domain 1 CHI (VL-CH1, inN- to C-terminal direction), and a peptide chain composed of the heavy chain variable domain VH and the light chain constant domain CL (VH-CL, in N- to C-terminal direction). For clarity, in a crossover Fab molecule wherein the variable domains of the Fab light chain and the Fab heavy chain are exchanged, the peptide chain comprising the heavy chain constant domain 1 CHI is referred to herein as the “heavy chain” of the (crossover) Fab molecule. Conversely, in a crossover Fab molecule wherein the constant domains of the Fab light chain and the Fab heavy chain are exchanged, the peptide chain comprising the heavy chain variable domain VH is referred to herein as the “heavy chain” of the (crossover) Fab molecule.

[0149] In contrast thereto, by a “conventional” Fab molecule is meant a Fab molecule in its natural format, i.e. comprising a heavy chain composed of the heavy chain variable and constant domains (VH-CH1, in N- to C-terminal direction), and a light chain composed of the light chain variable and constant domains (VL-CL, in N- to C-terminal direction). The term “Fc domain” or “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl -terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C- terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbering according to Kabat EU index). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including an Fc region (or a subunit of an Fc domain as defined herein) are denoted herein without C-terminal glycine-lysine dipeptide if not indicated otherwise. In one aspect, a heavy chain including an Fc region (subunit) as specified herein, comprised in an antibody according to the invention, comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447, numbering according to Kabat EU index). In one aspect, a heavy chain including an Fc region (subunit) as specified herein, comprised in an antibody according to the invention, comprises an additional C-terminal glycine residue (G446, numbering according to Kabat EU index). Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 (see also above). A “subunit” of an Fc domain as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e. a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self-association. For example, a subunit of an IgG Fc domain comprises an IgG CH2 and an IgG CH3 constant domain.

[0150] By “fused” is meant that the components (e.g. a Fab molecule and an Fc domain subunit) are linked by peptide bonds, either directly or via one or more peptide linkers.

[0151] The term “multispecific” means that the antibody is able to specifically bind to at least two distinct antigenic determinants. A multispecific antibody can be, for example, a bispecific antibody. Typically, a bispecific antibody comprises two antigen binding sites, each of which is specific for a different antigenic determinant. In certain aspects the multispecific (e.g.

[0152] T1 bispecific) antibody is capable of simultaneously binding two antigenic determinants, particularly two antigenic determinants expressed on two distinct cells.

[0153] The term “valent” as used herein denotes the presence of a specified number of antigen binding sites in an antigen binding molecule. As such, the term “monovalent binding to an antigen” denotes the presence of one (and not more than one) antigen binding site specific for the antigen in the antigen binding molecule.

[0154] An “antigen binding site” refers to the site, i.e. one or more amino acid residues, of an antigen binding molecule which provides interaction with the antigen. For example, the antigen binding site of an antibody comprises amino acid residues from the complementarity determining regions (CDRs). A native immunoglobulin molecule typically has two antigen binding sites, a Fab molecule typically has a single antigen binding site.

[0155] As used herein, the term "antigenic determinant" or "antigen" refers to a site (e.g. a contiguous stretch of amino acids or a conformational configuration made up of different regions of noncontiguous amino acids) on a polypeptide macromolecule to which a domain that binds to the antigen binds, forming a complex. Useful antigenic determinants can be found, for example, on the surfaces of tumor cells, on the surfaces of virus-infected cells, on the surfaces of other diseased cells, on the surface of immune cells, free in blood serum, and / or in the extracellular matrix (ECM). In a preferred aspect, the antigen is a human protein.

[0156] “CD3” refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g. humans), non-human primates (e.g. cynomolgus monkeys) and rodents (e.g. mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed CD3 as well as any form of CD3 that results from processing in the cell. The term also encompasses naturally occurring variants of CD3, e.g., splice variants or allelic variants. In one aspect, CD3 is human CD3, particularly the epsilon subunit of human CD3 (CD3s). The amino acid sequence of human CD3s is shown in SEQ ID NO: 102 (without signal peptide). See also UniProt (www.uniprot.org) accession no. P07766 (version 209), or NCBI (www.ncbi.nlm.nih.gov / ) RefSeq NP_000724.1. In another aspect, CD3 is cynomolgus (Macaca fascicularis) CD3, particularly cynomolgus CD3e. The amino acid sequence of cynomolgus CD3s is shown in SEQ ID NO: 101 (without signal peptide). See also NCBI GenBank no. BAB71849.1. In certain aspects the antibody of the invention binds to an epitope of CD3 that is conserved among the CD3 antigens from different species, particularly human and cynomolgus CD3. In preferred aspects, the antibody binds to human CD3. A “target cell antigen” as used herein refers to an antigenic determinant presented on the surface of a target cell, for example a cell in a tumor such as a cancer cell or a cell of the tumor stroma (in that case a “tumor cell antigen”). Preferably, the target cell antigen is not CD3, and / or is expressed on a different cell than CD3. According to the invention, the target cell antigen is FolRl, particularly human FolRl.

[0157] The terms “constant region derived from human origin” or “human constant region” as used in the current application denotes a constant heavy chain region of a human antibody of the subclass IgGi, IgG?, IgGs, or IgG4 and / or a constant light chain kappa or lambda region. Such constant regions are well known in the state of the art and e.g. described by Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also e.g. Johnson, G., and Wu, T.T., Nucleic Acids Res. 28 (2000) 214-218; Kabat, E.A., et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785- 2788). Unless otherwise specified herein, numbering of amino acid residues in the constant region is according to the EU numbering system, also called the EU index of Kabat, as described in Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

[0158] “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0159] An “effective amount” of an agent, e.g., a pharmaceutical composition, refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0160] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl -terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, EU numbering system). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including an Fc region are denoted herein without C-terminal glycine-lysine dipeptide if not indicated otherwise. In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody according to the invention, comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447, EU numbering system). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody according to the invention, comprises an additional C-terminal glycine residue (G446, numbering according to EU index). Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0161] “Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1-CDR-H1(CDR-L1)-FR2- CDR-H2(CDR-L2)- FR3- CDR-H3(CDR-L3)-FR4.

[0162] The terms “full length antibody”, “intact antibody”, and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0163] The terms “host cell”, “host cell line”, and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include “transformants” and “transformed cells”, which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0164] A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human-repertoire inspired antibody-encoding synthetic libraries. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. The term "domain that binds to" refers to the part of an antibody that comprises the area which binds to and is complementary to part or all of an antigen. A domain that binds to an antigen may be provided by, for example, one or more antibody variable domains (also called antibody variable regions). In preferred aspects, a domain that binds to an antigen e.g. FolRl or CD3 comprises an antibody light chain variable domain (VL) and an antibody heavy chain variable domain (VH).

[0165] A “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one aspect, for the VL, the subgroup is subgroup kappa II ( hIGKV2-28-01 ) as in Kabat et al., supra. In one aspect, for the VH, the subgroup is subgroup I and III ( hIGHVl-46-01, hIGHVl-46-02, hIGHV3-23-05) as in Kabat et al., supra.

[0166] A “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In certain aspects, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0167] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and complementarity determining regions (CDRs). See, e.g., Kindt et al., Kuby Immunology, 6thed., W.H. Freeman & Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150 880-881 (1993); Clarkson et al., Nature 352:624-628 (1991). As used herein in connection with variable region sequences, "Kabat numbering" refers to the numbering system set forth by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991).

[0168] Glutamine or glutamate residues at the N-terminus of antibody heavy or light chains may be converted to pyro-glutamate spontaneously (see e.g. Liu et al., Journal of Pharmaceutical Sciences 97, 2426-2447 (2008), Rehder et al., Journal of Chromatography A 1102, 164-175 (2006), Chelius et al., Anal Chem 78, 2370-2376 (2006)). Hence, variable regions or variable domains disclosed herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus of an the antibody heavy or light chain, may comprise an N- terminal pyro-glutamate (pyroE) residue instead of the N-terminal Q or E residue. Likewise, antibody heavy chains or light chains disclosed herein which comprise either a glutamine (Q) or a glutamate (E) amino acid residue at the N-terminus, may comprise an N terminal pyroglutamate (pyroE) residue instead of the N-terminal Q or E residue. Accordingly, for each antibody heavy chain, light chain, or variable domain or region sequence disclosed herein that contains an N-terminal Q or E residue, the corresponding sequence with an N-terminal pyroE residue is also encompassed.

[0169] As used herein, the amino acid positions of all constant regions and domains of the heavy and light chain are numbered according to the Kabat numbering system described in Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), referred to as “numbering according to Kabat” or “Kabat numbering” herein. Specifically the Kabat numbering system (see pages 647-660 of Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)) is used for the light chain constant domain CL of kappa and lambda isotype and the Kabat EU index numbering system (see pages 661- 723) is used for the heavy chain constant domains (CHI, hinge, CH2 and CH3), which is herein further clarified by referring to “numbering according to Kabat EU index” or “Kabat EU index numbering” in this case.

[0170] The term “hypervariable region” or “HVR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity, for example “complementarity determining regions” (“CDRs”). Generally, antibodies comprise six CDRs: three in the VH (CDR-H1, CDR-H2, CDR- H3), and three in the VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:

[0171] (a) hypervariable loops occurring at amino acid residues 26-32 (LI), 50-52 (L2), 91-96 (L3), 26-32 (Hl), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

[0172] (b) CDRs occurring at amino acid residues 24-34 (LI), 50-56 (L2), 89-97 (L3), 31-35b (Hl), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and

[0173] (c) antigen contacts occurring at amino acid residues 27c-36 (LI), 46-55 (L2), 89-96 (L3), 30-35b (Hl), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)).

[0174] Unless otherwise indicated, the CDRs are determined according to Kabat et al., supra. One of skill in the art will understand that the CDR designations can also be determined according to Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.

[0175] An “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.

[0176] An “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the individual or subject is a human.

[0177] An “isolated” antibody is one which has been separated from a component of its natural environment. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) methods. For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0178] The term “nucleic acid molecule” or “polynucleotide” includes any compound and / or substance that comprises a polymer of nucleotides. Each nucleotide is composed of a base, specifically a purine- or pyrimidine base (i.e. cytosine (C), guanine (G), adenine (A), thymine (T) or uracil (U)), a sugar (i.e. deoxyribose or ribose), and a phosphate group. Often, the nucleic acid molecule is described by the sequence of bases, whereby said bases represent the primary structure (linear structure) of a nucleic acid molecule. The sequence of bases is typically represented from 5’ to 3’. Herein, the term nucleic acid molecule encompasses deoxyribonucleic acid (DNA) including e.g., complementary DNA (cDNA) and genomic DNA, ribonucleic acid (RNA), in particular messenger RNA (mRNA), synthetic forms of DNA or RNA, and mixed polymers comprising two or more of these molecules. The nucleic acid molecule may be linear or circular. In addition, the term nucleic acid molecule includes both, sense and antisense strands, as well as single stranded and double stranded forms. Moreover, the herein described nucleic acid molecule can contain naturally occurring or non-naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include modified nucleotide bases with derivatized sugars or phosphate backbone linkages or chemically modified residues. Nucleic acid molecules also encompass DNA and RNA molecules which are suitable as a vector for direct expression of an antibody of the invention in vitro and / or in vivo, e.g., in a host or patient. Such DNA (e.g., cDNA) or RNA (e.g., mRNA) vectors, can be unmodified or modified. For example, mRNA can be chemically modified to enhance the stability of the RNA vector and / or expression of the encoded molecule so that mRNA can be injected into a subject to generate the antibody in vivo (see e.g., Stadler et al, Nature Medicine 2017, published online 12 June 2017, doi: 10.1038 / nm.4356 or EP 2 101 823 Bl).

[0179] An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0180] “Isolated nucleic acid encoding an antibody that binds to FolRl” refers to one or more nucleic acid molecules encoding anti-FolRl antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.

[0181] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

[0182] A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.

[0183] “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From N- to C-terminus, each heavy chain has a variable domain (VH), also called a variable heavy domain or a heavy chain variable region, followed by three constant heavy domains (CHI, CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable domain (VL), also called a variable light domain or a light chain variable region, followed by a constant light (CL) domain.

[0184] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.

[0185] “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity for the purposes of the alignment. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or the FASTA program package. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Alternatively, the percent identity values can be generated using the sequence comparison computer program ALIGN- 2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU5 10087 and is described in WO 2001 / 007611.

