Anti-CD93 structures and their use

Abstract

Providing anti-CD93 structures and their use. [Solution] This application provides an anti-CD93 construct that binds to CD93 (e.g., an anti-CD93 antibody), a nucleic acid molecule encoding the amino acid sequence of anti-CD93, a vector containing the nucleic acid molecule, a host cell containing the vector, a method for preparing an anti-CD93 construct, a pharmaceutical composition containing an anti-CD93 construct, and a method for using an anti-CD93 construct or composition. CD93 (surface antigen classification 93) is a protein encoded by the CD93 gene in humans. CD93 is a type C lectin transmembrane receptor that plays a role not only in cell-cell adhesion processes but also in host defense.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63 / 033,755 filed on 2 June 2020, U.S. Provisional Application No. 63 / 058,359 filed on 29 July 2020, and U.S. Provisional Application No. 63 / 084,474 filed on 28 September 2020, the contents of which are incorporated by reference in their entirety for all purposes.

[0002] Technical field This disclosure relates to anti-CD93 constructs (such as anti-CD93 antibodies) and their use.

[0003] Submission of sequence listings in ASCII text files. The contents of the following submission in ASCII text file are incorporated herein by reference in their entirety: Computer-Readable Format (CRF) of Sequence Listings (filename: 193852000240SEQLIST.TXT, date recorded: June 1, 2021, size: 185KB). [Background technology]

[0004] Background of this application CD93 (surface antigen classification 93) is a protein encoded by the CD93 gene in humans. CD93 is a C-type lectin transmembrane receptor that plays a role not only in cell-cell adhesion processes but also in host defense. While initially thought to be a receptor for C1q, CD93 is now believed to be involved in cell-cell adhesion and apoptotic cell clearance. The intracellular cytoplasmic tail of this protein contains two highly conserved domains that may be involved in CD93 function. Indeed, the highly charged perimembrane domain has been found to interact with moesin, a protein known to play a role in linking transmembrane proteins to the cytoskeleton and in cytoskeletal reorganization. This process appears to be crucial for adhesion, migration, and phagocytosis.

[0005] All publications, patents, patent applications, and published patent application disclosures referenced herein are incorporated herein by reference in their entirety. [Overview of the Initiative] [Means for solving the problem]

[0006] Brief summary of this application The following summary is illustrative and not intended to be limiting. That is, the following summary is provided to highlight the novel molecule and its uses, advantages, and merits. Therefore, the following summary is not intended to identify the essential features of the claimed subject matter, nor to be used in determining the scope of the claimed subject matter.

[0007] In one embodiment, this application relates to the heavy chain variable region (V H ) and light chain variable region (V L The present invention provides an anti-CD93 construct comprising an antibody moiety containing a second heavy chain variable region (V H-2 ) and the second light chain variable region (V L-2 The antibody or antibody fragment containing ) competes for the CD93 binding epitope, a)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6; b)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22; c) V H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 35, and V L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38; d) V H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, and V L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54; e) V H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 66, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, and V L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70; f) V H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 83, and V L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86; g) V H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, and V L-2This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102; h)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118; i)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134; j)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358; LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356; and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359; k)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166; l)V H-2It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182; m)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 194, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 195, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198; n)V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214; or o)V H-2 It includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294; p)V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, V L-2This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0008] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0009] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0010] In some embodiments, V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 35, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0011] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0012] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 66, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0013] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 83, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0014] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0015] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0016] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0017] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358; ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356; and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

[0018] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0019] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0020] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 194, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 195, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0021] In some embodiments, V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0022] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0023] In some embodiments, V H This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or its variants containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V L This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0024] In another aspect, this application relates to an anti-CD93 construct comprising an antibody moiety that specifically binds to CD93, a) V having the sequence shown in Sequence ID No. 13 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V, which has the sequence shown in Sequence ID No. 14. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; b) V having the sequence shown in any of sequence numbers 29 and 307-312 H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 30 and 313-318. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; c) V having the sequence shown in Sequence ID No. 45 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 46. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; d) V having the sequence shown in Sequence ID No. 61 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 62. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; e) V having the sequence shown in Sequence ID 77 HHC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V, which has the sequence shown in Sequence ID No. 78. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; f) V having the sequence shown in sequence number 93 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V, which has the sequence shown in Sequence ID No. 94. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; g) V having the sequence shown in Sequence ID No. 109 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 110. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; h) V having the sequence shown in Sequence ID No. 125 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 126. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; i) V having the sequence shown in Sequence ID 141 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 142. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; j) V having the sequence shown in any of SEQ ID NO: 157 and 360 - 362 H HC - CDR1, HC - CDR2, and HC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region, and V having the sequence shown in SEQ ID NO: 158 and any of 363 - 365 L LC - CDR1, LC - CDR2, and LC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region; k) V having the sequence shown in SEQ ID NO: 173 H HC - CDR1, HC - CDR2, and HC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region, and V having the sequence shown in SEQ ID NO: 174 L LC - CDR1, LC - CDR2, and LC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region; l) V having the sequence shown in any of SEQ ID NO: 189 and 347 - 349 H HC - CDR1, HC - CDR2, and HC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region, and V having the sequence shown in SEQ ID NO: 190 and any of 350 - 352 L LC - CDR1, LC - CDR2, and LC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region; m) V having the sequence shown in SEQ ID NO: 205 H HC - CDR1, HC - CDR2, and HC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region, and V having the sequence shown in SEQ ID NO: 206 L LC - CDR1, LC - CDR2, and LC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region; n) V having the sequence shown in SEQ ID NO: 221 H HC - CDR1, HC - CDR2, and HC - CDR3 each containing the amino acid sequences of CDR1, CDR2, and CDR3 respectively within the chain region, and V having the sequence shown in SEQ ID NO: 222L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequence of CDR1, CDR2, and CDR3 within the light chain region; o) V having the sequence shown in any of SEQ ID NO: 287 and 319 - 321 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy chain region, and V having the sequence shown in any of SEQ ID NO: 288 and 322 - 324 L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequence of CDR1, CDR2, and CDR3 within the light chain region; p) V having the sequence shown in any one of SEQ ID NO: 307 - 312 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy chain region, and V having the sequence shown in any one of SEQ ID NO: 313 - 318 L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequence of CDR1, CDR2, and CDR3 within the light chain region; or q) V having the sequence shown in any one of SEQ ID NO: 319 - 321 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequence of CDR1, CDR2, and CDR3 within the heavy chain region, and V having the sequence shown in any one of SEQ ID NO: 322 - 324 L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequence of CDR1, CDR2, and CDR3 within the light chain region is included.

[0025] In some embodiments with any of the above anti-CD93 constructs, V HThis includes a modifier comprising any one amino acid sequence of sequence numbers 13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 287, 307-312 and 319-321, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and / or V L This includes a modifier comprising any one of the amino acid sequences of SEQ ID NOs: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 288, 313-318 and 322-324, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 13; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of any of sequence numbers 29 and 307-312, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences of sequence 30 and 313-318. In some embodiments, V HThis includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 45, or any one of these; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 61; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 62, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 77, or a variant containing an amino acid sequence having sequence identity of at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 78, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 93; V LThis includes a modifier comprising the amino acid sequence of SEQ ID NO: 94, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 109; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 110, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 125; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 126, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 141; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 142, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V HThis includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 157; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 158, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 173; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of any of sequence numbers 189 and 347-349, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with any of the amino acid sequences of sequence 190 and 350-352. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 205; V LThis includes a modifier comprising the amino acid sequence of SEQ ID NO: 206, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 221; V L This includes a modifier comprising the amino acid sequence of SEQ ID NO: 222, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of any of sequence numbers 287 and 319-321, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having sequence identity of any of sequence numbers 288 and 322-324, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%).

[0026] In some embodiments of any of the above anti-CD93 constructs, the antibody portion is an antibody or its antigen-binding fragment selected from the group consisting of full-length antibodies, bispecific antibodies, single-stranded Fv(scFv) fragments, Fab fragments, Fab' fragments, F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, Fv-Fc fusions, scFv-Fc fusions, scFv-Fv fusions, diabodies, tribodies, and tetrabodies. In some embodiments, the antibody portion is a full-length antibody.

[0027] In some embodiments of any of the above anti-CD93 constructs, the antibody moiety has an Fc fragment selected from the group consisting of Fc fragments derived from IgG, IgA, IgD, IgE, and IgM, as well as combinations and hybrids thereof. In some embodiments, the Fc fragment is selected from the group consisting of Fc fragments derived from IgG1, IgG2, IgG3, and IgG4, as well as combinations and hybrids thereof. In some embodiments, the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has enhanced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has an extended serum half-life. In some embodiments, the Fc fragment has a decreased serum half-life.

[0028] In some embodiments of any of the above anti-CD93 constructs, the antibody portion blocks the binding of CD93 to IGFBP7 (such as human IGFBP7).

[0029] In some embodiments of any of the above anti-CD93 constructs, the antibody portion blocks the binding of CD93 to MMRN2 (such as human MMRN2).

[0030] In some embodiments of any of the above anti-CD93 constructs, the antibody portion blocks a) the binding of CD93 to IGFBP7 and / or b) the binding of CD93 to MMRN2.

[0031] In some embodiments of any of the above anti-CD93 constructs, CD93 is human CD93.

[0032] In another embodiment, this application provides a pharmaceutical composition comprising any of the above-described anti-CD93 constructs and a pharmaceutically acceptable carrier.

[0033] In another aspect, this application provides isolated nucleic acids encoding any of the above-described anti-CD93 constructs.

[0034] In another aspect, this application provides a vector comprising any of the above-mentioned isolated nucleic acids.

[0035] In another aspect, this application provides an isolated host cell containing either the isolated nucleic acid or vector described above.

[0036] In another embodiment, the present application provides an immunoconjugate comprising any of the above-mentioned anti-CD93 constructs linked to a therapeutic agent or label.