[0186] Unless otherwise indicated, for purposes herein, percent amino acid sequence identity values are generated using the ggsearch program of the FASTA package version 36.3.8c or later with a BLOSUM50 comparison matrix. The FASTA program package was authored by W. R. Pearson and D. J. Lipman (1988), “Improved Tools for Biological Sequence Analysis”, PNAS 85:2444-2448; W. R. Pearson (1996) “Effective protein sequence comparison” Meth. Enzymol. 266:227- 258; and Pearson et. al. (1997) Genomics 46:24-36 and is publicly available from www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www. ebi.ac.uk / Tools / sss / fasta. Alternatively, a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi can be used to compare the sequences, using the ggsearch (global protein: protein) program and default options (BLOSUM50; open: -10; ext: - 2; Ktup = 2) to ensure a global, rather than local, alignment is performed. Percent amino acid identity is given in the output alignment header.

[0187] The term “pharmaceutical composition” or “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the pharmaceutical composition would be administered. A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition or formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0188] The term “FolRl”, as used herein, refers to any native FolRl from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length”, unprocessed FolRl as well as any form of FolRl that results from processing in the cell. The term also encompasses naturally occurring variants of FolRl, e.g., splice variants or allelic variants. In a preferred aspect, FolRl is human FolRl. The amino acid sequence of an exemplary human FolRl is shown in SEQ ID NO: 100. See also UniProt entry no. P15328.

[0189] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of a disease in the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some aspects, antibodies of the invention are used to delay development of a disease or to slow the progression of a disease.

[0190] “T cell activation” as used herein refers to one or more cellular responses of a T lymphocyte, particularly a cytotoxic T lymphocyte, selected from: proliferation, differentiation, cytokine secretion, cytotoxic effector molecule release, cytotoxic activity, and expression of activation markers. Suitable assays to measure T cell activation are known in the art and described herein.

[0191] A “modification promoting the association of the first and the second subunit of the Fc domain” is a manipulation of the peptide backbone or the post-translational modifications of an Fc domain subunit that reduces or prevents the association of a polypeptide comprising the Fc domain subunit with an identical polypeptide to form a homodimer. A modification promoting association as used herein preferably includes separate modifications made to each of the two Fc domain subunits desired to associate (i.e. the first and the second subunit of the Fc domain), wherein the modifications are complementary to each other so as to promote association of the two Fc domain subunits. For example, a modification promoting association may alter the structure or charge of one or both of the Fc domain subunits so as to make their association sterically or electrostatically favorable, respectively. Thus, (hetero)dimerization occurs between a polypeptide comprising the first Fc domain subunit and a polypeptide comprising the second Fc domain subunit, which may be non-identical in the sense that further components fused to each of the subunits (e.g. domains that bind to an antigen e.g. FolRl or CD3) are not the same. In some aspects, the modification promoting the association of the first and the second subunit of the Fc domain comprises an amino acid mutation in the Fc domain, specifically an amino acid substitution. In a preferred aspect, the modification promoting the association of the first and the second subunit of the Fc domain comprises a separate amino acid mutation, specifically an amino acid substitution, in each of the two subunits of the Fc domain.

[0192] The term “effector functions” refers to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down regulation of cell surface receptors (e.g. B cell receptor), and B cell activation.

[0193] An “activating Fc receptor” is an Fc receptor that following engagement by an Fc domain of an antibody elicits signaling events that stimulate the receptor-bearing cell to perform effector functions. Human activating Fc receptors include FcyRIIIa (CD16a), FcyRI (CD64), FcyRIIa (CD32), and FcaRI (CD89).

[0194] Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune mechanism leading to the lysis of antibody-coated target cells by immune effector cells. The target cells are cells to which antibodies or derivatives therefore comprising an Fc region specifically bind, generally via the protein part that is N-terminal to the Fc region. As used herein, the term “reduced ADCC” is defined as either a reduction in the number of target cells that are lysed in a given time, at a given concentration of antibody in the medium surrounding the target cells, by the mechanism of ADCC defined above, and / or an increase in the concentration of antibody in the medium surrounding the target cells, required to achieve the lysis of a given number of target cells in a given time, by the mechanism of ADCC. The reduction in ADCC is relative to the ADCC mediated by the same antibody produced by the same type of host cells, using the same standard production, purification, formulation and storage methods (which are known to those skilled in the art), but that has not been engineered. For example, the reduction in ADCC mediated by an antibody comprising in its Fc domain an amino acid substitution that reduces ADCC, is relative to the ADCC mediated by the same antibody without this amino acid substitution in the Fc domain. Suitable assays to measure ADCC are well known in the art (see e.g. PCT publication no. WO 2006 / 082515 or PCT publication no. WO 2012 / 130831).

[0195] As used herein, the terms “engineer, engineered, engineering”, are considered to include any manipulation of the peptide backbone or the post-translational modifications of a naturally occurring or recombinant polypeptide or fragment thereof. Engineering includes modifications of the amino acid sequence, of the glycosylation pattern, or of the side chain group of individual amino acids, as well as combinations of these approaches.

[0196] The term “amino acid mutation” as used herein is meant to encompass amino acid substitutions, deletions, insertions, and modifications. Any combination of substitution, deletion, insertion, and modification can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., reduced binding to an Fc receptor, or increased association with another peptide. Amino acid sequence deletions and insertions include amino- and / or carboxy-terminal deletions and insertions of amino acids. Preferred amino acid mutations are amino acid substitutions. For the purpose of altering e.g. the binding characteristics of an Fc region, non-conservative amino acid substitutions, i.e. replacing one amino acid with another amino acid having different structural and / or chemical properties, are particularly preferred. Amino acid substitutions include replacement by non-naturally occurring amino acids or by naturally occurring amino acid derivatives of the twenty standard amino acids (e.g. 4-hydroxyproline, 3 -methylhistidine, ornithine, homoserine, 5 -hydroxylysine). Amino acid mutations can be generated using genetic or chemical methods well known in the art. Genetic methods may include site-directed mutagenesis, PCR, gene synthesis and the like. It is contemplated that methods of altering the side chain group of an amino acid by methods other than genetic engineering, such as chemical modification, may also be useful. Various designations may be used herein to indicate the same amino acid mutation. For example, a substitution from proline at position 329 of the Fc domain to glycine can be indicated as 329G, G329, G329, P329G, or Pro329Gly. The term “vector”, as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors”.

[0197] II. COMPOSITIONS AND METHODS

[0198] In one aspect, the invention is based, in part, on antibodies that bind FolRl preferentially at acidic pH as compared to neutral pH. In certain aspects, antibodies that bind to FolRl, wherein the antibodies bind to FolRl at neutral pH 7.4 with a first KD and at an acidic pH 6.5 with a second KD, wherein the first KD is greater than the second KD and the first KD and the second KD are measured by surface plasmon resonance (SPR) at 25 °C are provided. The antibodies show preferential binding at acidic pH as compared to neutral pH. Preferential binding at acidic pH as compared to neutral pH is a favorable property for therapeutic applications such as in cancer, for example with respect to safety and efficacy. Antibodies of the invention are useful, e.g., for the diagnosis or treatment of diseases such as cancer.

[0199] A. Exemplary pH responsive Antibodies that bind to FolRl

[0200] In one aspect, the invention provides antibodies that bind to FolRl, wherein the antibodies bind to FolRl at neutral pH 7.4 with a first KD and at an acidic pH 6.5 with a second KD, wherein the first KD is greater than the second KD and the first KD and the second KD are measured by surface plasmon resonance (SPR) at 25 °C. In one aspect, provided are isolated antibodies that bind to FolRl, wherein the antibodies bind to FolRl at neutral pH 7.4 with a first KD and at an acidic pH 6.5 with a second KD, wherein the first KD is greater than the second KD and the first KD and the second KD are measured by surface plasmon resonance (SPR) at 25 °C. In one aspect, the invention provides antibodies that specifically bind to FolRl, wherein the antibodies bind to FolRl at neutral pH 7.4 with a first KD and at an acidic pH 6.5 with a second KD, wherein the first KD is greater than the second KD and the first KD and the second KD are measured by surface plasmon resonance (SPR) at 25 °C. In certain aspects, an antibody that binds to FolRl preferentially binds to FolRl at acidic pH as compared to neutral pH. In some aspects, an antibody that binds to FolRl has a dissociation constant (KD) of < 47 nM (e.g. 47xl0'9M or less) at acidic pH 6.5 as measured by SPR at 25°C, particularly, the antibody that binds to FolRl additionally has a dissociation constant (KD) of > 46nM (e.g. 46 x 10'9M or more) at neutral pH 7.4 as measured by SPR at 25°C, wherein if the KD at neutral pH 7.4 is 46nM or more as measured by surface plasmon resonance (SPR) at 25 °C, the KD at neutral pH 7.4 is at least 2, at least 5, at least 8, at least 10, at least 11, at least 13, at least 16, at least 23, at least 31, at least 40, at least 60, at least 74 or at least 195 fold greater than the KD at acidic pH 6.5 as measured by SPR at 25°C.

[0201] In one aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 22 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 26.

[0202] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:22 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:22. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:22 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:22. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:22 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:22.

[0203] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 47 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 26.

[0204] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:47 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:47. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:47 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:47. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:47 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:47.

[0205] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26.

[0206] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 60 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 26.

[0207] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:60 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least %, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:60. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 60 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:60. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:60 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:60.

[0208] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26.

[0209] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 79 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 38.

[0210] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:79 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:79. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:79 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:79. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:79 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:79. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38.

[0211] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 22 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 38.

[0212] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:22 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:22. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:22 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:22. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:22 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:22.

[0213] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38.

[0214] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 52 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 26.

[0215] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:52 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:52. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 52 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:52. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 52 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:52.

[0216] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26.

[0217] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 47 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 38. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:47 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:47. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:47 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:47. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:47 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:47.

[0218] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38.

[0219] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 56 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 26.

[0220] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:56 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:56. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:56 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:56. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:56 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:56.

[0221] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26.

[0222] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 64 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 26.

[0223] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:64 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:64. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 64 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:64. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 64 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:64.

[0224] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26.

[0225] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 67 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 26.

[0226] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:67 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:67. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 67 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:67. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 67 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:67.

[0227] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:26 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:26.

[0228] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 76 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 38.

[0229] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:76 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:76. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:76 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:76. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:76 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:76.

[0230] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework ofat least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38.

[0231] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 82 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 38. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:82 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:82. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 82 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:82. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 82 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:82.

[0232] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38.

[0233] In a further aspect, an antibody that binds to FolRl comprises the CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of the VH domain of SEQ ID NOs: 85 and the CDR-L1, CDR- L2 and CDR-L3 amino acid sequences of the VL domain of SEQ ID NO: 38.

[0234] In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:85 and a framework ofat least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:85. In one aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO:85 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:85. In another aspect, the antibody that binds to FolRl comprises the three heavy chain CDR amino acid sequences of the VH domain of SEQ ID NO: 85 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VH domain of SEQ ID NO:85.

[0235] In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In one aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 95% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38. In another aspect, the antibody that binds to FolRl comprises the three light chain CDR amino acid sequences of the VL domain of SEQ ID NO:38 and a framework of at least 98% sequence identity to the framework amino acid sequence of the VL domain of SEQ ID NO:38.

[0236] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:23; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at leat 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:22, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:22. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26.

[0237] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:23; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:47, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:47. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26.

[0238] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:58; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:59; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:23; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 60, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:60. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26.

[0239] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:78; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:36; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:79, and a VL domain havingat least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:79. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38.

[0240] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:36; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:22, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:22. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38.

[0241] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:23; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 52, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:52. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26.

[0242] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:36; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:47, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:47. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38.

[0243] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:54; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:55; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:23; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:56. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26.

[0244] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:62; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:23; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 64, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:64. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:66; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:23; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 67, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:67. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26.

[0245] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:36; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:76, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:76. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38.

[0246] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:81; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:36; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 82, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:82. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38.

[0247] In one aspect, the antibody that binds to FolRl comprises (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44; (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45; (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:84; (d) CDR- L1 comprising the amino acid sequence of SEQ ID NO:36; (e) CDR-L2 comprising the amino acid sequence of SEQ ID NO:24; and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37, and a VH domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:85, and a VL domain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38; wherein the antibody specifically binds to FolRl. In one aspect, the VH domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:85. In one aspect, the VL domain has at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38.

[0248] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:22. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:22. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:22. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:22, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:21. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:26. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO:26, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:23, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:25.

[0249] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:22 and SEQ ID NO:26, respectively, including post-translational modifications of those sequences.

[0250] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:47. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:47. In certain aspects, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:47. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:47, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR-H1, comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:46. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:26. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO:26, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR-L1, comprising the amino acid sequence of SEQ ID NO:23, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:25.

[0251] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:47 and SEQ ID NO:26, respectively, including post-translational modifications of those sequences.

[0252] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence havingat least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:60. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:60. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:60. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO: 60, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:58, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:59. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:26. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO:26, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:23, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:25.

[0253] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:60 and SEQ ID NO:26, respectively, including post-translational modifications of those sequences. In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:79. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:79. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:79. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:79, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:78. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 38. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:38. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO: 38, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:36, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:37.

[0254] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:79 and SEQ ID NO:38, respectively, including post-translational modifications of those sequences.

[0255] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:22. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:22. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:22. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:22, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:21. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:38. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:38. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO: 38, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:36, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:37.

[0256] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:22 and SEQ ID NO:38, respectively, including post-translational modifications of those sequences.

[0257] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:52. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:52. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:52. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO: 52, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO:49, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:50, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:51. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:26. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO:26, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:23, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:25.

[0258] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:52 and SEQ ID NO:26, respectively, including post-translational modifications of those sequences.

[0259] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:47. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:47. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl . In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:47. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:47, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:46. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 38. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:38. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO: 38, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:36, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:37.

[0260] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:47 and SEQ ID NO:38, respectively, including post-translational modifications of those sequences.

[0261] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:56. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:56. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:56. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:56, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO:54, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:55, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:21. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:26. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO:26, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:23, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:25.

[0262] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:56 and SEQ ID NO:26, respectively, including post-translational modifications of those sequences.

[0263] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having mat least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:64. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:64. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:64. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO: 64, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:62, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:63. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:26. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO:26, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:23, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:25.

[0264] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:64 and SEQ ID NO:26, respectively, including post-translational modifications of those sequences.

[0265] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:67. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:67. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:67. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO: 67, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:66, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:21. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:26. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:26. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:26. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO:26, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:23, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:25.

[0266] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:67 and SEQ ID NO:26, respectively, including post-translational modifications of those sequences.

[0267] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:76. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:76. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:76. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:76, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:21. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 38. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:38. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO: 38, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- LI, comprising the amino acid sequence of SEQ ID NO:36, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:37.

[0268] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:76 and SEQ ID NO:38, respectively, including post-translational modifications of those sequences.

[0269] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:82. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:82. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:82. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO: 82, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:81. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 38. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:38. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO: 38, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:36, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:37.

[0270] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:82 and SEQ ID NO:38, respectively, including post-translational modifications of those sequences.

[0271] In another aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:85. In one aspect, an antibody that binds to FolRl comprises a heavy chain variable domain (VH) sequence having at least 95%, sequence identity to the amino acid sequence of SEQ ID NO:85. In certain aspects, a VH sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:85. In certain aspects, substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VH sequence in SEQ ID NO:85, including post-translational modifications of that sequence. In a particular aspect, the VH comprises one, two or three CDRs selected from: (a) CDR- Hl, comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2, comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3, comprising the amino acid sequence of SEQ ID NO:84. In another aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO:38. In one aspect, an antibody that binds to FolRl comprises a light chain variable domain (VL) sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 38. In certain aspects, a VL sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an antibody that binds to FolRl comprising that sequence retains the ability to bind to FolRl. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted and / or deleted in SEQ ID NO:38. In certain aspects, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the antibody that binds to FolRl comprises the VL sequence in SEQ ID NO: 38, including post-translational modifications of that sequence. In a particular aspect, the VL comprises one, two or three CDRs selected from: (a) CDR- Ll, comprising the amino acid sequence of SEQ ID NO:36, (b) CDR-L2, comprising the amino acid sequence of SEQ ID NO:24, and (c) CDR-L3, comprising the amino acid sequence of SEQ ID NO:37.

[0272] In another aspect, an antibody that binds to FolRl comprises a VH sequence as in any of the aspects provided above, and a VL sequence as in any of the aspects provided above. In one aspect, the antibody comprises the VH and VL sequences in SEQ ID NO:85 and SEQ ID NO:38, respectively, including post-translational modifications of those sequences.

[0273] In a further aspect of the invention, an antibody that binds to FolRl according to any of the above aspects is a monoclonal antibody, including a human antibody. In one aspect, an antibody that binds to FolRl is an antibody fragment, e.g., a Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment.

[0274] In another aspect, the antibody is a full length antibody, IgGi antibody or other antibody class or isotype as defined herein.

[0275] In a further aspect, the antibody as described herein is of IgGi isotype / subclass and comprises a constant heavy chain domain of SEQ ID NO: 111 or the constant parts of the heavy chain amino acid sequence of SEQ ID NO: 111. In one aspect, additionally the C-terminal glycine (Gly446) is present. In one aspect, additionally the C-terminal glycine (Gly446) and the C-terminal lysine (Lys447) is present.

[0276] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 17 and the full heavy chain sequence (full H) of SEQ ID NO: 18.

[0277] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 17 and the full heavy chain sequence (full H) of SEQ ID NO:43. In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 17 and the full heavy chain sequence (full H) of SEQ ID NO:57.

[0278] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 35 and the full heavy chain sequence (full H) of SEQ ID NO: 77.

[0279] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 35 and the full heavy chain sequence (full H) of SEQ ID NO:34.

[0280] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 17 and the full heavy chain sequence (full H) of SEQ ID NO: 48.

[0281] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 35 and the full heavy chain sequence (full H) of SEQ ID NO: 43.

[0282] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 17 and the full heavy chain sequence (full H) of SEQ ID NO: 53.

[0283] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 17 and the full heavy chain sequence (full H) of SEQ ID NO: 61.

[0284] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 17 and the full heavy chain sequence (full H) of SEQ ID NO: 65.

[0285] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 35 and the full heavy chain sequence (full H) of SEQ ID NO: 75.

[0286] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 35 and the full heavy chain sequence (full H) of SEQ ID NO: 80.

[0287] In one aspect, the antibody that binds to FolRl comprises the full light chain sequence (full L) of SEQ ID NO: 35 and the full heavy chain sequence (full H) of SEQ ID NO: 83.

[0288] Table 10 shows an overview of sequences of antibodies of the invention. It also includes full H and full L sequences of full IgGs.

[0289] In a further aspect, an antibody that binds to FolRl according to any of the above aspects may incorporate any of the features, singly or in combination, as described in Sections 1-7 below:

[0290] / . Antibody Fragments

[0291] In certain aspects, an antibody provided herein is an antibody fragment.

[0292] In one aspect, the antibody fragment is a Fab, Fab’, Fab’-SH, or F(ab’)2 fragment, in particular a Fab fragment. Papain digestion of intact antibodies produces two identical antigenbinding fragments, called “Fab” fragments containing each the heavy- and light-chain variable domains (VH and VL, respectively) and also the constant domain of the light chain (CL) and the first constant domain of the heavy chain (CHI). The term “Fab fragment” thus refers to an antibody fragment comprising a light chain comprising a VL domain and a CL domain, and a heavy chain fragment comprising a VH domain and a CHI domain. “Fab’ fragments” differ from Fab fragments by the addition of residues at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region. Fab’-SH are Fab’ fragments in which the cysteine residue(s) of the constant domains bear a free thiol group. Pepsin treatment yields an F(ab')2 fragment that has two antigen-binding sites (two Fab fragments) and a part of the Fc region. For discussion of Fab and F(ab')2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046.

[0293] In another aspect, the antibody fragment is a diabody, a triabody or a tetrabody. “Diabodies” are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al., Nat. Med. 9: 129- 134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9: 129-134 (2003).

[0294] In a further aspect, the antibody fragment is a single chain Fab fragment. A “single chain Fab fragment” or “scFab” is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CHI), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein said antibody domains and said linker have one of the following orders in N-terminal to C-terminal direction: a) VH-CH1 -linker- VL-CL, b) VL-CL-linker-VH-CHl, c) VH-CL-linker-VL-CHl or d) VL-CH1 -linker- VH-CL. In particular, said linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids. Said single chain Fab fragments are stabilized via the natural disulfide bond between the CL domain and the CHI domain. In addition, these single chain Fab fragments might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering).

[0295] In another aspect, the antibody fragment is single-chain variable fragment (scFv). A “single-chain variable fragment” or “scFv” is a fusion protein of the variable domains of the heavy (VH) and light chains (VL) of an antibody, connected by a linker. In particular, the linker is a short polypeptide of 10 to 25 amino acids and is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original antibody, despite removal of the constant regions and the introduction of the linker. For a review of scFv fragments, see, e.g., Pliickthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93 / 16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. In another aspect, the antibody fragment is a single-domain antibody. “Single-domain antibodies” are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain aspects, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 Bl).

[0296] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as recombinant production by recombinant host cells (e.g., E. coli), as described herein.

[0297] 2. Human Antibodies

[0298] In certain aspects, an antibody provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0299] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No. 5,770,429 describing HUMAB® technology; U.S. Patent No. 7,041,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007 / 0061900, describing VELOCIMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

[0300] Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3): 185-91 (2005).

[0301] Human antibodies may also be generated by isolating variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

[0302] 3. Library-Derived Antibodies

[0303] In certain aspects, an antibody provided herein is derived from a library. Antibodies of the invention may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. Methods for screening combinatorial libraries are reviewed, e.g., in Lerner et al. in Nature Reviews 16:498-508 (2016). For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Frenzel et al. in mAbs 8: 1177-1194 (2016); Bazan et al. in Human Vaccines and Immunotherapeutics 8: 1817-1828 (2012) and Zhao et al. in Critical Reviews in Biotechnology 36:276-289 (2016) as well as in Hoogenboom et al. n Methods in Molecular Biology 178: 1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001) and in Marks and Bradbury in Methods in Molecular Biology 248: 161-175 (Lo, ed., Human Press, Totowa, NJ, 2003).

[0304] In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for anti gen -binding phage as described in Winter et al. in Annual Review of Immunology 12: 433-455 (1994). Phage typically display antibody fragments, either as singlechain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al. in EMBO Journal 12: 725-734 (1993). Furthermore, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter in Journal of Molecular Biology 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: US Patent Nos. 5,750,373; 7,985,840; 7,785,903 and 8,679,490 as well as US Patent Publication Nos. 2005 / 0079574, 2007 / 0117126, 2007 / 0237764 and 2007 / 0292936.

[0305] Further examples of methods known in the art for screening combinatorial libraries for antibodies with a desired activity or activities include ribosome and mRNA display, as well as methods for antibody display and selection on bacteria, mammalian cells, insect cells or yeast cells. Methods for yeast surface display are reviewed, e.g., in Scholler et al. in Methods in Molecular Biology 503: 135-56 (2012) and in Cherf et al. in Methods in Molecular biology 1319: 155-175 (2015) as well as in Zhao et al. in Methods in Molecular Biology 889:73-84 (2012). Methods for ribosome display are described, e.g., in He et al. in Nucleic Acids Research 25:5132-5134 (1997) and in Hanes et al. in PNAS 94:4937-4942 (1997).

[0306] Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

[0307] 4. Multispecific Antibodies

[0308] In certain aspects, an antibody provided herein is a multispecific antibody, e.g., a bispecific antibody. “Multispecific antibodies” are monoclonal antibodies that have binding specificities for at least two different sites, i.e., different epitopes on different antigens or different epitopes on the same antigen. In certain aspects, the multispecific antibody has three or more binding specificities. In certain aspects, one of the binding specificities is for FolRl and the other specificity is for any other antigen. In certain aspects, bispecific antibodies may bind to two (or more) different epitopes of FolRl. In one aspect of the invention, one of the binding specificities is for CD3 and the other specificity is for FolRl. Multispecific (e.g., bispecific) antibodies may also be used to localize cytotoxic agents or cells to cells which express FolRl. Multispecific antibodies may be prepared as full length antibodies or antibody fragments.

[0309] Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)) and “knob-in-hole” engineering (see, e.g., U.S. Patent No. 5,731,168, and Atwell et al., J. Mol. Biol. 270:26 (1997)). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (see, e.g., WO 2009 / 089004); crosslinking two or more antibodies or fragments (see, e.g., US Patent No. 4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5): 1547-1553 (1992) and WO 2011 / 034605); using the common light chain technology for circumventing the light chain mis-pairing problem (see, e.g., WO 98 / 50431); using “diabody” technology for making bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using singlechain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol. 147: 60 (1991).

[0310] Engineered antibodies with three or more antigen binding sites, including for example, “Octopus antibodies”, or DVD-Ig are also included herein (see, e.g., WO 2001 / 77342 and WO 2008 / 024715). Other examples of multispecific antibodies with three or more antigen binding sites can be found in WO 2010 / 115589, WO 2010 / 112193, WO 2010 / 136172, WO 2010 / 145792, and WO 2013 / 026831. The bispecific antibody or antigen binding fragment thereof also includes a “Dual Acting FAb” or “DAF” comprising an antigen binding site that binds to FolRl as well as another different antigen, or two different epitopes of FolRl (see, e.g., US 2008 / 0069820 and WO 2015 / 095539).