[0037] In another aspect, the present application provides a method for producing an anti-CD93 construct, comprising: a) culturing isolated host cells as described in claim 25 under conditions effective for expressing the anti-CD93 construct; and b) obtaining the expressed anti-CD93 construct from the host cells.

[0038] In another embodiment, the present application provides a method for treating a disease or condition in an individual, comprising administering to the individual an effective amount of either the above anti-CD93 construct or pharmaceutical composition. In some embodiments, the disease or condition is associated with abnormal vascular structure. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer comprises CD93+ endothelial cells. In some embodiments, the cancer comprises IGFBP7+ vessels. In some embodiments, the cancer is characterized by tumor hypoxia. In some embodiments, the cancer is locally advanced or metastatic cancer. In some embodiments, the cancer is selected from the group consisting of lymphoma, colon cancer, brain cancer, breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, prostate cancer, cervical cancer, kidney cancer, bladder cancer, gastric cancer, non-small cell lung cancer, melanoma, and pancreatic cancer. In some embodiments, the anti-CD93 construct is administered parenterally to the individual. In some embodiments, the method further comprises administering a second treatment. In some embodiments, the second treatment is selected from the group consisting of surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and chemotherapy. In some embodiments, the second treatment is immunotherapy. In some embodiments, the immunotherapy includes administering an immunomodulator. In some embodiments, the immunomodulator is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor includes an anti-PD-L1 antibody or an anti-PD-1 antibody. In some embodiments, the individual is a human. In certain embodiments, for example, the following items are provided: (Item 1) Heavy chain variable region (V H ) and light chain variable region (V L An anti-CD93 construct comprising an antibody moiety containing a second heavy chain variable region (V H-2 ) and the second light chain variable region (V L-2 The antibody or antibody fragment containing ) competes for the CD93 binding epitope, a) The above V H-2This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6; b) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22; c) Said V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 35, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38; d) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54; e) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, and SEQ ID NO: 6 HC-CDR2 containing the amino acid sequence of 6, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, and the V L-2This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70; f) Said V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 83, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86; g) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102; h) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118; i) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134; j) The above V H-2This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358; LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356; and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359; k) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166; l) Said V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182; m) Said V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 194, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 195, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198; n) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, and the V L-2This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214; o) The above V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294; or p) The V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and the V L-2 The anti-CD93 construct comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22. (Item 2) The anti-CD93 structure described in item 1, a) The above V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. b) The above V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. c) Said V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 35, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. d) The above V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. e) The above V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 66, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. f) Said V H i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and iii) amino acids of SEQ ID NO: 83 The V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. g) The above V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. h) The above V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. i) The above V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. j) The above V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. k) The above V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. l) Said V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. m) Said V H i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, ii) iii) HC-CDR2 containing the amino acid sequence of sequence number 194, and iii) HC-CDR3 containing the amino acid sequence of sequence number 195, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR, or n) The above V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. o) The above V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR, or p) The V H This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and the V L The anti-CD93 construct comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22. (Item 3) The aforementioned V HThe HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 4) The aforementioned V H The HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 5) The aforementioned V H However, i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and iii) the amino acid sequence of SEQ ID NO: 35 HC-CDR3 containing, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; the V LThe anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 6) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 7) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 66, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 8) The aforementioned V HHowever, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 83, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 9) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 10) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L However, the LC-CDR includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. , the anti-CD93 structures described in item 2. (Item 11) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 12) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct described in item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358; ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356; and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359; or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 13) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V LThe anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 14) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 15) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 194, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 195, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 16) The aforementioned V H However, i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and iii) amino acid sequence of SEQ ID NO: 211 The HC-CDR3 comprises an acid sequence, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 17) The aforementioned V H However, the HC-CDR includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and the V L The anti-CD93 construct according to item 2, comprising i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. (Item 18) An anti-CD93 construct comprising an antibody moiety that specifically binds to CD93, a) V having the sequence shown in Sequence ID No. 13 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V, which has the sequence shown in Sequence ID No. 14. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; b) V having the sequence shown in any of sequence numbers 29 and 307-312 HHC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 30 and 313-318. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; c) V having the sequence shown in Sequence ID No. 45 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 46. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; d) V having the sequence shown in Sequence ID No. 61 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 62. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; e) V having the sequence shown in Sequence ID 77 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V, which has the sequence shown in Sequence ID No. 78. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; f) V having the sequence shown in sequence number 93 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V, which has the sequence shown in Sequence ID No. 94. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; g) V having the sequence shown in Sequence ID No. 109 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 110. L CDR1 and CD are located within the chain region. LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of R2 and CDR3, respectively; h) V having the sequence shown in Sequence ID No. 125 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 126. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; i) V having the sequence shown in Sequence ID 141 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 142. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; j) V having the sequence shown in any of sequence numbers 157 and 360-362 H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 158 and 363-365. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; k) V having the sequence shown in Sequence ID No. 173 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in SEQ ID NO: 174. LLC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; l) V having the sequence shown in sequence number 189 and any of 347-349 H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 190 and 350-352. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; m) V having the sequence shown in Sequence ID No. 205 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in SEQ ID NO: 206. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; n) V having the sequence shown in sequence number 221 H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V having the sequence shown in Sequence ID No. 222. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; o) V having the sequence shown in sequence numbers 287 and 319-321 H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 288 and 322-324. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; p) V having the sequence shown in any one of sequence numbers 307-312 HV has the sequence shown in HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as the sequence shown in any one of SEQ ID NOs. 313 to 318. L LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within its chain region; or q) V having the sequence shown in any one of sequence numbers 319 to 321 H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, as well as any one of SEQ ID NOs. 322-324 V has an array L Anti-CD93 constructs comprising LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions. (Item 19) The aforementioned V H The modified form includes any one of the amino acid sequences of sequence numbers 13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 287, 307-312 and 319-321, or an amino acid sequence having at least about 80% sequence identity; and / or the V L An anti-CD93 construct according to any one of items 1 to 18, comprising, however, one amino acid sequence of any one of sequence numbers 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 288, 313-318 and 322-324, or a modifier having at least about 80% sequence identity with an amino acid sequence. (Item 20) The anti-CD93 structure described in item 19, a) The above V H This includes a variant comprising the amino acid sequence of Sequence ID No. 13, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence having at least approximately 80% sequence identity. b) The above V H This includes a modified version comprising the amino acid sequence of SEQ ID NOs. 29 and 307-312, or an amino acid sequence having at least approximately 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 30 and any of 313-318, or an amino acid sequence having at least approximately 80% sequence identity. c) Said V H This includes a variant comprising the amino acid sequence of Sequence ID No. 45, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 46, or an amino acid sequence having at least approximately 80% sequence identity. d) The above V H This includes a variant comprising the amino acid sequence of Sequence ID No. 61, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 62, or an amino acid sequence having at least approximately 80% sequence identity. e) The above V H This includes a variant comprising the amino acid sequence of Sequence ID No. 77, or an amino acid sequence having at least approximately 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 78, or an amino acid sequence having at least approximately 80% sequence identity. f) Said V H This includes a variant comprising the amino acid sequence of Sequence ID No. 93, or an amino acid sequence having at least approximately 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 94, or an amino acid sequence having at least approximately 80% sequence identity. g) The above V H This includes a variant comprising the amino acid sequence of Sequence ID No. 109, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 110, or an amino acid sequence having at least approximately 80% sequence identity. h) The above V HThis includes a variant comprising the amino acid sequence of Sequence ID No. 125, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 126, or an amino acid sequence having at least approximately 80% sequence identity. i) The above V H This includes a variant comprising the amino acid sequence of Sequence ID No. 141, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 142, or an amino acid sequence having at least approximately 80% sequence identity. j) The above V H This includes a variant comprising the amino acid sequence of Sequence ID No. 157, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 158, or an amino acid sequence having at least approximately 80% sequence identity. k) The above V H This is the amino acid sequence of sequence number 173, or at least approximately 80% of the sequence. Includes a variant containing a monomorphic amino acid sequence; V L This includes a modified version containing the amino acid sequence of Sequence ID No. 174, or an amino acid sequence having at least approximately 80% sequence identity. l) Said V H This includes a modified version comprising the amino acid sequence of SEQ ID NOs. 189 and 347-349, or an amino acid sequence having at least approximately 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 190 and any of 350-352, or an amino acid sequence having at least approximately 80% sequence identity. m) Said V H This includes a variant comprising the amino acid sequence of Sequence ID No. 205, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of Sequence ID No. 206, or an amino acid sequence having at least approximately 80% sequence identity. n) The above V HThis includes a variant comprising the amino acid sequence of Sequence ID No. 221, or an amino acid sequence having at least about 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 222, or an amino acid sequence having at least approximately 80% sequence identity. o) The above V H This includes a modified version comprising the amino acid sequence of sequence numbers 287 and 319-321, or an amino acid sequence having at least approximately 80% sequence identity; the V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 288 and any of 322-324, or an amino acid sequence having at least approximately 80% sequence identity. p) The V H This includes a modified version containing one of the amino acid sequences of sequence numbers 307-312, or an amino acid sequence having at least approximately 80% sequence identity; the V L This includes a modified version containing one of the amino acid sequences from sequence numbers 313 to 318, or an amino acid sequence having at least approximately 80% sequence identity, or q) The above V H This includes a modified version comprising any one amino acid sequence from sequence numbers 319 to 321, or an amino acid sequence having at least approximately 80% sequence identity; the V L This is an anti-CD93 construct comprising a modified amino acid sequence containing any one of sequence numbers 322-324, or an amino acid sequence having at least approximately 80% sequence identity. (Item 21) The anti-CD93 construct according to any one of items 1 to 20, wherein the antibody portion is an antibody or antigen-binding fragment selected from the group consisting of a full-length antibody, a bispecific antibody, a single-stranded Fv(scFv) fragment, a Fab fragment, a Fab' fragment, F(ab')2, an Fv fragment, a disulfide-stabilized Fv fragment (dsFv), (dsFv)2, an Fv-Fc fusion, an scFv-Fc fusion, an scFv-Fv fusion, a diabody, a tribody, and a tetrabody. (Item 22) The anti-CD93 construct described in item 21, wherein the antibody portion is a full-length antibody. (Item 23) The anti-CD93 construct according to any one of items 1 to 22, wherein the antibody portion comprises an Fc fragment selected from the group consisting of Fc fragments derived from IgG, IgA, IgD, IgE, and IgM, as well as combinations and hybrids thereof. (Item 24) The anti-CD93 construct according to item 23, wherein the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof. (Item 25) An anti-CD93 construct according to item 23 or item 24, wherein the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment. (Item 26) The anti-CD93 construct according to item 23 or item 24, wherein the Fc fragment has enhanced effector capabilities compared to the corresponding wild-type Fc fragment. (Item 27) An anti-CD93 construct according to any one of items 1 to 26, wherein the antibody portion blocks the binding of CD93 to IGFBP7. (Item 28) An anti-CD93 construct according to any one of items 1 to 27, wherein the antibody portion blocks the binding of CD93 to MMRN2. (Item 29) An anti-CD93 construct according to any one of items 1 to 22, wherein the CD93 is human CD93. (Item 30) A pharmaceutical composition comprising an anti-CD93 construct described in any one of items 1 to 29 and a pharmaceutically acceptable carrier. (Item 31) An isolated nucleic acid encoding an anti-CD93 construct or a portion thereof as described in any one of items 1 through 29. (Item 32) A vector containing isolated nucleic acids as described in item 31. (Item 33) Isolated host cells containing isolated nucleic acids as described in item 31 or vectors as described in item 30. (Item 34) An immunoconjugate comprising an anti-CD93 construct described in any one of items 1 to 29, linked to a therapeutic agent or label. (Item 35) A method for producing an anti-CD93 construct, a) Culturing the isolated host cells described in item 33 under conditions effective for expressing the anti-CD93 construct, b) A method comprising obtaining the expressed anti-CD93 construct from the host cells. (Item 36) A method for treating a disease or condition in an individual, comprising administering to the individual an effective amount of an anti-CD93 construct described in any one of items 1 to 29, or a pharmaceutical composition described in item 30. (Item 37) The method according to item 36, wherein the disease or condition is related to an abnormal vascular structure. (Item 38) The method described in item 36 or item 37, wherein the disease or condition is cancer. (Item 39) The method according to item 38, wherein the cancer is a solid tumor. (Item 40) The method described in item 38 or item 39, wherein the cancer comprises CD93+ endothelial cells. (Item 41) The method according to any one of items 38-40, wherein the aforementioned cancer includes IGFBP7+ vessels. (Item 42) The method according to any one of items 38-41, wherein the aforementioned cancer includes MMRN2+ vessels. (Item 43) The method according to any one of items 38 to 42, wherein the cancer is characterized by tumor hypoxia. (Item 44) The method according to any one of items 38 to 43, wherein the cancer is locally advanced or metastatic. (Item 45) The method according to any one of items 38 to 44, wherein the cancer is selected from the group consisting of lymphoma, colon cancer, brain tumor, breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, prostate cancer, cervical cancer, kidney cancer, bladder cancer, gastric cancer, non-small cell lung cancer, melanoma, and pancreatic cancer. (Item 46) The method according to any one of items 36 to 45, wherein the anti-CD93 construct is administered parenterally to the individual. (Item 47) The method described in any one of items 36 to 46, further comprising administering a second treatment. (Item 48) The method according to item 47, wherein the second treatment is selected from the group consisting of surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and chemotherapy. (Item 49) The method described in item 48, wherein the second treatment is immunotherapy. (Item 50) The method according to item 49, wherein the immunotherapy comprises administering an immunomodulator. (Item 51) The method according to item 50, wherein the immunomodulator is an immune checkpoint inhibitor. (Item 52) The method according to item 51, wherein the immune checkpoint inhibitor comprises an anti-PD-L1 antibody or an anti-PD-1 antibody. (Item 53) The method according to any one of items 36 to 52, wherein the individual is a human. [Brief explanation of the drawing]