[0311] Multi-specific antibodies may also be provided in an asymmetric form with a domain crossover in one or more binding arms of the same antigen specificity, i.e. by exchanging the VH / VL domains (see e.g., WO 2009 / 080252 and WO 2015 / 150447), the CH1 / CL domains (see e.g., WO 2009 / 080253) or the complete Fab arms (see e.g., WO 2009 / 080251, WO 2016 / 016299, also see Schaefer et al, PNAS, 108 (2011) 1187-1191, and Klein at al., MAbs 8 (2016) 1010-20). In one aspect, the multispecific antibody comprises a cross-Fab fragment. The term “cross-Fab fragment” or “xFab fragment” or “crossover Fab fragment” refers to a Fab fragment, wherein either the variable regions or the constant regions of the heavy and light chain are exchanged. A cross-Fab fragment comprises a polypeptide chain composed of the light chain variable region (VL) and the heavy chain constant region 1 (CHI), and a polypeptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL). Asymmetrical Fab arms can also be engineered by introducing charged or non-charged amino acid mutations into domain interfaces to direct correct Fab pairing. See e.g., WO 2016 / 172485.

[0312] Various further molecular formats for multispecific antibodies are known in the art and are included herein (see e.g., Spiess et al., Mol Immunol 67 (2015) 95-106). A particular type of multispecific antibodies, also included herein, are bispecific antibodies designed to simultaneously bind to a surface antigen on a target cell, e.g., a tumor cell, and to an activating, invariant component of the T cell receptor (TCR) complex, such as CD3, for retargeting of T cells to kill target cells. Hence, in certain aspects, an antibody provided herein is a multispecific antibody, particularly a bispecific antibody, wherein one of the binding specificities is for FolRl and the other is for CD3.

[0313] Examples of bispecific antibody formats that may be useful for this purpose include, but are not limited to, the so-called “BiTE” (bispecific T cell engager) molecules wherein two scFv molecules are fused by a flexible linker (see, e.g., WO 2004 / 106381, WO 2005 / 061547, WO 2007 / 042261, and WO 2008 / 119567, Nagorsen and Bauerle, Exp Cell Res 317, 1255-1260 (2011)); diabodies (Holliger et al., Prot Eng 9, 299-305 (1996)) and derivatives thereof, such as tandem diabodies (“TandAb”; Kipriyanov et al., J Mol Biol 293, 41-56 (1999)); “DART” (dual affinity retargeting) molecules which are based on the diabody format but feature a C-terminal disulfide bridge for additional stabilization (Johnson et al., J Mol Biol 399, 436-449 (2010)), and so-called triomabs, which are whole hybrid mouse / rat IgG molecules (reviewed in Seimetz et al., Cancer Treat Rev 36, 458-467 (2010)). Particular T cell bispecific antibody formats included herein are described in WO 2013 / 026833, WO 2013 / 026839, WO 2016 / 020309; Bacac et al., Oncoimmunology 5(8) (2016) el203498.

[0314] Certain aspects of the antibody of the present invention are described in the following.

[0315] In one aspect, the invention provides an antibody that binds to CD3 and FolRl, comprising a domain that binds to CD3 and comprising a first and optionally a second domain that binds to FolRl as described herein.

[0316] According to certain aspects of the invention, the domains comprised in the antibody are Fab molecules (i.e. domains that bind to an antigen e.g. FolRl or CD3 composed of a heavy and a light chain, each comprising a variable and a constant domain). In one aspect, the domains that bind to CD3 and FolRl are a Fab molecule. In one aspect, said Fab molecule is human. In another aspect, said Fab molecule is humanized. In yet another aspect, said Fab molecule comprises human heavy and light chain constant domains.

[0317] Preferably, at least one of the domains that bind to the CD3 or FolRl is a crossover Fab molecule. Such modification reduces mispairing of heavy and light chains from different Fab molecules, thereby improving the yield and purity of the multispecific antibody according to the invention in recombinant production. In a preferred crossover Fab molecule useful for the multispecific antibody according to the invention, the variable domains of the Fab light chain and the Fab heavy chain (VL and VH, respectively) are exchanged. Even with this domain exchange, however, the preparation of the multispecific antibody may comprise certain side products due to a so-called Bence Jones-type interaction between mispaired heavy and light chains (see Schaefer et al, PNAS, 108 (2011) 11187-11191). To further reduce mispairing of heavy and light chains from different Fab molecules and thus increase the purity and yield of the desired multispecific antibody, charged amino acids with opposite charges may be introduced at specific amino acid positions in the CHI and CL domains of either the Fab molecule binding to CD3, or the Fab molecule(s) binding to FolRl, as further described herein. Charge modifications are made either in the conventional Fab molecule(s) comprised in the multispecific antibody (such as shown e.g. in Figures 15 A-C, G-J), or in the VH / VL crossover Fab molecule(s) comprised in the multispecific antibody (such as shown e.g. in Figure 15 D- F, K-N) (but not in both). In preferred aspects, the charge modifications are made in the conventional Fab molecule(s) comprised in the multispecific antibody (which in preferred aspects bind(s) to FolRl).

[0318] In a certain aspect of the invention, the multispecific antibody is capable of simultaneous binding to CD3 and FolRl. In one aspect, the multispecific antibody is capable of crosslinking a T cell and a target cell by simultaneous binding to CD3 and FolRl . In an even more preferred aspect, such simultaneous binding results in lysis of the target cell, particularly a FolRl - expressing target cell such as a tumor cell. In one aspect, such simultaneous binding results in activation of the T cell. In other aspects, such simultaneous binding results in a cellular response of a T lymphocyte, particularly a cytotoxic T lymphocyte, selected from the group of proliferation, differentiation, cytokine secretion, cytotoxic effector molecule release, cytotoxic activity, and expression of activation markers. In one aspect, binding of the multispecific antibody to CD3 without simultaneous binding to FolRl does not result in T cell activation.

[0319] In one aspect, the multispecific antibody is capable of re-directing cytotoxic activity of a T cell to a target cell. In a preferred aspect, said re-direction is independent of MHC-mediated peptide antigen presentation by the target cell and and / or specificity of the T cell.

[0320] Preferably, a T cell according to any of the aspects of the invention is a cytotoxic T cell. In some aspects the T cell is a CD4+or a CD8+T cell, particularly a CD8+T cell. a) CD3 binding domain In one aspect, a multispecific antibody according to the invention comprises at least one domain that binds to CD3. In preferred aspects, CD3 is human CD3 (SEQ ID NO: 102) or cynomolgus CD3 (SEQ ID NO: 101) most particularly human CD3. In one aspect the domain that binds to CD3 is cross-reactive for (i.e. specifically binds to) human and cynomolgus CD3. In some aspects, CD3 is the epsilon subunit of CD3 (CD3 epsilon).

[0321] In a preferred aspect, the multispecific antibody comprises not more than one domain that binds to CD3. In one aspect the multispecific antibody provides monovalent binding to CD3.

[0322] In one aspect, the domain that binds to CD3 comprises a VH of SEQ ID NO: 115 and a VL of SEQ ID NO: 116.

[0323] In one aspect, the domain that binds to CD3 is an antibody fragment selected from the group of an Fv molecule, a scFv molecule, a Fab molecule, and a F(ab’)2 molecule. In a preferred aspect, the domain that binds to CD3 is a Fab molecule.

[0324] In preferred aspects, the domain that binds to CD3 is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CHI and CL of the Fab heavy and light chains are exchanged / replaced by each other. In such aspects, the domain(s) that binds to FolRl is preferably a conventional Fab molecule. In aspects where there is more than one domain that binds to antigens e.g. CD3 and / or FolRl, particularly Fab molecule, that binds to FolRl comprised in the multispecific antibody, the domain that binds to CD3 preferably is a crossover Fab molecule and the domain that binds to FolRl are conventional Fab molecules.

[0325] In alternative aspects, the domain that binds to CD3 is a conventional Fab molecule. In such aspects, the domain(s) that binds FolRl is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CHI and CL of the Fab heavy and light chains are exchanged / replaced by each other. In aspects where there is more than one domain that binds to antigen(s) e.g. FolRl and / or CD3, particularly Fab molecule, that binds to CD3 comprised in the multispecific antibody, the domain that binds to FolRl preferably is a crossover Fab molecule and the domains that bind to CD3 are conventional Fab molecules.

[0326] In certain aspects, the domain that binds to CD3 is a Fab molecule wherein the variable domains VL and VH or the constant domains CL and CHI, particularly the variable domains VL and VH, of the Fab light chain and the Fab heavy chain are replaced by each other (i.e. according to such aspect, the domain that binds to CD3 is a crossover Fab molecule wherein the variable or constant domains of the Fab light chain and the Fab heavy chain are exchanged). In one such aspect, the antigen domain(s) that binds to FolRl is a conventional Fab molecule.

[0327] In one aspect, not more than one domain that binds to CD3 is present in the multispecific antibody (i.e. the antibody provides monovalent binding to CD3). b) FolRl binding domain

[0328] A multispecific antibody according to the invention comprises at least one domain , particularly a Fab molecule, that binds to FolRl. The domain that binds to FolRl is able to direct the (multispecific) antibody to a target site, for example to a specific type of cell that expresses FolRl.

[0329] In one aspect, the domain that binds to FolRl is an antibody fragment selected from the group of an Fv molecule, a scFv molecule, a Fab molecule, and a F(ab’)2 molecule. In a preferred aspect, the domain that binds to FolRl is a Fab molecule.

[0330] In certain aspects, the (multispecific) antibody comprises two domains, particularly Fab molecules, that bind to FolRl. In a preferred aspect, all of these domains are identical, i.e. they have the same molecular format (e.g. conventional or crossover Fab molecule) and comprise the same amino acid sequences including the same amino acid substitutions in the CHI and CL domain as described herein (if any). In one aspect, the (multispecific) antibody comprises not more than two domains, particularly Fab molecules, that bind to FolRl.

[0331] In preferred aspects, the domain(s) that bind to FolRl is / are a conventional Fab molecule. In such aspects, the domain(s) that binds to CD3 is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CHI and CL of the Fab heavy and light chains are exchanged / replaced by each other.

[0332] In alternative aspects, the domain(s) that bind to FolRl is / are a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CHI and CL of the Fab heavy and light chains are exchanged / replaced by each other. In such aspects, the domain(s) that binds to CD3 is a conventional Fab molecule.

[0333] In one aspect, the domain(s) that bind to FolRl comprises a human constant region. In one aspect, the domain(s) that binds to FolRl is a Fab molecule comprising a human constant region, particularly a human CHI and / or CL domain. Exemplary sequences of human constant domains are given in SEQ ID NOs 109 and 110 (human kappa and lambda CL domains, respectively) and SEQ ID NO: 111 (human IgGi heavy chain constant domains CH1-CH2- CH3). In one aspect, the domain(s) that binds to FolRl comprises a light chain constant region comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 109 or SEQ ID NO: 110, particularly the amino acid sequence of SEQ ID NO: 109. Particularly, the light chain constant region may comprise amino acid mutations as described herein under “charge modifications” and / or may comprise deletion or substitutions of one or more (particularly two) N-terminal amino acids if in a crossover Fab molecule. In some aspects, the domain(s) that binds to FolRl comprises a heavy chain constant region comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the CHI domain sequence comprised in the amino acid sequence of SEQ ID NO: 111. Particularly, the heavy chain constant region (specifically CHI domain) may comprise amino acid mutations as described herein under “charge modifications”.

[0334] In one aspect, the domain(s) that bind to FolRl comprises any of the features of the antibodies that bind to FolRl described above. c) Charge modifications

[0335] The (multi specific) antibody of the invention may comprise amino acid substitutions in Fab molecules comprised therein which are particularly efficient in reducing mispairing of light chains with non-matching heavy chains (Bence-Jones-type side products), which can occur in the production of Fab-based multispecific antibodies with a VH / VL exchange in one (or more, in case of molecules comprising more than two antigen-binding Fab molecules) of their binding arms (see also PCT publication no. WO 2015 / 150447, particularly the examples therein, incorporated herein by reference in its entirety). The ratio of a desired (multispecific) antibody compared to undesired side products, in particular Bence Jones-type side products occurring in multispecific antibodies with a VH / VL domain exchange in one of their binding arms, can be improved by the introduction of charged amino acids with opposite charges at specific amino acid positions in the CHI and CL domains (sometimes referred to herein as “charge modifications”). Accordingly, in some aspects wherein the domain that binds to CD3 and the domain(s) that bind to FolRl of the multispecific antibody are both Fab molecules, and in one of the domains (particularly the domain that binds to CD3) the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, i) in the constant domain CL of the domain(s) that bind to FolRl the amino acid at position 124 is substituted by a positively charged amino acid (numbering according to Kabat), and wherein in the constant domain CHI of the domain(s) that bind to FolRl the amino acid at position 147 or the amino acid at position 213 is substituted by a negatively charged amino acid (numbering according to Kabat EU index); or ii) in the constant domain CL of the domain that binds to CD3 the amino acid at position 124 is substituted by a positively charged amino acid (numbering according to Kabat), and wherein in the constant domain CHI of the domain that binds to CD3 the amino acid at position 147 or the amino acid at position 213 is substituted by a negatively charged amino acid (numbering according to Kabat EU index).

[0336] The (multi specific) antibody does not comprise both modifications mentioned under i) and ii). The constant domains CL and CHI of the domain(s) having the VH / VL exchange are not replaced by each other (i.e. remain unexchanged).

[0337] In a more specific aspect, i) in the constant domain CL of the domain(s) that bind to FolRl the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain(s) that bind to FolRl the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index); or ii) in the constant domain CL of the domain that binds to CD3 the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain that binds to CD3 the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0338] In one such aspect, in the constant domain CL of the domain(s) that bind to FolRl the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain(s) that bind to FolRl the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0339] In a further aspect, in the constant domain CL of the domain(s) that bind to FolRl the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain(s) that bind to FolRl the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0340] In a preferred aspect, in the constant domain CL of the domain(s) that bind to FolRl the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain(s) that bind to FolRl the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0341] In a more preferred aspect, in the constant domain CL of the domain(s) that bind to FolRl the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by lysine (K) (numbering according to Kabat), and in the constant domain CHI of the domain(s) that bind to FolRl the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index). In an even more preferred aspect, in the constant domain CL of the domain(s) that bind to FolRl the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) (numbering according to Kabat), and in the constant domain CHI of the domain(s) that bind to FolRl the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index).

[0342] In preferred aspects, if amino acid substitutions according to the above aspects are made in the constant domain CL and the constant domain CHI of the domain(s) that bind to FolRl, the constant domain CL of the domain(s) that bind to FolRl is of kappa isotype. Alternatively, the amino acid substitutions according to the above aspects may be made in the constant domain CL and the constant domain CHI of the domain that binds to CD3 instead of in the constant domain CL and the constant domain CHI of the domain(s) that bind to FolRl. In preferred such aspects, the constant domain CL of the domain that binds to CD3 is of kappa isotype.

[0343] Accordingly, in one aspect, in the constant domain CL of the domain that binds to CD3 the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain that binds to CD3 the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0344] In a further aspect, in the constant domain CL of the domain that binds to CD3 the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain that binds to CD3 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0345] In still another aspect, in the constant domain CL of the domain that binds to CD3 the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI of the domain that binds to CD3 the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

[0346] In one aspect, in the constant domain CL of the domain that binds to CD3 the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by lysine (K) (numbering according to Kabat), and in the constant domain CHI of the domain that binds to CD3the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index).

[0347] In another aspect, in the constant domain CL of the domain that binds to CD3 the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) (numbering according to Kabat), and in the constant domain CHI of the domain that binds to CD3 the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index). d) Multispecific antibody formats

[0348] The (multi specific) antibody according to the present invention can have a variety of configurations. Exemplary configurations are depicted in Figure 15.

[0349] In preferred aspects, the domains that bind to CD3 and / or FolRl comprised in the (multispecific) antibody are Fab molecules.

[0350] In one aspect, the domains that bind to FolRl and CD3 of the (multispecific) antibody are fused to each other, optionally via a peptide linker. In preferred aspects, the domains that bind to FolRl and CD3 are each a Fab molecule. In one such aspect, the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to FolRl. In another such aspect, the domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3. In aspects wherein either (i) the domain that binds to CD3 is fused at the C- terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to FolRl or (ii) the domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3, additionally the Fab light chain of the domain that binds to CD3 and the Fab light chain of the domain that binds to FolRl may be fused to each other, optionally via a peptide linker.

[0351] A (multispecific) antibody with a single domain (such as a Fab molecule) that binds to FolRl, (for example as shown in Figure 15A, 15D, 15G, 15H, 15K, 15L) is useful, particularly in cases where internalization of the FolRl antigen is to be expected following binding of a domain with high affinity for FolRl. In such cases, the presence of more than one domain that binds to FolRl may enhance internalization of the FolRl antigen, thereby reducing its availability.

[0352] In other cases, however, it will be advantageous to have a (multispecific) antibody comprising two or more domains (such as Fab molecules) that bind to FolRl, (see examples shown in Figure 15B, 15C, 15E, 15F, 151, 15J, 15M or 15N), for example to optimize targeting to the target site or to allow crosslinking of target cell antigens. Accordingly, in some aspects, the (multispecific) antibody according to the present invention comprises a second domain that binds to FolRl.

[0353] In one aspect, the second domain that binds to FolRl is a Fab molecule.

[0354] In one aspect, the second domain that binds to FolRl is identical to the other domain that binds to FolRl, i.e. the first domain that binds to FolRl.

[0355] In some aspects, the first and the second domain that bind to FolRl are each a Fab molecule and the second domain that binds to FolRl is identical to the first domain that binds FolRl. Thus, in these aspects, the first and second domain that bind to FolRl comprise the same heavy and light chain amino acid sequences and have the same arrangement of domains (i.e. conventional or crossover). Furthermore, in these aspects, the second domain that binds to FolRl comprises the same amino acid substitutions, if any, as the first domain that binds to FolRl. For example, the amino acid substitutions described herein as “charge modifications” will be made in the constant domain CL and the constant domain CHI of each of the first domain that binds to FolRl and the second domain that binds to FolRl. Alternatively, said amino acid substitutions may be made in the constant domain CL and the constant domain CHI of the domain that binds to CD3 (which in preferred aspects is also a Fab molecule), but not in the constant domain CL and the constant domain CHI of the first domain that binds to FolRl and the second domain that binds to FolRl .

[0356] Like the first domain that binds to FolRl, the second domain that binds to FolRl preferably is a conventional Fab molecule. Aspects wherein the first and second domains that bind to FolRl are crossover Fab molecules (and the domain that binds to CD3 is a conventional Fab molecule) are, however, also contemplated. Thus, in preferred aspects, the first and second domains that bind to FolRl are each a conventional Fab molecule, and the domain that binds to CD3 is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CL and CHI of the Fab heavy and light chains are exchanged / replaced by each other. In other aspects, the domains that bind to FolRl are each a crossover Fab molecule and the domain that binds to CD3 is a conventional Fab molecule.

[0357] In preferred aspects, the (multispecific) antibody of the invention comprises an Fc domain, particularly a human IgGi Fc domain, composed of a first and a second subunit. The first and the second subunit of the Fc domain are capable of stable association. The (multispecific) antibody according to the invention can have different configurations, i.e. the domain that binds to CD3, the domain that binds to FolRl (and optionally the second domain that binds to FolRl) may be fused to each other and to the Fc domain in different ways. The components may be fused to each other directly or, preferably, via one or more suitable peptide linkers. Where fusion of a Fab molecule is to the N-terminus of a subunit of the Fc domain, it is typically via an immunoglobulin hinge region.

[0358] In some aspects, the domains that bind to CD3 and FolRl are each a Fab molecule and the domain that bind to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or the second subunit of the Fc domain. In such aspects, the domain that binds to FolRl may be fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3 or to the N-terminus of the other one of the subunits of the Fc domain. In preferred such aspects, the domain that binds to FolRl is a conventional Fab molecule, and the domain that binds to CD3 is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CL and CHI of the Fab heavy and light chains are exchanged / replaced by each other. In other such aspects, the domain that binds to FolRl is a crossover Fab molecule and the domain that binds to CD3 is a conventional Fab molecule.

[0359] In one aspect, the domains that bind to CD3 and FolRl are each a Fab molecule, the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or the second subunit of the Fc domain, and the domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3. In a specific aspect, the (multispecific) antibody essentially consists of the Fab molecule that binds to CD3 and the Fab molecule that binds to FolRl, the Fc domain composed of a first and a second subunit, and optionally one or more peptide linkers, wherein the Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the Fab molecule that binds to CD3, and the Fab molecule that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or the second subunit of the Fc domain. Such a configuration is schematically depicted in Figures 15G and 15K (with the domain that binds to CD3 in these examples being a VH / VL crossover Fab molecule). Optionally, the Fab light chain of the Fab molecule that binds to CD3 and the Fab light chain of the Fab molecule that binds to FolRl may additionally be fused to each other. In another aspect, the domain that binds to CD3 and the domain that binds to FolRl are each a Fab molecule and the domains are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain. In a specific aspect, the (multispecific) antibody essentially consists of the Fab molecule that binds to CD3 and the Fab molecule that binds to FolRl, the Fc domain composed of a first and a second subunit, and optionally one or more peptide linkers, wherein the Fab molecules are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain. Such a configuration is schematically depicted in Figures 15A and 15D (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule and the domain that binds to FolRl being a conventional Fab molecule). The Fab molecules may be fused to the Fc domain directly or through a peptide linker. In a preferred aspect the Fab molecules are each fused to the Fc domain through an immunoglobulin hinge region. In a specific aspect, the immunoglobulin hinge region is a human IgGi hinge region, particularly where the Fc domain is an IgGi Fc domain, more particularly where the Fc domain is a human IgGi Fc domain.

[0360] In some aspects, the domain that bind to CD3 and the domain that binds to FolRl are each a Fab molecule and the domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or the second subunit of the Fc domain. In such aspects, the domain that binds to CD3 may be fused at the C-terminus of the Fab heavy chain to the N- terminus of the Fab heavy chain of the domain that binds to CD3 or (as described above) to the N-terminus of the other one of the subunits of the Fc domain. In preferred such aspects, said domain that binds to FolRl is a conventional Fab molecule, and domain that binds CD3 is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CL and CHI of the Fab heavy and light chains are exchanged / replaced by each other. In other such aspects, said domain that binds to FolRl is a crossover Fab molecule and the domain that binds to CD3 is a conventional Fab molecule.

[0361] In one aspect, the domain that binds to CD3 and the domain that binds to FolRl are each a Fab molecule, the domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or the second subunit of the Fc domain, and the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to FolRl. In a specific aspect, the (multispecific) antibody essentially consists of the Fab molecule that binds to CD3 and the Fab molecule that binds to FolRl, the Fc domain composed of a first and a second subunit, and optionally one or more peptide linkers, wherein the Fab molecule that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the Fab molecule that binds to Folrl, and the Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or the second subunit of the Fc domain. Such a configuration is schematically depicted in Figures 15H and 15L (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule and the domain that binds to FolRl being a conventional Fab molecule). Optionally, the Fab light chain of the Fab molecule that binds to CD3 and the Fab light chain of the Fab molecule that binds to FolRl may additionally be fused to each other.

[0362] In some aspects, a second domain that binds to FolRl, particularly a second Fab molecule binding to FolRl, is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or second subunit of the Fc domain. In preferred such aspects, the domain that binds to FolRl and the domain that binds to CD3 are each a conventional Fab molecule, and the domain that binds to CD3 is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CL and CHI of the Fab heavy and light chains are exchanged / replaced by each other. In other such aspects, said domains (first and second) binding to FolRl are each a crossover Fab molecule and the domain that binds to CD3 is a conventional Fab molecule.

[0363] In one such aspect, the domain that binds to CD3 and the second domain that binds to FolRl are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain, and the first domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the Fab molecule binding to CD3. In a specific aspect, the (multispecific) antibody essentially consists of the Fab molecule binding to CD3 and the first and second Fab molecules binding to FolRl, the Fc domain composed of a first and a second subunit, and optionally one or more peptide linkers, wherein the first Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the Fab molecule that binds to CD3, and the Fab molecule that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the second Fab molecule that binds to FolRl is fused at the C- terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain. Such a configuration is schematically depicted in Figure 15B and 15E (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule, and the first and second domains binding to FolRl being conventional Fab molecules), and Figure 15J and 15N (in these examples with the domain that binds to CD3 being a conventional Fab molecule, and the domains that bind to FolRl being a VH / VL crossover Fab molecule). The Fab molecule that binds to CD3 and the second Fab molecule that binds to FolRl may be fused to the Fc domain directly or through a peptide linker. In a preferred aspect, the Fab molecule that binds to CD3 and the Fab molecule that binds to FolRl are each fused to the Fc domain through an immunoglobulin hinge region. In a specific aspect, the immunoglobulin hinge region is a human IgGi hinge region, particularly where the Fc domain is an IgGi Fc domain, more particularly a human IgGi Fc domain. Optionally, the Fab light chain of the Fab molecule that binds CD3 and the Fab light chain of the Fab molecule that binds FolRl may additionally be fused to each other.