[0039] [Figure 1] Figure 1 shows the binding affinities of 16E4 and MM01 to human or cynomolgus monkey CD93.

[0040] [Figure 2] Figure 2 shows the binding of various anti-CD93 antibodies to CD93-expressing CHO cells.

[0041] [Figure 3-1] Figures 3A to 3D show the inhibition of the interaction between CD93 and IGFBP7 by 16E4 and MM01 compared to various concentrations of mIgG isotypes. [Figure 3-2] Figures 3A to 3D show the inhibition of the interaction between CD93 and IGFBP7 by 16E4 and MM01 compared to various concentrations of mIgG isotypes.

[0042] [Figure 4-1] Figures 4A to 4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to a control. [Figure 4-2] Figures 4A to 4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to a control. [Figure 4-3] Figures 4A to 4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to a control. [Figure 4-4] Figures 4A to 4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to a control.

[0043] [Figure 5] Figures 5A and 5B show the results of epitope binning of various anti-CD93 antibodies using Octet competition.

[0044] [Figure 6A] Figures 6A and 6B show the cross-binding activity of various anti-CD93 antibodies against human and cynomolgus monkey CD93 as measured by biolayer interferometry (BLI) assays. [Figure 6B] Figures 6A and 6B show the cross-binding activity of various anti-CD93 antibodies against human and cynomolgus monkey CD93 as measured by biolayer interferometry (BLI) assays.

[0045] [Figure 7A]Figures 7A and 7B show the alignment of VH and VL CDRs using Kabat numbering. From top to bottom, the sequences in Figure 7A are sequence numbers 393 to 406, and the sequences in Figure 7B are sequence numbers 407 to 420. [Figure 7B] Same as above.

[0046] [Figure 8A] Figures 8A and 8B show the alignment of VH and VL CDR determined by the VBASE2 tool. From top to bottom, the sequences in Figure 8A are sequence numbers 393 to 406, and the sequences in Figure 8B are sequence numbers 407 to 420. [Figure 8B] Same as above.

[0047] [Figure 9] Figure 9 shows the binding affinities of 10B1 and 7F3 to human CD93.

[0048] [Figure 10] Figure 10 shows the binding of 16E4, 10B1, and 7F3 to human CD93-expressing CHO cells, as well as the lack of binding to CHO-K1 cells.

[0049] [Figure 11] Figures 11A and 11B show the inhibition of the interaction between CD93 and MMRN2 by 16E4, 10B1, and 7F3 compared to 50 μg / mL mIgG isotypes.

[0050] [Figure 12] Figure 12 shows the inhibition of the interaction between CD93 and MMRN2 by 7F3 at different MMRN2 concentrations compared to a control (IgG2a).

[0051] [Figure 13] Figure 13 shows the inhibition of the interaction between CD93 and MMRN2 by 7F3 compared to the control (IgG1).

[0052] [Figure 14]Figure 14 shows the inhibition of the interaction between CD93 and IGFBP7 by 7F3 compared to various concentrations of mIgG1 isotypes.

[0053] [Figure 15A] Figures 15A and 15B show the inhibition of HUVEC tube formation by 16E4 and 7F3 at two concentrations compared to a control. [Figure 15B] Figures 15A and 15B show the inhibition of HUVEC tube formation by 16E4 and 7F3 at two concentrations compared to a control.

[0054] [Figure 16] Figure 16 shows an exemplary multispecific anti-CD93 construct that also recognizes VEGF.

[0055] [Figure 17] Figure 17 shows tumor volume in mice treated with an exemplary anti-CD93 construct.

[0056] [Figure 18] Figure 18 shows the tumor volume in mice treated with humanized 17B10 anti-CD93 antibody.

[0057] [Figure 19] Figure 19 shows the binding of anti-CD93 antibody to primary HUVEC cells in the presence of human serum, as determined by flow cytometry.

[0058] [Figure 20] Figure 20 shows the binding of anti-CD93 antibody to primary HUVEC cells in the absence of human serum, as determined by flow cytometry.

[0059] [Figure 21] Figure 21 shows the binding of anti-CD93 antibodies to hCD93 CHO cells in the presence of human serum, as determined by flow cytometry assay.

[0060] [Figure 22] Figure 22 shows the binding of anti-CD93 antibody to U937 cells as determined by flow cytometry assay.

[0061] [Figure 23] Figure 23 shows the exemplary inhibitory effect of humanized 17B10 antibody on HUVEC tube formation. [Figure 24] Figure 24 shows the exemplary inhibitory effect of humanized 17B10 antibody on HUVEC tube formation.

[0062] [Figure 25A] Figures 25A and 25B show exemplary binding of humanized 17B10 antibodies to CHO cells overexpressing human CD93. [Figure 25B] Figures 25A and 25B show exemplary binding of humanized 17B10 antibodies to CHO cells overexpressing human CD93.

[0063] [Figure 26] Figures 26A and 26B show exemplary binding of humanized 17B10 antibodies to KG1a and U937 cells.

[0064] [Figure 27] Figure 27 shows the binding of humanized anti-CD93 antibody 17B10 to mouse CD93 cell surface-expressing CHO cells as determined by fluorescence-activated cell sorting (FACS) assay.

[0065] [Figure 28] Figure 28 shows exemplary binding of humanized 17B10 antibody to mouse CD93 cell surface-expressing HEK cells as determined by fluorescence-activated cell sorting (FACS) assay.

[0066] [Figure 29] Figure 29 shows SDS-PAGE analysis of exemplary humanized 16E4 and humanized 7F3 antibodies.

[0067] [Figure 30] Figure 30 shows ELISA analysis of exemplary humanized 16E4 and 7F3 antibodies binding to human CD93 (hCD93).

[0068] [Figure 31] Figure 31 shows the ELISA analysis of exemplary h7F3 (humanized 7F3) antibody binding to human CD93 (hCD93).

[0069] [Figure 32] Figure 32 shows ELISA analysis of exemplary hybridoma or humanized 16E4 antibody binding to hCD93.

[0070] [Figure 33] Figure 33 shows ELISA analysis of exemplary hybridoma or humanized 17B10 antibody binding to hCD93.

[0071] [Figure 34] Figure 34 shows the ELISA analysis of exemplary humanized 17B10 binding to hCD93.

[0072] [Figure 35] Figure 35 shows FACS analysis of the binding of 16E4-hIgG1 and 7F3-hIgG1 antibodies to CHO-hCD93 cells.

[0073] [Figure 36] Figure 36 shows the FACS analysis of the binding of humanized 7F3 to CHO-hCD93 cells.

[0074] [Figure 37] Figure 37 shows the FACS analysis of the binding of h16E4 (humanized 16E4) to CHO-hCD93 cells.

[0075] [Figure 38] Figure 38 shows the FACS analysis of the binding of humanized 7F3 to HUVEC cells.

[0076] [Figure 39] Figure 39 shows the FACS analysis of the binding of humanized 7F3 to KG1a cells.

[0077] [Figure 40] Figure 40 shows the FACS analysis of the binding of humanized 16E4 to KG1a cells.

[0078] [Figure 41] Figure 41 illustrates the characterization of the binding dynamics of exemplary 16E4 and 7F3 antibodies to hCD93.

[0079] [Figure 42] Figure 42 illustrates the characterization of the binding dynamics of an exemplary humanized 16E4 antibody to hCD93.

[0080] [Figure 43] Figure 43 shows a summary of the binding affinities of exemplary 16E4 and 7F3 antibodies to human CD93 as measured by octet and human CD93-expressing CHO cells, HUVEC cells, or KG1a cells as measured by flow cytometry.

[0081] [Figure 44] Figure 44 shows the FACS analysis of the blocking effect of humanized 7F3 on the binding of human MMRN2 to CHO-hCD93 cells.

[0082] [Figure 45] Figure 45 shows FACS analysis of the blocking effects of humanized 16E4 and 7F3 antibodies on MMRN2 binding to CHO-hCD93 cells.

[0083] [Figure 46] Figure 46 shows a FACS analysis of the blocking effect of exemplary humanized 7F3 antibodies on the binding of human IGFBP7 to HUVEC cells.

[0084] [Figure 47]Figure 47 shows Octet analysis of the blocking effects of exemplary 7F3 or 16E4 antibodies on the binding of human IGFBP7 to human CD93.

[0085] [Figure 48] Figure 48 shows the Octet analysis of the blocking effect of exemplary 16E4 antibodies on the binding of human IGFBP7 to human CD93.

[0086] [Figure 49] Figure 49 shows the effects of exemplary humanized 7F3 and 16E4 antibodies on HUVEC tube formation. [Figure 50] Figure 50 shows the effects of exemplary humanized 7F3 and 16E4 antibodies on HUVEC tube formation.

[0087] [Figure 51] Figure 51 shows an overview of the characteristics of an exemplary anti-CD93 antibody. [Modes for carrying out the invention]

[0088] Detailed description of the present invention This application provides novel anti-CD93 constructs that specifically bind to CD93 (e.g., anti-CD93 monoclonal antibodies or multispecific antibodies), methods for preparing anti-CD93 constructs, and methods for using the constructs (e.g., methods for treating diseases or conditions).

[0089] Anti-CD93 antibodies (e.g., anti-CD93 antibodies that block the interaction between CD93 and IGFBP7) may effectively treat tumors or cancers, block abnormal tumor angiogenesis, normalize immature and leaky tumor blood vessels, promote functional vascular networks in tumors, promote vascular maturation, promote a favorable tumor microenvironment, increase immune cell infiltration in tumors, increase tumor perfusion, reduce hyperplasia in tumors, sensitize tumors to a second treatment, and / or facilitate delivery of a second drug. See, for example, WO2021062128A1, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the anti-CD93 constructs described herein reduce tumor size. In some embodiments, the anti-CD93 constructs described herein promote immune cell infiltration in tumors. In some embodiments, the anti-CD93 constructs described herein promote vascular maturation in tumors. In some embodiments, the anti-CD93 constructs described herein sensitize tumors to a second treatment or facilitate the delivery of a second drug.

[0090] I. Definition The term "antibody," used in its broadest sense, encompasses a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and their antigen-binding fragments, as long as they exhibit the desired antigen-binding activity. The term "antibody moiety" refers to the full-length antibody or its antigen-binding fragment.

[0091] Full-length antibodies contain two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable domains of the heavy and light chains are each called "V H " and "V LThe variable regions of both chains generally contain three highly variable loops called complementarity-determining regions (CDRs) (the light chain (LC) CDRs, including LC-CDR1, LC-CDR2, and LC-CDR3, and the heavy chain (HC) CDRs, including HC-CDR1, HC-CDR2, and HC-CDR3). The CDR boundaries of the antibody and antigen-binding fragments disclosed herein may be defined or identified by the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDRs of the heavy or light chain are more highly conserved than the CDRs and interpose between adjacent stretches known as framework regions (FRs) that form a scaffold for supporting the hypervariable loops. The constant regions of the heavy and light chains do not participate in antigen binding but exhibit various effector functions. Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chain. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by the presence of α, δ, ε, γ, and μ heavy chains, respectively. Some of the major antibody classes are divided into subclasses such as IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain).

[0092] As used herein, the term “antigen-binding fragment” refers to an antibody fragment that includes, for example, a diabody, Fab, Fab', F(ab')2, Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabody (dsdiabody), single-stranded Fv (scFv), scFv dimer (bivalent diabody), a multispecific antibody formed from a portion of an antibody containing one or more CDRs, a camel-shaped single-domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not contain a complete antibody structure. An antigen-binding fragment can bind to the same antigen to which a parent antibody or parent antibody fragment (e.g., parent scFv) binds. In some embodiments, an antigen-binding fragment may contain one or more CDRs derived from a particular human antibody grafted onto a framework region derived from a different human antibody.

[0093] "Fv" is the smallest antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer in which one heavy chain variable domain and one light chain variable domain are closely and non-covalently bonded. The folding of these two domains gives rise to six hypervariable loops (three from the heavy chain and three from the light chain, respectively) that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of the Fv containing only three antigen-specific CDRs) has the ability to recognize and bind to the antigen, but often with lower affinity than the entire binding site.

[0094] A "single-chain Fv" (also abbreviated as "sFv" or "scFv") is a single polypeptide chain to which V is linked. H and V L It is an antibody fragment containing an antibody domain. In some embodiments, the scFv polypeptide allows the scFv to form a desired structure for antigen binding. H Domain and V LIt further includes polypeptide linkers between the domains. For a review of scFv, see Plueckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994).

[0095] As used herein, the terms “CDR” or “complementarity-determining region” are intended to mean discontinuous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. These specific regions are described in Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al. al.,USDept.of Health and Human Services, "Sequences of proteins of immunological interest" (1991);Chothia et al.,J.Mol.Biol.196:901-917(1987);Al-Lazikani B.et al.,J.Mol.Biol.,273:927-948(1997);MacCallum et al. al.,J.Mol.Biol.262:732-745(1996);Abhinandan and Martin,Mol.Immunol.,45:3832-3839(2008);Lefranc MPet al.,Dev.Comp.Immunol.,27:55-77(2003);and Honegger and The definition is described in Pluckthun, J. Mol. Biol., 309:657-670 (2001), where the definition includes overlaps or subsets of amino acid residues when compared to one another. Nevertheless, the application of any definition to refer to a CDR of an antibody or graft antibody or its variant is intended to be within the scope of the terms defined and used herein. For comparison, the amino acid residues encompassing a CDR as defined by each of the references cited above are shown in Table 1 below. CDR prediction algorithms and interfaces are publicly known in the art, e.g., Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38:D301-D307 (2010); and Adolf-Bryfogle J. et al. al., Nucleic Acids Res., 43:D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for use in this application and for the possibility of inclusion in one or more claims herein. In some embodiments, the CDR sequences provided herein are based on the IMGT definition. For example, the CDR sequence may be determined by the VBASE2 tool (http: / / www.vbase2.org / vbase2.php, see also Retter I, Althaus HH, Munch R, Muller W: VBASE2, an embedded V gene database, Nucleic Acids Res. 2005 Jan 1;33 (database publication):D671-4, which is incorporated herein by reference in its entirety). [Table 1]

[0096] The expressions "Kabat variable domain residue numbering" or "Kabat amino acid position numbering," and their variations, refer to the numbering system used for the heavy-chain or light-chain variable domains in the editing of Kabat et al. antibodies described above. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to the shortening or insertion of the FR or hypervariable region (HVR) of the variable domain. For example, the heavy-chain variable domain may contain a single amino acid insertion after H2 residue 52 (residue 52a according to Kabat) and an inserted residue after heavy-chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues can be determined for a given antibody by alignment of the antibody sequence with a homology region of a "standard" Kabat numbering sequence.

[0097] Unless otherwise indicated herein, the residue numbering in immunoglobulin heavy chains is the same as the EU index numbering by Kabat et al. "EU index by Kabat" refers to the residue numbering of human IgG1 EU antibody.

[0098] A “framework” or “FR” residue is a variable domain residue other than a CDR residue as defined herein.