[0364] In another such aspect, the domains that bind to Folrl are each fused at the C -terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain, and the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to FolRl . In a specific aspect, the (multispecific) antibody essentially consists of the Fab molecule that binds to CD3 and the Fab molecules that bind to FolRl, the Fc domain composed of a first and a second subunit, and optionally one or more peptide linkers, wherein the Fab molecule that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first Fab molecule that binds to FolRl, and the first Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, and wherein the second Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N- terminus of the second subunit of the Fc domain. Such a configuration is schematically depicted in Figure 15C and 15F (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule, and the domains that bind to FolRl being a conventional Fab molecule) and in Figure 151 and 15M (in these examples with the domain that binds to CD3 being a conventional Fab molecule, and the domains binding to FolRl being a VH / VL crossover Fab molecule). The Fab molecules that bind to FolRl may be fused to the Fc domain directly or through a peptide linker. In a preferred aspect the Fab molecules that bind to FolRl are each fused to the Fc domain through an immunoglobulin hinge region. In a specific aspect, the immunoglobulin hinge region is a human IgGi hinge region, particularly where the Fc domain is an IgGi Fc domain, more particularly where the Fc domain is a human IgGi Fc domain. Optionally, the Fab light chain of the Fab molecule that binds to CD3 and the Fab light chain of the first Fab molecule that binds to FolRl may additionally be fused to each other.

[0365] In configurations of the (multispecific) antibody wherein a Fab molecule is fused at the C- terminus of the Fab heavy chain to the N-terminus of each of the subunits of the Fc domain through an immunoglobulin hinge region, the two Fab molecules, the hinge regions and the Fc domain essentially form an immunoglobulin molecule. In a preferred aspect the immunoglobulin molecule is an IgG class immunoglobulin. In an even more preferred aspect the immunoglobulin is an IgGi subclass immunoglobulin. In another aspect the immunoglobulin is an IgG4 subclass immunoglobulin. In a further preferred aspect the immunoglobulin is a human immunoglobulin. In other aspects the immunoglobulin is a chimeric immunoglobulin or a humanized immunoglobulin. In one aspect, the immunoglobulin comprises a human constant region, particularly a human Fc region.

[0366] In some of the (multispecific) antibodies of the invention, the Fab light chain of the Fab molecule that binds to CD3 and the Fab light chain of the first Fab molecule that binds to FolRl are fused to each other, optionally via a peptide linker. Depending on the configuration of the Fab molecule that binds to CD3 and the first Fab molecule that binds to FolRl, the Fab light chain of the Fab molecule that binds to CD3 may be fused at its C-terminus to the N-terminus of the Fab light chain of the first Fab molecule that binds to FolRl, or the Fab light chain of the first Fab molecule that binds to FolRl may be fused at its C-terminus to the N-terminus of the Fab light chain of the Fab molecule that binds to CD3. Fusion of the Fab light chains of the Fab molecule that binds to CD3 and the first Fab molecule that binds to FolRl further reduces mispairing of unmatched Fab heavy and light chains, and also reduces the number of plasmids needed for expression of some of the (multispecific) antibody of the invention.

[0367] The antigen domains that bind to FolRl and CD3 may be fused to the Fc domain or to each other directly or through a peptide linker, comprising one or more amino acids, typically about 2-20 amino acids. Peptide linkers are known in the art and are described herein. Suitable, non- immunogenic peptide linkers include, for example, (G4S)n, (SG4)n, (G4S)n, G4(SG4)n or (G4S)nGs peptide linkers, “n” is generally an integer from 1 to 10, typically from 2 to 4. In one aspect said peptide linker has a length of at least 5 amino acids, in one aspect a length of 5 to 100, in a further aspect of 10 to 50 amino acids. In one aspect said peptide linker is (GxS)nor (GxS)nGm with G=glycine, S=serine, and (x=3, n= 3, 4, 5 or 6, and m=0, 1, 2 or 3) or (x=4, n=l, 2, 3, 4 or 5 and m= 0, 1, 2, 3, 4 or 5), in one aspect x=4 and n=2 or 3, in a further aspect x=4 and n=2, in yet a further aspect x=4, n=l and m=5. In one aspect said peptide linker is (648)2. In another aspect, said peptide linker is G4SG5. A particularly suitable peptide linker for fusing the Fab light chains of the first and the second Fab molecule to each other is (648)2. An exemplary peptide linker suitable for connecting the Fab heavy chains of the first and the second Fab fragments comprises the sequence (D)-(G4S)2 (SEQ ID NOs 103 and 104). Another suitable such linker comprises the sequence (D)-G4SGs (SEQ ID NOs 105 and 106). Additionally, linkers may comprise (a portion of) an immunoglobulin hinge region. Particularly where a Fab molecule is fused to the N-terminus of an Fc domain subunit, it may be fused via an immunoglobulin hinge region or a portion thereof, with or without an additional peptide linker.

[0368] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy-terminal peptide bond with an Fc domain subunit (VL(i)-CHl (i)-CH2-CH3(-CH4)), and a polypeptide wherein the Fab heavy chain of the second Fab molecule shares a carboxy-terminal peptide bond with an Fc domain subunit (VH(2)-CH1(2)- CH2-CH3(-CH4)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (VH(i)-CL(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In certain aspects the polypeptides are covalently linked, e.g., by a disulfide bond.

[0369] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy-terminal peptide bond with an Fc domain subunit (VH(i)-CL(i)-CH2-CH3(-CH4)), and a polypeptide wherein the Fab heavy chain of the second Fab molecule shares a carboxy-terminal peptide bond with an Fc domain subunit (VH(2)-CH1(2)- CH2-CH3(-CH4)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (VL(i)-CHl(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In certain aspects the polypeptides are covalently linked, e.g., by a disulfide bond. In some aspects, the (multispecific) antibody comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with an Fc domain subunit (VL(i)-CHl(i)-VH(2)- CH1 (2)-CH2-CH3(-CH4)). In other aspects, the (multispecific) antibody comprises a polypeptide wherein the Fab heavy chain of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab light chain variable region of the Fab molecule that binds to CD3 which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy-terminal peptide bond with an Fc domain subunit (VH(2)-CHl(2)-VL(i)-CHl(i)-CH2-CH3(-CH4)). In some of these aspects the (multispecific) antibody further comprises a crossover Fab light chain polypeptide of the Fab molecule that binds to CD3, wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (VH(i)-CL(i)), and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In others of these aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the Fab that binds to CD3 molecule shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 which in turn shares a carboxy-terminal peptide bond with the Fab light chain polypeptide of the second Fab molecule (VH(i)-CL(i)-VL(2)- CL(2)), or a polypeptide wherein the Fab light chain polypeptide of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of the Fab molecule that binds to CD3 which in turn shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab that binds to CD3 molecule (VL(2)-CL(2)-VH(i)-CL(i)), as appropriate. The (multispecific) antibody according to these aspects may further comprise (i) an Fc domain subunit polypeptide (CH2-CH3(-CH4)), or (ii) a polypeptide wherein the Fab heavy chain of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with an Fc domain subunit (VH(3)-CH1(3)-CH2-CH3(-CH4)) and the Fab light chain polypeptide of a second Fab molecule that binds to FolRl (VL(3)-CL(3)). In certain aspects the polypeptides are covalently linked, e.g., by a disulfide bond. In some aspects, the (multispecific) antibody comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with an Fc domain subunit (VH(i)-CL(i)-VH(2)- CH1 (2)-CH2-CH3(-CH4)). In other aspects, the (multispecific) antibody comprises a polypeptide wherein the Fab heavy chain of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of the Fab molecule that binds to CD3 which in turn shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy-terminal peptide bond with an Fc domain subunit (VH(2)-CHl(2)-VH(i)-CL(i)-CH2-CH3(-CH4)). In some of these aspects the (multispecific) antibody further comprises a crossover Fab light chain polypeptide of the Fab molecule that binds to CD3, wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (VL(i)-CHl(i)), and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In others of these aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 which in turn shares a carboxy-terminal peptide bond with the Fab light chain polypeptide of the second Fab molecule (VL(i)-CHl(i)-VL(2)-CL(2)), or a polypeptide wherein the Fab light chain polypeptide of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of the Fab molecule that binds to CD3 which in turn shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (VL(2)- CL(2)-VH(i)-CL(i)), as appropriate. The (multispecific) antibody according to these aspects may further comprise (i) an Fc domain subunit polypeptide (CH2-CH3(-CH4)), or (ii) a polypeptide wherein the Fab heavy chain of a second Fab molecule that binds to FolRl shares a carboxy- terminal peptide bond with an Fc domain subunit (VH(3)-CH1(3)-CH2-CH3(-CH4)) and the Fab light chain polypeptide of a second Fab molecule that binds to FolRl (VL(3)-CL(3)). In certain aspects the polypeptides are covalently linked, e.g., by a disulfide bond. In certain aspects, the (multispecific) antibody does not comprise an Fc domain. In preferred such aspects, the (first) domain that binds to FolRl and, if present, second domain that binds to FolRl are each a conventional Fab molecule, and the domain that binds CD3 is a crossover Fab molecule as described herein, i.e. a Fab molecule wherein the variable domains VH and VL or the constant domains CL and CHI of the Fab heavy and light chains are exchanged / replaced by each other. In other such aspects, the first and, if present, second domain are each a crossover Fab molecule and the domain that binds to CD3 is a conventional Fab molecule.

[0370] In one such aspect, the (multispecific) antibody essentially consists of the domain that binds to CD3 and the domain that binds to FolRl, and optionally one or more peptide linkers, wherein the domains are both Fab molecules and the domain that binds to FolRl is fused at the C- terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds CD3. Such a configuration is schematically depicted in Figures 150 and 15S (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule and the domain that binds to FolRl being a conventional Fab molecule).

[0371] In another such aspect, the (multispecific) antibody essentially consists of the domain that binds to CD3 and the domain that binds to FolRl, and optionally one or more peptide linkers, wherein the domains are both Fab molecules and the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to FolRl. Such a configuration is schematically depicted in Figures 15P and 15T (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule and the domain that binds to FolRl being a conventional Fab molecule).

[0372] In some aspects, the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the Fab molecule that binds to CD3, and the (multispecific) antibody further comprises a second domain that binds to FolRl, particularly a second Fab molecule that binds to FolRl, wherein said second Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first Fab molecule that binds to FolRl. In certain such aspects, the (multispecific) antibody essentially consists of the Fab molecule that binds to CD3 and the first and second Fab molecules that bind to FolRl, and optionally one or more peptide linkers, wherein the first Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the Fab molecule that binds to CD3, and the second Fab molecule that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first Fab molecule that binds to FolRl. Such a configuration is schematically depicted in Figures 15Q and 15U (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule and the first and second domains binding to FolRl each being a conventional Fab molecule), or Figures 15X and 15Z (in these examples with the domain that binds to CD3 being a conventional Fab molecule and the first and second domains that bind to FolRl each being a VH / VL crossover Fab molecule).

[0373] In some aspects, the Fab molecule that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first Fab molecule that binds to FolRl, and the (multispecific) antibody further comprises a second domain that binds to FolRl, particularly a second Fab molecule that binds to FolRl, wherein said second Fab molecule that binds to FolRl is fused at the N-terminus of the Fab heavy chain to the C-terminus of the Fab heavy chain of the first Fab molecule that binds to FolRl. In certain such aspects, the (multispecific) antibody essentially consists of the Fab molecule that binds to CD3 and the first and second Fab molecules that bind to FolRl, and optionally one or more peptide linkers, wherein the Fab molecule that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first Fab molecule that binds to FolRl, and the second Fab molecule that binds to FolRl is fused at the N-terminus of the Fab heavy chain to the C-terminus of the Fab heavy chain of the first Fab molecule that binds to FolRl. Such a configuration is schematically depicted in Figures 15R and 15V (in these examples with the domain that binds to CD3 being a VH / VL crossover Fab molecule and the first and second domains that bind to FolRl each being a conventional Fab molecule), or Figures 15W and 15Y (in these examples with the domain that binds to CD3 being a conventional Fab molecule and the first and second domains binding to FolRl each being a VH / VL crossover Fab molecule).

[0374] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain of the first Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab light chain variable region of the Fab molecule that binds to CD3, which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region) (VH(2)-CHl(2)-VL(i)-CHl(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (VH(i)-CL(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)).

[0375] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab that binds to CD3 molecule comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of the first Fab molecule that binds FolRl (VL(i)-CHl(i)-VH(2)-CHl(2)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (VH(i)-CL(i)) and the Fab light chain polypeptide of the first Fab molecule that binds to FolRl (VL(2)-CL(2)).

[0376] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of the Fab molecule that binds to CD3, which in turn shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region) (VH(2)-CHl(2)-VH(i)-CL(i). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (VL(i)-CHl(i)) and the Fab light chain polypeptide of the first Fab molecule that binds to FolRl (VL(2)-CL(2)).

[0377] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of the second Fab molecule (VH(i)-CL(i)-VH(2)-CHl(2)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (VL(i)-CHl(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)).

[0378] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab heavy chain of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with the Fab light chain variable region of the Fab molecule that binds to CD3, which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region) (VH(3)-CHl(3)-VH(2)-CHl(2)-VL(i)-CHl(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (VH(i)-CL(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In some aspects the (multispecific) antibody further comprises the Fab light chain polypeptide of a second Fab molecule that binds to FolRl (VL(3)-CL(3)).

[0379] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab heavy chain of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of the Fab molecule that binds to CD3, which in turn shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region) (VH(3)-CH1(3)-VH(2)-CH1(2)- VH D-CL D). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (VL(i)-CHl(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In some aspects the (multispecific) antibody further comprises the Fab light chain polypeptide of a second Fab molecule that binds to FolRl (VL(3)-CL(3)). In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy -terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of a second Fab molecule that binds to FolRl (VL(i)-CHl(i)-VH(2)-CHl(2)-VH(3)-CHl(3)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (VH(i)-CL(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In some aspects the (multispecific) antibody further comprises the Fab light chain polypeptide of a second Fab molecule that binds to FolRl (VL(3)-CL(3)).

[0380] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain constant region of the Fab molecule that binds to CD3 (i.e. the Fab molecule that binds to CD3 comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain of a second Fab molecule that binds to FolRl (VH(i)-CL(i)-VH(2)-CHl(2)-VH(3)-CHl(3)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the Fab molecule that binds to CD3 (VL(i)-CHl(i)) and the Fab light chain polypeptide of the second Fab molecule (VL(2)-CL(2)). In some aspects the (multispecific) antibody further comprises the Fab light chain polypeptide of a second Fab molecule that binds to FolRl (VL(3)-CL(3)).

[0381] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab light chain variable region of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the second Fab molecule (i.e. the second Fab molecule comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy-terminal peptide bond with the Fab light chain variable region of a second Fab molecule that binds to FolRl, which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of a second Fab molecule that binds to FolRl (i.e. the second Fab molecule that binds to FolRl comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region) (VH(i)- CHl(i)-VL(2)-CHl(2)-VL(3)-CHl(3)). In some aspects the (multi specific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab light chain constant region of the second Fab molecule (VH(2)-CL(2)) and the Fab light chain polypeptide of the that binds to CD3 Fab molecule (VL(i)-CL(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab light chain constant region of a second Fab molecule that binds to FolRl (VH(3)-CL(3)).

[0382] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain of the Fab molecule that binds to CD3 shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of the second Fab molecule, which in turn shares a carboxy-terminal peptide bond with the Fab light chain constant region of the second Fab molecule (i.e. the second Fab molecule comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of a second Fab molecule that binds to FolRl, which in turn shares a carboxy-terminal peptide bond with the Fab light chain constant region of a second Fab molecule that binds to FolRl (i.e. the second Fab molecule that binds to FolRl comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region) (VH(i)- CH1 (i)-VH(2)-CL(2)-VH(3)-CL(3)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the second Fab molecule (VL(2)-CH1(2)) and the Fab light chain polypeptide of the Fab molecule that binds to CD3 (VL(i)-CL(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of a second Fab molecule that binds to FolRl (VL(3)-CH1(3)). In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab light chain variable region of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of a second Fab molecule that binds to FolRl (i.e. the second Fab molecule that binds to FolRl comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy-terminal peptide bond with the Fab light chain variable region of the second Fab molecule, which in turn shares a carboxy- terminal peptide bond with the Fab heavy chain constant region of the second Fab molecule (i.e. the second Fab molecule comprises a crossover Fab heavy chain, wherein the heavy chain variable region is replaced by a light chain variable region), which in turn shares a carboxy- terminal peptide bond with the Fab heavy chain of the Fab molecule that binds to CD3 (VL(3)- CH1(3)-VL(2)-CH1 (2)-VH(i)-CHl(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab light chain constant region of the second Fab molecule (VH(2)-CL(2)) and the Fab light chain polypeptide of the Fab molecule that binds to CD3 (VL(i)-CL(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab heavy chain variable region of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab light chain constant region of a second Fab molecule that binds to FolRl (VH(3)-CL(3)).

[0383] In certain aspects the (multispecific) antibody according to the invention comprises a polypeptide wherein the Fab heavy chain variable region of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab light chain constant region of a second Fab molecule that binds to FolRl (i.e. the second Fab molecule that binds to FolRl comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy-terminal peptide bond with the Fab heavy chain variable region of the second Fab molecule, which in turn shares a carboxy- terminal peptide bond with the Fab light chain constant region of the second Fab molecule (i.e. the second Fab molecule comprises a crossover Fab heavy chain, wherein the heavy chain constant region is replaced by a light chain constant region), which in turn shares a carboxy- terminal peptide bond with the Fab heavy chain of the Fab molecule that binds to CD3 (VHp)- CL(3)-VH(2)-CL(2)-VH(i)-CHl(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of the second Fab molecule shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of the second Fab molecule (VL(2)-CH1(2)) and the Fab light chain polypeptide of the Fab molecule that binds to CD3 (VL(i)-CL(i)). In some aspects the (multispecific) antibody further comprises a polypeptide wherein the Fab light chain variable region of a second Fab molecule that binds to FolRl shares a carboxy-terminal peptide bond with the Fab heavy chain constant region of a second Fab molecule that binds to FolRl (VL(3)-CH1(3)).

[0384] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 132, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 133, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 134 , and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 135.

[0385] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 136, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 137, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 138 , and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 139. In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 140, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 141, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 142, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 143.

[0386] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 144, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 145, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 146, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 147.

[0387] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 148, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 149, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 150, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 151.

[0388] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 156, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 157, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 158, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 159.

[0389] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 164, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 165, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 166, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 167. In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 168, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 169, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 170, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 171.

[0390] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 172, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 173, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 174, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 175.

[0391] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 176, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 177, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 178, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 179.

[0392] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 180, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 181, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 182, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 183.

[0393] In one aspect the invention provides a multispecific antibody that binds to CD3 and FolRl, wherein the antibody comprises a chain B comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 184, a chain H comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 185, a chain K comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 186, and a chain A comprising a polypeptide comprising an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence of SEQ ID NO: 187 . Table 12 shows an overview of sequences of antibodies of the invention in 2+1 TCB format.

[0394] Table 13 shows an overview of sequences of antibodies of the invention in 1+1 TCB format.

[0395] 5. Fc domain variants

[0396] In preferred aspects, the (multispecific) antibody of the invention comprises an Fc domain composed of a first and a second subunit.

[0397] The Fc domain of the (multispecific) antibody consists of a pair of polypeptide chains comprising heavy chain domains of an immunoglobulin molecule. For example, the Fc domain of an immunoglobulin G (IgG) molecule is a dimer, each subunit of which comprises the CH2 and CH3 IgG heavy chain constant domains. The two subunits of the Fc domain are capable of stable association with each other. In one aspect, the (multispecific) antibody of the invention comprises not more than one Fc domain.

[0398] In one aspect, the Fc domain of the (multispecific) antibody is an IgG Fc domain. In a preferred aspect, the Fc domain is an IgGi Fc domain, more particularly a human IgGi Fc domain. In another aspect the Fc domain is an IgG4 Fc domain. In a more specific aspect, the Fc domain is an IgG4Fc domain comprising an amino acid substitution at position S228 (Kabat EU index numbering), particularly the amino acid substitution S228P. This amino acid substitution reduces in vivo Fab arm exchange of IgG4antibodies (see Stubenrauch et al., Drug Metabolism and Disposition 38, 84-91 (2010)). In a further preferred aspect, the Fc domain is a human Fc domain. In an even more preferred aspect, the Fc domain is a human IgGi Fc domain. An exemplary sequence of a human IgGi Fc region is given in SEQ ID NO: 123. a) Fc domain modifications promoting heterodimerization

[0399] (Multi specific) antibodies according to the invention comprise different domains that bind to FolRl and CD3, which may be fused to one or the other of the two subunits of the Fc domain, thus the two subunits of the Fc domain are typically comprised in two non-identical polypeptide chains. Recombinant co-expression of these polypeptides and subsequent dimerization leads to several possible combinations of the two polypeptides. To improve the yield and purity of (multispecific) antibodies in recombinant production, it will thus be advantageous to introduce in the Fc domain of the (multispecific) antibody a modification promoting the association of the desired polypeptides.

[0400] Accordingly, in preferred aspects, the Fc domain of the (multispecific) antibody according to the invention comprises a modification promoting the association of the first and the second subunit of the Fc domain. The site of most extensive protein-protein interaction between the two subunits of a human IgG Fc domain is in the CH3 domain of the Fc domain. Thus, in one aspect said modification is in the CH3 domain of the Fc domain.

[0401] There exist several approaches for modifications in the CH3 domain of the Fc domain in order to enforce heterodimerization, which are well described e.g. in WO 96 / 27011, WO 98 / 050431, EP 1870459, WO 2007 / 110205, WO 2007 / 147901, WO 2009 / 089004, WO 2010 / 129304, WO 2011 / 90754, WO 2011 / 143545, WO 2012058768, WO 2013157954, WO 2013096291. Typically, in all such approaches the CH3 domain of the first subunit of the Fc domain and the CH3 domain of the second subunit of the Fc domain are both engineered in a complementary manner so that each CH3 domain (or the heavy chain comprising it) can no longer homodimerize with itself but is forced to heterodimerize with the complementarily engineered other CH3 domain (so that the first and second CH3 domain heterodimerize and no homodimers between the two first or the two second CH3 domains are formed). These different approaches for improved heavy chain heterodimerization are contemplated as different alternatives in combination with the heavy-light chain modifications (e.g. VH and VL exchange / replacement in one binding arm and the introduction of substitutions of charged amino acids with opposite charges in the CH1 / CL interface) in the (multispecific) antibody which reduce heavy / light chain mispairing and Bence Jones-type side products.

[0402] In a specific aspect said modification promoting the association of the first and the second subunit of the Fc domain is a so-called “knob-into-hole” modification, comprising a “knob” modification in one of the two subunits of the Fc domain and a “hole” modification in the other one of the two subunits of the Fc domain.

[0403] The knob-into-hole technology is described e.g. in US 5,731,168; US 7,695,936; Ridgway et al., Prot Eng 9, 617-621 (1996) and Carter, J Immunol Meth 248, 7-15 (2001). Generally, the method involves introducing a protuberance (“knob”) at the interface of a first polypeptide and a corresponding cavity (“hole”) in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heterodimer formation and hinder homodimer formation. Protuberances are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g. tyrosine or tryptophan). Compensatory cavities of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine).

[0404] Accordingly, in a preferred aspect, in the CH3 domain of the first subunit of the Fc domain of the (multispecific) antibody an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is positionable.

[0405] Preferably said amino acid residue having a larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), and tryptophan (W).

[0406] Preferably said amino acid residue having a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), and valine (V).

[0407] The protuberance and cavity can be made by altering the nucleic acid encoding the polypeptides, e.g. by site-specific mutagenesis, or by peptide synthesis.

[0408] In a specific aspect, in (the CH3 domain of) the first subunit of the Fc domain (the “knobs” subunit) the threonine residue at position 366 is replaced with a tryptophan residue (T366W), and in (the CH3 domain of) the second subunit of the Fc domain (the “hole” subunit) the tyrosine residue at position 407 is replaced with a valine residue (Y407V). In one aspect, in the second subunit of the Fc domain additionally the ...