[0099] The "humanized" form of a non-human (e.g., rodent) antibody is a chimeric antibody containing the minimal sequence derived from the non-human antibody. In most cases, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's hypervariable region (HVR) are replaced with residues from the hypervariable region of a non-human species (donor antibody), such as mouse, rat, rabbit, or non-human primate, possessing the desired antibody specificity, affinity, and capability. In some examples, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, a humanized antibody may contain residues not found in the recipient or donor antibody. These modifications are made to further improve the performance of the antibody. Generally, a humanized antibody contains substantially all of at least one, typically two, variable domains, all or substantially all of the hypervariable loops correspond to those of the non-human immunoglobulin, and all or substantially all of the FRs are from the human immunoglobulin sequence. A humanized antibody also contains, if necessary, at least a portion of the immunoglobulin constant region (Fc) (typically that of human immunoglobulin). For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0100] A “human antibody” is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human, and / or is prepared using any of the techniques for producing human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. (Hoogenboom and Winter, J.Mol.Biol., 227:381 (1991); Marks et al., J.Mol.Biol., 222:581 (1991)). Methods available for the preparation of human monoclonal antibodies include those described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J.Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be prepared by administering antigens to transgenic animals, such as immunized xenos, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous gene locus has been deactivated (see, for example, U.S. Patents 6,075,181 and 6,150,584, relating to XENOMOUSE®). See also Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006), relating to human antibodies produced via human B-cell hybridoma technology.

[0101] "Percent (%) amino acid sequence identity" or "homology" for polypeptides and antibody sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the polypeptide being compared, after the sequences have been aligned, taking into account any conservative substitutions as part of the sequence identity. Alignment for determining percent amino acid sequence identity can be achieved in various ways within the scope of the art using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for measuring the alignment, including any algorithm necessary to achieve maximum alignment over the entire length of the sequences being compared. However, for the purposes of this specification, the % amino acid sequence identity value is generated using the sequence comparison computer program MUSCLE (Edgar, RC, Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, RC, BMC Bioinformatics 5(1):113, 2004).

[0102] "Homologie" refers to the sequence similarity or sequence identity between two polypeptides or two nucleic acid molecules. Two compared sequences are homologous at a given position if both positions are occupied by the same base or amino acid monomer subunit. For example, if each position in two protein molecules is occupied by lysine, or if each position in two DNA molecules is occupied by adenine. The percentage of homology between two sequences is a function of the number of identical or homologous positions shared by the two sequences, divided by the number of positions compared, multiplied by 100. For example, if 6 out of 10 positions in two sequences are identical or homologous, the two sequences are 60% homologous. As an example, the protein sequences SGTSTD and TGTSDA share 50% homology. Generally, a comparison is made when the two sequences are aligned to obtain the maximum homology.

[0103] The term "constant domain" refers to the portion of the immunoglobulin molecule that contains the antigen-binding site and has a more conserved amino acid sequence compared to the variable domain. The constant domain is the C of the heavy chain. H 1. C H 2 and C H 3 domains (collectively C H ) and the light chain CHL (or C L ) Includes domains.

[0104] The "light chains" of antibodies (immunoglobulins) derived from any mammalian species can be assigned to one of two distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domains.

[0105] The "CH1 domain" (also known as the "C1" in the "H1" domain) typically consists of approximately 118 to 215 amino acids (according to the EU numbering system).

[0106] The "hinge region" is generally defined as the region in IgG corresponding to Glu216-Pro230 in human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). Hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine ​​residues that form the inter-heavy chain disulfide bonds in the same position.

[0107] The "CH2 domain" (also called the "C2" domain) in the human IgG Fc region typically spans from approximately 231 to 340 amino acids. The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are sandwiched between the two CH2 domains in an intact, natural IgG molecule. It is hypothesized that the carbohydrates may provide a substitute for domain-domain pairing, thus aiding in the stabilization of the CH2 domain. (Burton, Molec Immunol. 22:161-206 (1985)).

[0108] The "CH3 domain" (also called the "C2" domain) includes a C-terminal stretch of residues relative to the CH2 domain in the Fc region (i.e., from approximately amino acid residue 341 to the C-terminus of the antibody sequence, typically amino acid residues 446 or 447 of IgG).

[0109] In this specification, the terms “Fc region” or “fragment crystallizable region” are used to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and modified Fc regions. While the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is typically defined as extending from the amino acid residue at position Cys226 or Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombination of the nucleic acid encoding the antibody heavy chain. Thus, compositions of intact antibodies may include antibody populations with all K447 residues removed, antibody populations with and without K447 residues, and antibody populations with mixtures of antibodies having and not having K447 residues. Suitable native sequence Fc regions for use in the antibodies described herein include human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4.

[0110] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. Preferred FcRs are human FcRs of natural sequence. Furthermore, preferred FcRs bind to IgG antibodies (gamma receptors) and include receptors of the FcγRI, FcγRII, FcRN, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. The FcγRII receptor includes FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine activating motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) in its cytoplasmic domain. (See M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997). FcRN is important for the reuse of antibodies in blood, which allows for an increase in the serum half-life of antibodies. FcR is Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel This is outlined in et al., Immunomethods 4:25-34 (1994); and de Haas et al., J.Lab.Clin.Med.126:330-41 (1995). Other FcRs, including those to be identified in the future, are included in the term “FcR” herein.

[0111] As used herein, the term “epitope” refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody moiety binds. Two antibodies or antibody moieties may bind to the same epitope within an antigen if they exhibit competitive binding to the antigen.

[0112] As used herein, a first antibody or fragment "competes" with a second antibody or fragment for binding to a target antigen if the first antibody or fragment inhibits the binding of the second antibody or fragment to the target antigen by at least about 50% (e.g., at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%) in the presence of an equimolar concentration of the first antibody or fragment, and vice versa. A high-throughput process for antibody "binning" based on cross-competition is described in PCT publication number WO 03 / 48731.

[0113] As used herein, the terms “specifically bind,” “specifically recognize,” and “specific to” refer to measurable and reproducible interactions, such as binding between a target and an antibody or antibody moiety, that determine the presence of a target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody or antibody moiety that specifically recognizes a target (which may be an epitope) is an antibody or antibody moiety that binds to this target with higher affinity, avidity, more readily, and / or for a longer duration than binding to other targets. In some embodiments, the degree of antibody binding to unrelated targets is less than about 10% of antibody binding to the target, as measured, for example, by radioimmunoassay (RIA). In some embodiments, an antibody that specifically binds to a target is ≤10 -5 M, ≤10 -6 M, ≤10 -7 M, ≤10 -8 M, ≤10 -9 M, ≤10 -10 M, ≤10 -11 M, or ≤10 -12 The dissociation constant (K) of M D) are present. In some embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins of different species. In some embodiments, specific binding may include, but is not required, exclusive binding. The binding specificity of the antibody or antigen-binding domain can be experimentally determined by methods known in the art. Such methods include, but are not limited to, Western blotting, ELISA-, BLI, RIA-, ECL-, IRMA-, EIA-, BIACORE®-, and peptide scanning.

[0114] As used herein, "blocking" the binding of molecule A (e.g., an anti-CD93 construct as described herein) to molecule B (e.g., CD93) and molecule C (e.g., IGFBP7 or MMRN2) refers to both direct and indirect blocking. For example, instead of directly blocking the binding of CD93 to IGFBP7 or MMRN2 by occupying at least a portion of the binding site on CD93 that is involved in the binding of IGFBP7 or MMRN2, an anti-CD93 construct described herein may block the binding of CD93 to IGFBP7 or MMRN2 by altering the structure of CD93 so that IGFBP7 / MMRN2 cannot bind to it.

[0115] "Isolated" or "purified" antibodies (or constructs) are identified, separated, and / or recovered from components of their production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is not associated with any other components from its production environment.

[0116] The “isolated” nucleic acid molecules encoding the constructs, antibodies, or their antigen-binding fragments described herein are nucleic acid molecules identified and isolated from at least one contaminating nucleic acid molecule with which it normally associates in the environment in which it is produced. Preferably, the isolated nucleic acid is not associated with all components related to the production environment. The isolated nucleic acid molecules encoding polypeptides and antibodies described herein are in a form or situation other than that which is found in nature. Thus, the isolated nucleic acid molecules are distinct from the nucleic acids encoding polypeptides and antibodies described herein that naturally exist within cells. The isolated nucleic acid contains nucleic acid molecules that are normally found in cells, but the nucleic acid molecule is located outside the chromosome or at a chromosomal location different from its natural chromosomal location.

[0117] The term "regulatory sequence" refers to the DNA sequence required for the expression of an operablely linked coding sequence in a particular host organism. Regulatory sequences suitable for prokaryotes include, for example, promoters, optionally operator sequences, and ribosome binding sites. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0118] Nucleic acids are "operably ligated" when they are placed in a functional relationship with another nucleic acid sequence. For example, DNA for a pre-sequence or secretion leader is operably ligated to DNA for a polypeptide if it is expressed as a preprotein involved in polypeptide secretion; a promoter or enhancer is operably ligated to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably ligated to a coding sequence if it is positioned to facilitate translation. Generally, "operably ligated" means that the ligated DNA sequences are contiguous, and in the case of a secretion leader, that they are contiguous and within the reading frame. Enhancers, however, do not need to be contiguous. Ligation is achieved by ligation at a convenient restriction site. If such a site does not exist, synthetic oligonucleotide adapters or linkers are used according to conventional practice.

[0119] As used herein, the term “vector” refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is ligated. This term includes vectors as self-replicating nucleic acid structures, as well as vectors integrated into the genome of a host cell into which they are introduced. Certain vectors can direct the expression of the nucleic acid to which they are operably ligated. Such vectors are referred herein to as “expression vectors.”

[0120] As used herein, the terms “transfected,” “transformed,” or “transduced” refer to the process by which an exogenous nucleic acid is transferred to or introduced into a host cell. A “transfected,” “transformed,” or “transduced” cell is a cell that has been transfected, transformed, or transduced with an exogenous nucleic acid. Cells include primary target cells and their offspring.

[0121] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acids have been introduced, including the offspring of such cells. Host cells include “transformers” and “transformed cells,” which include primary transformed cells and their offspring, regardless of passage number. Offspring do not have to be exactly identical in nucleic acid content to the parent cells and may contain mutations. Mutant offspring having the same function or biological activity as those screened or selected in the initially transformed cells are included herein.

[0122] The term “immunoconjugate” includes references to the covalent bonding of a therapeutic agent or detectable label to an antibody, such as the antibody moiety described herein. The linkage may be direct or indirect, via a linker (such as a peptide linker).

[0123] As used herein, “treatment” or “treating” is an approach to obtain beneficial or desired outcomes, including clinical outcomes. For the purposes of this application, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: relief of one or more symptoms caused by the disease; reduction of the disease; stabilization of the disease (e.g., prevention or delay of disease exacerbation); prevention or delay of disease progression (e.g., metastasis); prevention or delay of disease recurrence; delay or slowing of disease progression; improvement of the disease state; provision of remission (partial or whole) of the disease; reduction of one or more doses of other medicines required to treat the disease; delay of disease progression; improvement or enhancement of quality of life; increased weight gain; and / or extension of survival. Reduction of pathological outcomes of cancer (e.g., tumor volume) is also included in “treatment.” The methods of this application intend one or more of these embodiments of treatment.

[0124] In the context of cancer, the term “treatment” includes any or all of the following: inhibiting the growth of cancer cells, inhibiting the replication of cancer cells, reducing the overall tumor burden, and improving one or more symptoms associated with the disease.

[0125] The terms “inhibit” or “suppress” refer to a reduction or cessation of any phenotypic trait, or a reduction or cessation of the occurrence, degree, or possibility of that trait. To “reduce” or “inhibit” is to reduce, reduce, or cessate activity, function, and / or quantity compared to a baseline. In certain embodiments, “reduce” or “inhibit” means the ability to cause an overall reduction of 20% or more. In another embodiment, “reduce” or “inhibit” means the ability to cause an overall reduction of 50% or more. In yet another embodiment, “reduce” or “inhibit” means the ability to cause an overall reduction of 75%, 85%, 90%, 95%, or more.

[0126] As used herein, “reference” refers to any sample, standard, or level used for comparative purposes. References may be obtained from healthy and / or non-disease samples. In some examples, references may be obtained from untreated samples. In some examples, references may be obtained from non-disease or untreated samples of individuals. In some examples, references may be obtained from one or more healthy individuals that are not individuals or patients.

[0127] As used herein, “delaying the onset of disease” means delaying, interfering with, slowing, preventing, stabilizing, suppressing, and / or postponing the onset of a disease (such as cancer). This delay can be of varying lengths depending on the disease being treated and / or the individual’s medical history. As will be apparent to those skilled in the art, a sufficient or significant delay may effectively encompass prevention in that the individual does not develop the disease. For example, late-stage cancers, such as the development of metastases, may be delayed.

[0128] As used herein, “prevent” includes providing prevention with respect to the occurrence or recurrence of a disease in an individual who may be predisposed to the disease but has not yet been diagnosed with the disease.

[0129] As used herein, “suppressing” function or activity means reducing function or activity compared to conditions that are otherwise identical except for the condition or parameter of interest, or compared to different conditions. For example, an antibody that suppresses tumor growth reduces the rate of tumor growth compared to the rate of tumor growth in the absence of the antibody.

[0130] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to mammals, including but not limited to humans, cattle, horses, cats, dogs, rodents, or primates. In some embodiments, the individual is human.

[0131] The “effective dose” of a drug refers to the amount effective in the required dosage and duration to achieve the desired therapeutic or prophylactic outcome. The specific dose may vary depending on one or more of the following: the particular drug selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue being imaged, and the physical delivery system on which it is carried.

[0132] The "therapeutic effective dose" of a substance / molecule, agonist, or antagonist in this application may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the substance / molecule, agonist, or antagonist's ability to induce a desired response in the individual. The therapeutic effective dose is also the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the substance / molecule, agonist, or antagonist. The therapeutic effective dose may be delivered in one or more doses.

[0133] The "prophylactic effective dose" refers to the amount of medication that is effective in the required dosage and duration to achieve the desired preventive outcome. While not always the case, the prophylactic effective dose is typically less than the therapeutic effective dose, as prophylactic doses are usually used for pre-disease or early-stage disease.

[0134] The terms “pharmaceutical preparation” and “pharmaceutical composition” refer to preparations that are in a form that enables the biological activity of the active ingredient(s) and do not contain additional components that are unacceptably toxic to the individual to whom the preparation is administered. Such preparations may be sterile.

[0135] A "pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or carrier commonly used in the art for use with a therapeutic agent containing a "pharmaceutical composition" for administration to an individual. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration used and is compatible with the other components of the formulation. A pharmaceutically acceptable carrier is suitable for the formulation in which it is used.

[0136] A “sterile” preparation is either sterile or essentially free of living microorganisms and their spores.

[0137] Administration “in combination” with one or more additional therapeutic agents includes simultaneous (concurrent) and sequential or sequential administration in any order.

[0138] The term “concurrently” is used herein to refer to the administration of two or more therapeutic agents in which at least a portion of the administrations overlap in time, or in which the administration of one therapeutic agent occurs within a shorter period of time compared to the administration of another therapeutic agent. For example, two or more therapeutic agents are administered within a time interval of no more than approximately 60 minutes, for example, no more than approximately 30, 15, 10, 5, or 1 minute.

[0139] The term “sequential” is used herein to refer to the administration of two or more therapeutic agents in which the administration of one or more agents follows the discontinuation of the administration of one or more other agents. For example, the administration of two or more therapeutic agents is administered at time intervals of more than about 15 minutes, for example, about 20, 30, 40, 50 or 60 minutes, one day, two days, three days, one week, two weeks or one month, or longer.

[0140] As used herein, “in combination with” means administering one treatment modality in addition to another treatment modality. Thus, “in combination with” means administering one treatment modality before, during, or after the administration of other treatment modalities to an individual.

[0141] The term “package insert” is used to refer to instructions that are typically included in the market packaging of a therapeutic product and that contain information relating to the indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings for the use of such therapeutic product.

[0142] "Product" is any product (e.g., package or container) or kit comprising at least one reagent, for example, a pharmaceutical product for treating a disease or disorder (e.g., cancer), or a probe for specifically detecting a biomarker described herein. In certain embodiments, the product or kit is promoted, distributed, or sold as a unit for carrying out the method described herein.

[0143] Embodiments of the present application described herein are understood to include "consisting" and / or "consisting essentially of".

[0144] In this specification, any reference to a value or parameter using the term "about" includes (and describes) the variation of that value or parameter itself. For example, the statement "about X" includes the statement "X".

[0145] Where used herein, references to values ​​or parameters "not" generally mean and describe things "other than" values ​​or parameters. For example, "This method is not used to treat type X cancer" means "This method is used to treat cancers other than type X."

[0146] In this context, "approximately X to Y" is synonymous with "approximately X to approximately Y".

[0147] As used herein and in the appended claims, the singular forms "a," "or," and "the" refer to multiple subjects unless the context clearly indicates otherwise.

[0148] II. Anti-CD93 Structures This application provides an anti-CD93 construct comprising an anti-CD93 antibody moiety that specifically binds to CD93 as described herein.

[0149] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6.

[0150] In some embodiments, V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 7, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 8, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 9, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 10, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 11, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 12, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0151] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6.

[0152] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 13. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V, which has the sequence shown in Sequence ID No. 14. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0153] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 13; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 14.

[0154] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0155] In some embodiments, VH This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 23, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 24, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 25, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 26, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 27, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 28, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0156] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0157] In some embodiments, the antibody portion has the sequence shown in SEQ ID NOs. 29 and 307-312. H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 30 and 313-318. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0158] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of any of sequence numbers 29 and 307-312, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having sequence identity of any of sequence numbers 30 and 313-318, or at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of an amino acid sequence.

[0159] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 35, and the VL-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38.

[0160] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 35, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 39, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 40, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 41, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 42, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 43, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 44, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0161] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V HIt comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 34, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 35, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 36, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38.

[0162] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 45. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 46. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0163] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 45, or any one of these; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 46.

[0164] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54.

[0165] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 55, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 56, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 57, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 58, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 59, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 60, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0166] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 52, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 53, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 54.

[0167] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 61. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 62. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0168] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 61; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 62.

[0169] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 66, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70.

[0170] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 66, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 71, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 72, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 73, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 74, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 75, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 76, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0171] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 65, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 66, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 67, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 68, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 69, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 70.

[0172] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 77. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V, which has the sequence shown in Sequence ID No. 78. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0173] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 77, or a variant containing an amino acid sequence having sequence identity of at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 78.

[0174] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope.H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 83, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86.

[0175] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 83, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 87, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 88, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 89, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 90, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 91, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 92, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0176] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 81, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 82, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 83, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 84, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 85, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 86.

[0177] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 93. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V, which has the sequence shown in Sequence ID No. 94. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0178] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 93; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 94.

[0179] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V LThe antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102.

[0180] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 103, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 104, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 105, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 106, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 107, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 108, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0181] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 97, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 98, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 99, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 100, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 101, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 102.

[0182] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 109. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 110. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0183] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 109; VL This includes a modified version containing the amino acid sequence of SEQ ID NO: 110, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0184] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118.

[0185] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 119, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 120, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 121, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 122, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 123, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 124, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0186] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 116, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118.

[0187] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 125. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 126. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0188] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 125; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of sequence 126.

[0189] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134.

[0190] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 135, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 136, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 137, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 138, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 139, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 140, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0191] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 129, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 130, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 131, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 132, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 133, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 134.

[0192] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 141. HHC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in Sequence ID No. 142. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0193] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 141; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 142.

[0194] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358; LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356; and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359.

[0195] In some embodiments, V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 151, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 152, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 153, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 154, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 155, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 156, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0196] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 145, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 146, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 147, V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 148, 355, or 358; ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 149 or 356; and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 150, 357, or 359.