Claims

WHAT IS CLAIMED IS:

1. An antibody that binds to FolRl, wherein the antibody binds to FolRl at neutral pH with a first KD and at an acidic pH with a second KD, wherein the first KD is greater than the second KD and the first KD and the second KD are measured by surface plasmon resonance (SPR) at 25 °C.

2. The antibody of claim 1, wherein the acidic pH ranges from 6.0 to 6.6 and the neutral pH ranges from 7.0 to 7.4, particularly wherein the acidic pH is 6.5 or 6.1 and the neutral pH is 7.0 or 7.4, more particularly wherein the acidic pH is 6.5 and the neutral pH is 7.4.

3. The antibody of claim 1 or 2, wherein the first KD is greater than the second KD by a factor of at least 2, at least 5, at least 8, at least 10, at least 11, at least 13, at least 16, at least 23, at least 31, at least 40, at least 60, at least 74 or at least 195 or more.

4. The antibody of claim 3, wherein the second KD is equal to 47nM or less at pH 6.5 and the first KD is equal to 46 nM or more at pH 7.4.

5. The antibody of any one of claims 1 to 4, wherein the first KD is greater than the second KD by a factor ranging from 2 to 195 or from 5 to 195.

6. The antibody of any one of claims 1 to 5, wherein the antibody is a monoclonal antibody.

7. The antibody of any one of claims 1 to 6, wherein the antibody is a human antibody.

8. The antibody according to any one of claims 1 to 7, wherein the antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of X2YYX3H SEQ ID NO:88, (b) CDR-H2 comprising the amino acid sequence of X4INPX5X6GX7TX8YAQKFQG (SEQ ID NO:89), and (c) CDR-H3 comprising the amino acid sequence of GDX9X10X11LDY (SEQ ID NO:90), and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of RSSQSLLHX12NGYX13YLD (SEQ ID NO:86), (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of MQALQGX14X15X16T (SEQ ID NO:87), wherein X2 is S, T or E, X3 is M or I, X4 is I or V, X5 is S or R, X6 is D or G, X7 is R, S, or N, X8 is S, R, N or T, X9 is F or Y, X10 is D or E, XI 1 is A, G or S, X12 is A or S, X13 N or H, X14 is P or L, XI 5 is Y or A and XI 6 is N or D, optionally wherein when XI 5 is Y XI 6 is N and when X15 is A X16 is D.

9. The antibody according to any one of claims 1 to 8, wherein the antibody comprises a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising an amino acidsequence selected from the group consisting of SEQ ID NOs: 19, 44, 49, 54, and 58, (b) CDR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 45, 50, 55, 59, 62, and 66, and (c) CDR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:21, 46, 51, 60, 63, 78, 81, and 84, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 23, 36, and 40, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25, 37, and 41.

10. The antibody according to any one of claims 1 to 9, wherein the antibody comprisesA) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;B) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;C) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;D) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:78, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;E) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;G) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:50, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:51, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;H) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;I) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:54, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:55, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising theamino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;J) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of (SEQ ID NO: 19), (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:62, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:63, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;K) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:66, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;L) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;M) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:81, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37; orN) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:84, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37.

11. An antibody that binds to FolRl, wherein the antibody comprisesA) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;B) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;C) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:58, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:59, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;D) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence ofSEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:78, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;E) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;G) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:49, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:50, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:51, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;H) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:46, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;I) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:54, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:55, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acidsequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;J) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of (SEQ ID NO: 19), (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:62, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:63, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;K) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 19, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:66, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:25;L) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37;M) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:81, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37; orN) a heavy chain variable domain (VH) comprising (a) CDR-H1 comprising the amino acid sequence of SEQ ID NO:44, (b) CDR-H2 comprising the amino acid sequence of SEQ ID NO:45, and (c) CDR-H3 comprising the amino acid sequence of SEQ ID NO:84, and a light chain variable domain (VL) comprising (d) CDR-L1 comprising the amino acid sequence of SEQ ID NO:36, (e) CDR-L2 comprising the amino acid sequence of LGSNRAS (SEQ ID NO:24), and (f) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 37.

12. The antibody of any one of claims 8 to 11, further comprising a light chain variable domain framework FR1 sequence of SEQ ID NO:91, FR2 sequence of SEQ ID NO:92, FR3 sequence of SEQ ID NO:93, FR4 sequence of SEQ ID NO:94, and / or a heavy chain variable domain framework FR1 sequence of SEQ ID NO:95 or SEQ ID NO:96, FR2 sequence of SEQ ID NO:97, FR3 sequence of SEQ ID NO:98, and FR4 sequence of SEQ ID NO:99.

13. The antibody of any one of claims 1 to 12, wherein the antibody comprises a VH comprising an amino acid sequence ofQVQLVQSGAEVKKPGASVKVSCKASGYTFX17X2YYX3HWVRQAPGQGLEWMGX4I NPX5X6GX7TX8YAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGDX9X1 0X11LDYWGQGTLVTVSS (SEQ ID NO: 107), and / or a VL comprising an amino acid sequence ofDIVMTQSPLSLPVTPGEPASISCRSSQSLLHX12NGYX13YLDWYLQKPGQSPQLLIYL GSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQGX14X15X16TFGQG TKVEIK (SEQ ID NO: 108), wherein X2 is S, T or E, X3 is M or I, X4 is I or V, X5 is S or R, X6 is D or G, X7 is R, S, or N, X8 is S, R, N or T, X9 is F or Y, X10 is D or E, XI 1 is A, G or S, X12 is A or S, X13 N or H, X14 is P or L, X15 is Y or A, X16 is N or D and X17 is T or S, optionally wherein when XI 5 is Y XI 6 is N and when XI 5 is A XI 6 is D.

14. The antibody of any one of claims 1 to 13, wherein the antibody comprisesA) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;B) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQID NO: 47, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;C) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 60, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;D) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 79, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;E) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;G) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 52, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;H) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;I) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 56, and / or a VL comprising an amino acid sequence that is at least 95%, at least96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;J) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 64, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;K) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 67, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 26;L) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 76, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38;M) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 82, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38; orN) a VH comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 85, and / or a VL comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 38.

15. The antibody of any one of claims 1 to 14, wherein the antibody comprisesA) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;B) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;C) a VH comprising an amino acid sequence of SEQ ID NO: 60, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;D) a VH comprising an amino acid sequence of SEQ ID NO: 79, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;E) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;G) a VH comprising an amino acid sequence of SEQ ID NO: 52, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;H) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;I) a VH comprising an amino acid sequence of SEQ ID NO: 56, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;J) a VH comprising an amino acid sequence of SEQ ID NO: 64, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;K) a VH comprising an amino acid sequence of SEQ ID NO: 67, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;L) a VH comprising an amino acid sequence of SEQ ID NO: 76, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;M) a VH comprising an amino acid sequence of SEQ ID NO: 82, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38; orN) a VH comprising an amino acid sequence of SEQ ID NO: 85, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38.

16. An antibody that binds to FolRl, wherein the antibody comprisesA) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;B) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;C) a VH comprising an amino acid sequence of SEQ ID NO: 60, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;D) a VH comprising an amino acid sequence of SEQ ID NO: 79, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;E) a VH comprising an amino acid sequence of SEQ ID NO: 22, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;G) a VH comprising an amino acid sequence of SEQ ID NO: 52, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;H) a VH comprising an amino acid sequence of SEQ ID NO: 47, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;I) a VH comprising an amino acid sequence of SEQ ID NO: 56, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;J) a VH comprising an amino acid sequence of SEQ ID NO: 64, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;K) a VH comprising an amino acid sequence of SEQ ID NO: 67, and / or a VL comprising an amino acid sequence of SEQ ID NO: 26;L) a VH comprising an amino acid sequence of SEQ ID NO: 76, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38;M) a VH comprising an amino acid sequence of SEQ ID NO: 82, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38; orN) a VH comprising an amino acid sequence of SEQ ID NO: 85, and / or a VL comprising an amino acid sequence of SEQ ID NO: 38.

17. The antibody of any one of claims 1 to 16, wherein the antibody is an antibody fragment that binds FolRl.

18. The antibody of any one of claims 1 to 17, wherein the antibody fragment is a Fab molecule.

19. The antibody of any one of claims 1 to 16, wherein the antibody is a full length IgGi antibody.

20. The antibody of any one of claims 1 to 19, comprising an Fc domain composed of a first and a second subunit.

21. The antibody of any one of claims 1 to 20, wherein the antibody is multispecific.

22. The antibody of any one of claims 1 to 21 wherein the antibody is a bispecific antibody comprising at least one domain that binds to CD3 and at least one domain that binds to FolRl.

23. The antibody of claim 22, wherein the domain that binds to CD3 is a Fab molecule wherein the variable domains VL and VH or the constant domains CL and CHI, particularly the variable domains VL and VH, of the Fab light chain and the Fab heavy chain are replaced by each other.

24. The antibody of claim 22 or 23, wherein the domain that binds to FolRl is a Fab molecule wherein in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat), and in the constant domain CHI the amino acid at position 147 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E), or aspartic acid (D) (numbering according to Kabat EU index).

25. The antibody of any one of claims 18, 23 or 24, wherein the Fab molecule is a conventional Fab molecule.

26. The antibody of any one of claims 22 to 25, wherein the domain that binds to CD3 and the domain that binds to FolRl are fused to each other, optionally via a peptide linker.

27. The antibody of any one of claims 1 to 26, comprising a domain that binds to CD3 and a domain that binds to FolRl, wherein the domain that binds to CD3 and the domain that binds to FolRl are each a Fab molecule and either (i) the domain that binds to FolRl is fused at the C -terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3, or (ii) the domain that binds to CD3 is fused at the C -terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to FolRl.

28. The antibody of any one of claims 1 to 27, comprising a domain that binds to CD3 and a first domain that binds to FolRl, optionally a second domain that binds to FolRl, wherein thedomain that binds to CD3 and the domain that binds to FolRl are each a Fab molecule and the antibody comprises an Fc domain composed of a first and a second subunit; and wherein either (i) the first domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the domain that binds to CD3 and the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain, or (ii) the domain that binds to CD3 is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first domain that binds to FolRl and the first domain that binds to FolRl is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit of the Fc domain; and the second domain that binds to FolRl, where present, is fused at the C-terminus of the Fab heavy chain to the N-terminus of the second subunit of the Fc domain.

29. The antibody of claim 20 or 28, wherein the Fc domain is an IgG Fc domain, particularly an IgGi Fc domain, more particularly a human IgGi Fc domain.

30. The antibody of any one of claims 20, 28 or 29, wherein the Fc domain is a human Fc domain.

31. The antibody of any one of claims 20 or 28 to 30, wherein the Fc comprises a modification promoting the association of the first and the second subunit of the Fc domain.

32. The antibody of any one of claims 20 or 28 to 31, wherein the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor and / or effector function.

33. The antibody of any one of claims 20 or 28 to 32, wherein the antibody comprises an Fc region derived from a human IgGi Fc region and comprising the substitutions L234A, L235A and P329G (LALA-PG).

34. An immunoconjugate comprising the antibody of any one of claims 1 to 33 and a cytotoxic agent.

35. An isolated nucleic acid encoding the antibody of any of claims 1 to 34.

36. A host cell comprising the nucleic acid of claim 35.

37. A method of producing an antibody that binds to FolRl comprising culturing the host cell of claim 36 under conditions suitable for the expression of the antibody.

38. The method of claim 37, further comprising recovering the antibody from the host cell.

39. An antibody produced by the method of claim 37 or 38.

40. A pharmaceutical composition comprising the antibody of any of claims 1 to 33 and a pharmaceutically acceptable carrier.

41. The antibody of any one of claims 1 to 33 or 39 or the pharmaceutical composition of claim 40 for use as a medicament.

42. The antibody of any one of claims 1 to 33 or 39 or the pharmaceutical composition of claim 40 for use in treating cancer.

43. Use of the antibody of any one of claims 1 to 33 or 39 or the pharmaceutical composition of claim 40 in the manufacture of a medicament for treatment of cancer.

44. Use of the antibody of any one of claims 1 to 33 or 39 or the pharmaceutical composition of claim 40 in the manufacture of a medicament for pH dependent T-cell redirection and pH dependent T-cell mediated cancer cell killing.

45. A method of treating an individual having cancer comprising administering to the individual an effective amount of the antibody of any one of claims 1 to 33 or 39 or the pharmaceutical composition of claim 40.

46. A method of pH dependent T-cell redirection and T-cell mediated cancer cell killing in an individual comprising administering to the individual an effective amount of the antibody of any of claims 1 to 33 or 39 or the pharmaceutical composition of claim 40 to redirect T cells and mediate T-cells to kill cancer cells in a pH dependent manner.***

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