[0197] In some embodiments, the antibody portion has the sequence shown in SEQ ID NOs: 157 and 360-362. H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 158 and 363-365. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0198] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of any of sequence numbers 157 and 360-362, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier containing an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 158 and any of sequences 363-365.

[0199] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 157; V LThis includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 158.

[0200] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 360, or an amino acid sequence having at least approximately 80% sequence identity (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 363.

[0201] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 360, or an amino acid sequence having at least approximately 80% sequence identity (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 364, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0202] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 360, or an amino acid sequence having at least approximately 80% sequence identity (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 365.

[0203] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 361, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 363.

[0204] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 361, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 364, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0205] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 361, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 365.

[0206] In some embodiments, V HThis includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 362; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 363.

[0207] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 362; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 364, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0208] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 362; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 365.

[0209] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166.

[0210] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 167, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 168, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 169, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 170, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 171, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 172, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0211] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 161, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 162, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 163, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 164, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 165, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 166.

[0212] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 173. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in SEQ ID NO: 174. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0213] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 173; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 174.

[0214] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V LThe antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182.

[0215] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182. In some embodiments, V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 183, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 184, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 185, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 186, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 187, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 188, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0216] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 179, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 180 or 353, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 181 or 354, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 182.

[0217] In some embodiments, the antibody portion has the sequence shown in SEQ ID NOs. 189 and 347-349. H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 190 and 350-352. LIt contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0218] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of any of sequence numbers 189 and 347-349, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having sequence identity of any of sequence numbers 190 and 350-352, or at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of an amino acid sequence.

[0219] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 189, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 190.

[0220] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 347, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0221] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 347, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 351.

[0222] In some embodiments, V H This includes a variant containing any amino acid sequence of Sequence ID No. 347, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of any of the amino acid sequences of Sequence ID No. 352, or at least about 80% (for example, at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of an amino acid sequence.

[0223] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 348, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0224] In some embodiments, V HThis includes a variant containing the amino acid sequence of SEQ ID NO: 348, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 351.

[0225] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 348, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 352.

[0226] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 349; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0227] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 349; VL This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 351.

[0228] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence number 349; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 352.

[0229] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 194, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 195, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198.

[0230] In some embodiments, V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 194, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 195, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 199, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 200, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 201, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 202, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 203, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 204, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0231] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 193, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 194, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 195, V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 196, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 197, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 198.

[0232] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 205. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, respectively, as well as V having the sequence shown in SEQ ID NO: 206. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0233] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 205; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 206.

[0234] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, and the V L-2This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214.

[0235] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 215, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 216, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 217, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 218, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 219, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 220, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0236] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V HIt comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 212, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 213, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 214.

[0237] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 221. H HC-CDR1, HC-CDR2, and HC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3 within their chain regions, as well as V having the sequence shown in Sequence ID No. 222. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0238] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 221; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of SEQ ID NO: 222.

[0239] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294.

[0240] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 295, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 296, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 297, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 298, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 299, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 300, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0241] In some embodiments, the anti-CD93 antibody portion is the heavy chain variable region (VH ) and light chain variable region (V L It is a humanized antibody derived from an anti-CD93 antibody containing V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294.

[0242] In some embodiments, the antibody portion has the sequence shown in SEQ ID NOs. 287 and 319-321. H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 288 and 322-324. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0243] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of any of sequence numbers 287 and 319-321, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%); V L This includes a modifier comprising an amino acid sequence having sequence identity of any of sequence numbers 288 and 322-324, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%).

[0244] In some embodiments, the antibody portion has the sequence shown in SEQ ID NOs. 287 and 319-321. HHC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 288 and 322-324. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0245] In some embodiments, V H This includes a variant containing one of the amino acid sequences of sequence numbers 319-321, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier containing one of the amino acid sequences of sequence numbers 322-324, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0246] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 319, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 322.

[0247] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 319, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V LThis includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of sequence 323.

[0248] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 319, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 324.

[0249] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 320, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 322.

[0250] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 320, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of sequence 323.

[0251] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 320, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 324.

[0252] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 321, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 322.

[0253] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 321, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of sequence 323.

[0254] In some embodiments, V HThis includes a variant containing the amino acid sequence of SEQ ID NO: 321, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of sequence 324.

[0255] In some embodiments, the anti-CD93 construct has a heavy chain variable region (V H ) and light chain variable region (V L The antibody portion includes an antibody portion containing a second heavy chain variable region (V) with respect to the CD93 binding epitope. H-2 ) and the second light chain variable region (V L-2 ) competes with antibodies or antibody fragments containing the V H-2 This includes HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and the V L-2 This includes LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0256] In some embodiments, V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0257] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0258] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 301, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0259] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 302, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0260] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 303, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0261] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 306, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0262] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0263] In some embodiments, anti-CD93 V HIt comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 301, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0264] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 302, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0265] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 303, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0266] In some embodiments, anti-CD93 V H It comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, and is anti-CD93V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 306, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22.

[0267] In some embodiments, the antibody portion has the sequence shown in SEQ ID NO: 29 and any of 307-312. H HC-CDR1, HC-CDR2, and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within their chain regions, as well as V having the sequence shown in SEQ ID NOs. 30 and 313-318. L It contains LC-CDR1, LC-CDR2, and LC-CDR3, each containing the amino acid sequences of CDR1, CDR2, and CDR3, respectively, within its chain region.

[0268] In some embodiments, V H This includes a variant containing one amino acid sequence from sequence numbers 307 to 312, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier containing one of the amino acid sequences of sequence numbers 313-318, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0269] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 307, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 313.

[0270] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 307, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 314.

[0271] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 307, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 315.

[0272] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 307, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0273] In some embodiments, V HThis includes a variant containing the amino acid sequence of Sequence ID No. 307, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 317.

[0274] In some embodiments, V H This includes a variant containing the amino acid sequence of Sequence ID No. 307, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 318.

[0275] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 308, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 313.

[0276] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 308, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; VL This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 314.

[0277] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 308, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 315.

[0278] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 308, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0279] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 308, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V LThis includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 317.

[0280] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 308, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 318.

[0281] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 309, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 313.

[0282] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 309, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 314.

[0283] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 309, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 315.

[0284] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 309, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0285] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 309, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 317.

[0286] In some embodiments, V HThis includes a variant containing the amino acid sequence of SEQ ID NO: 309, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 318.

[0287] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 310; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 313.

[0288] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 310; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 314.

[0289] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 310; VL This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 315.

[0290] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 310; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0291] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 310; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 317.

[0292] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 310; V LThis includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 318.

[0293] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 311, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 313.

[0294] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 311, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 314.

[0295] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 311, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 315.

[0296] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 311, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modified version containing the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0297] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 311, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 317.

[0298] In some embodiments, V H This includes a variant containing the amino acid sequence of SEQ ID NO: 311, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 318.

[0299] In some embodiments, V HThis includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of SEQ ID NO: 312, or any one of these; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 313.

[0300] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of SEQ ID NO: 312, or any one of these; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 314.

[0301] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of SEQ ID NO: 312, or any one of these; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 315.

[0302] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of SEQ ID NO: 312, or any one of these; VL This includes a modified version containing the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0303] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of SEQ ID NO: 312, or any one of these; V L This includes a modifier comprising an amino acid sequence having sequence identity of at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of Sequence ID No. 317.

[0304] In some embodiments, V H This includes a variant containing an amino acid sequence having sequence identity of at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the amino acid sequence of SEQ ID NO: 312, or any one of these; V L This includes a modifier comprising an amino acid sequence having at least approximately 80% (for example, at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity with the amino acid sequence of Sequence ID No. 318.

[0305] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including V HThis comprises i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 33, ii) HC-CDR2 containing the amino acid sequence RIFPGDGDX1X2YX3GKFKG (SEQ ID NO: 233) (wherein X1 and X2 are AN or TD, and / or X3 is N or D), and iii) HC-CDR3 containing the amino acid sequence TGAAYX1FDPFPY (SEQ ID NO: 234) (wherein X1 is D or E); V L This includes i) LC-CDR1 containing the amino acid sequence SSX1KSLLHSX2GX3TYLY (SEQ ID NO: 235) (wherein X1 is S or T, X2 is N or S, and / or X3 is V or I), ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 37, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 38.

[0306] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including V H This includes i) HC-CDR1 containing the amino acid sequence X1YWX2N (SEQ ID NO: 236) (wherein X1 is S or T, and / or X2 is L or M), ii) HC-CDR2 containing the amino acid sequence RIX1PGDGDX2X3YX4GKFKG (SEQ ID NO: 237) (wherein X1 is Y or F, X2X3 is TD or AN, and / or X4 is N or D), and iii) HC-CDR3 containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 35, 163, and 179; V LThis includes i) LC-CDR1 containing the amino acid sequence X1X2X3KSLLHSX4GX5TYLY (SEQ ID NO: 238) (wherein X1X2X3 is SSS, SST, or RFS, X4 is N or S, and / or X5 is V or I), ii) LC-CDR2 containing the amino acid sequence X1MSNLAS (SEQ ID NO: 239) (wherein X1 is R or Q), and iii) LC-CDR3 containing the amino acid sequence AQX1LEX2PX3T (SEQ ID NO: 240) (wherein X1 is M or N, X2 is R or L, and / or X3 is F or W). In some embodiments, LC-CDR3 contains an amino acid sequence selected from the group consisting of SEQ ID NOs: 38, 166, and 182.

[0307] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including V H This includes i) HC-CDR1 containing the amino acid sequence X1YVX2H (SEQ ID NO: 241) (wherein X1 is A or S, and / or X2 is M or I), ii) HC-CDR2 containing the amino acid sequence YIX1PYX2DX3TX4YNEKFKG (SEQ ID NO: 242) (wherein X1 is F or N, X2 is N or S, X3 is G or Y, and / or X4 is E or Q), and iii) HC-CDR3 containing the amino acid sequence RX1DGNPYX2MDY (SEQ ID NO: 243) (wherein X1 is T or A, and / or X2 is T or A); V L This includes i) LC-CDR1 (wherein X1 is A or V) containing the amino acid sequence of KASQDVSTAVX1 (SEQ ID NO: 244), ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 118. In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 115 or 221.

[0308] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including VH This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V L This includes i) LC-CDR1 containing the amino acid sequence KASQX1VX2TX3VX4 (SEQ ID NO: 245) (wherein X1 is N or D, X2 is G or S, X3 is N or A, and / or X4 is A or V), ii) LC-CDR2 containing the amino acid sequence SASYRX1X2 (SEQ ID NO: 246) (wherein a) X1 is F or Y and X2 is I or T, or b) X1X2 is FI or YT), and iii) LC-CDR3 containing the amino acid sequence QQX1X2X3X4PX5T (SEQ ID NO: 247) (wherein X1X2X3X4 is YNRN or HYST, and / or X5 is I or F). In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 6, 118, or 214. In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 6.

[0309] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 115, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V LThis includes i) LC-CDR1 containing the amino acid sequence KASQX1VX2TX3VX4 (SEQ ID NO: 245) (wherein X1 is N or D, X2 is G or S, X3 is N or A, and / or X4 is A or V), ii) LC-CDR2 containing the amino acid sequence SASYRX1X2 (SEQ ID NO: 246) (wherein a) X1 is F or Y and X2 is I or T, or b) X1X2 is FI or YT), and iii) LC-CDR3 containing the amino acid sequence QQX1X2X3X4PX5T (SEQ ID NO: 247) (wherein X1X2X3X4 is YNRN or HYST, and / or X5 is I or F). In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 6, 118, or 214. In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 118.

[0310] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 209, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 210, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 211, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V LThis includes i) LC-CDR1 containing the amino acid sequence KASQX1VX2TX3VX4 (SEQ ID NO: 245) (wherein X1 is N or D, X2 is G or S, X3 is N or A, and / or X4 is A or V), ii) LC-CDR2 containing the amino acid sequence SASYRX1X2 (SEQ ID NO: 246) (wherein a) X1 is F or Y and X2 is I or T, or b) X1X2 is FI or YT), and iii) LC-CDR3 containing the amino acid sequence QQX1X2X3X4PX5T (SEQ ID NO: 247) (wherein X1X2X3X4 is YNRN or HYST, and / or X5 is I or F). In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 6, 118, or 214. In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 214.

[0311] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V LThis includes i) LC-CDR1 containing the amino acid sequence X1ASQSVX2X3X4X5X6SYMX7 (SEQ ID NO: 248) (wherein X1 is K or R, X2X3X4X5X6 is DYAGD or STSSY, and / or X7 is N or H), ii) LC-CDR2 containing the amino acid sequence X1ASNLES (SEQ ID NO: 249) (wherein X1 is A or Y), and iii) LC-CDR3 containing the amino acid sequence QX1X2X3X4X5PX6T (SEQ ID NO: 250) (wherein X1X2X3X4X5 is QTNED or HSWEI, and / or X6 is R or F). In some embodiments, LC-CDR3 contains the amino acid sequence described in SEQ ID NO: 22 or 54. In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 22.

[0312] In some embodiments, the antibody portion is the heavy chain variable region (V H ) and light chain variable region (V L ) including V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 49, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 50, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 51, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; V L This includes i) LC-CDR1 containing the amino acid sequence X1ASQSVX2X3X4X5X6SYMX7 (SEQ ID NO: 248) (wherein X1 is K or R, X2X3X4X5X6 is DYAGD or STSSY, and / or X7 is N or H), ii) LC-CDR2 containing the amino acid sequence X1ASNLES (SEQ ID NO: 249) (wherein X1 is A or Y), and iii) LC-CDR3 containing the amino acid sequence QX1X2X3X4X5PX6T (SEQ ID NO: 250) (wherein X1X2X3X4X5 is QTNED or HSWEI, and / or X6 is R or F). In some embodiments, LC-CDR3 contains the amino acid sequence described in SEQ ID NO: 22 or 54. In some embodiments, LC-CDR3 contains the amino acid sequence shown in SEQ ID NO: 54.

[0313] In some embodiments, the construct consists of an antibody moiety comprising a full-length antibody, a bispecific antibody, a single-stranded Fv(scFv) fragment, a Fab fragment, a Fab' fragment, F(ab')2, a Fv fragment, a disulfide-stabilized Fv fragment (dsFv), a (dsFv)2, and a V fragment. H The antibody or its antigen-binding fragment is selected from the group consisting of H, Fv-Fc fusions, scFv-Fc fusions, scFv-Fv fusions, diabodies, tribodies, and tetrabodies.

[0314] In some embodiments, the anti-CD93 antibody portion is a full-length antibody.

[0315] In some embodiments, the anti-CD93 antibody portion is scFv.

[0316] In some embodiments, the anti-CD93 antibody moiety comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some embodiments, the anti-CD93 antibody moiety or full-length antibody comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof. In some embodiments, the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has enhanced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment is modified to have an increased serum half-life compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment is modified to have a decreased serum half-life compared to the corresponding wild-type Fc fragment.

[0317] In some embodiments, the antibody moiety comprises a humanized antibody of any of the antibody moieties described herein.

[0318] In some embodiments, the anti-CD93 construct includes or is an anti-CD93 fusion protein.

[0319] In some embodiments, the anti-CD93 construct includes or is a multispecific anti-CD93 construct (such as a bispecific antibody).

[0320] In some embodiments, the anti-CD93 construct comprises or is an anti-CD93 immunoconjugate.

[0321] In some embodiments, the anti-CD93 construct blocks the binding of CD93 to IGFBP7. In some embodiments, IGFBP7 is human IGFBP7. In some embodiments, the binding of CD93 to IGFBP7 is blocked by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more after pre-incubation of the anti-CD93 antibody with CD93 or CD93-expressing cells. In some embodiments, the doses of the anti-CD93 antibody and CD93 are in ratios of approximately 1:10, 1:6, 1:3, 1:1.5, 1:1, 4:3, 2:1, or 5:1. In some embodiments, the binding of CD93 to IGFBP7 is blocked by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more after pre-incubation with anti-CD93 antibody at concentrations of approximately 50 μg / ml, 25 μg / ml, 10 μg / ml, 5 μg / ml, 2 μg / ml, 1 μg / ml, 0.8 μg / ml, 0.6 μg / ml, or 0.4 μg / ml.

[0322] In some embodiments, the anti-CD93 construct blocks the binding of CD93 to MMRN2. In some embodiments, MMRN2 is human MMRN2. In some embodiments, MMRN2 is MMRN2 495-674It is a fragment. In some embodiments, the binding of CD93 to MMRN2 is blocked by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more after pre-incubation of CD93 or CD93-expressing cells with an anti-CD93 antibody. In some embodiments, the anti-CD93 construct does not block the binding of CD93 to MMRN2.

[0323] In some embodiments, the anti-CD93 construct blocks the binding of CD93 to both IGFBP7 and MMRN2.

[0324] In some embodiments, the anti-CD93 construct does not block the interaction between CD93 and IGFBP7. In some embodiments, the anti-CD93 construct does not block the interaction between CD93 and MMRN2. In some embodiments, the anti-CD93 construct does not block the interaction between either IGFBP7 or MMRN2.

[0325] In some embodiments, CD93 is human CD93.

[0326] a) Antibody affinity The binding specificity of the antibody moiety can be experimentally determined by methods known in the art. Such methods include, but are not limited to, Western blotting, ELISA, RIA, ECL, IRMA, EIA, BLI, BIACORE® tests, flow cytometry, and peptide scanning.

[0327] In some embodiments, the binding of the antibody moiety to CD93 is K D It is about 10 -7 M~about 10 -12 M, about 10 -7 M~about 10 -8 M, about 10 -8 M~about 10 -9 M, about 10 -9 M~about 10 -10 M, about 10 -10 M~about 10 -11 M, about 10-11 M~about 10 -12 M, about 10 -7 M~about 10 -12 M, about 10 -8 M~about 10 -12 M, about 10 -9 M~about 10 -12 M, about 10 -10 M~about 10 -12 M, about 10 -7 M~about 10 -11 M, about 10 -8 M~about 10 -11 M, about 10 -9 M~about 10 -11 M, about 10 -7 M~about 10 -10 M, about 10 -8 M~about 10 -10 M, or about 10 -7 M~about 10 -9 In some embodiments, the binding between the antibody moiety and CD93 is K D It is about 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 Stronger than any one of M. In some embodiments, CD93 is human CD93.

[0328] In some embodiments, the binding between the antibody moiety and CD93 is K on It is about 10 3 M -1 s -1 ~about 10 8 M -1 s -1 , about 10 3 M -1 s -1 ~about 10 4 M -1 s -1 , about 10 4 M -1 s -1 ~about 10 5 M -1 s -1 , about 10 5 M -1 s -1 ~about 106 M -1 s -1 、 about 10 6 M -1 s -1 ~ about 10 7 M -1 s -1 、 or about 10 7 M -1 s -1 ~ about 10 8 M -1 s -1 . In some embodiments, the K on of the binding between the antibody portion and CD93 is about 10 3 M -1 s -1 ~ about 10 5 M -1 s -1 、 about 10 4 M -1 s -1 ~ about 10 6 M -1 s -1 、 about 10 5 M -1 s -1 ~ about 10 7 M -1 s -1 、 about 10 6 M -1 s -1 ~ about 10 8 M -1 s -1 、 about 10 4 M -1 s -1 ~ about 10 7 M -1 s -1 、 or about 10 5 M -1 s -1 ~ about 10 8 M -1 s -1 . In some embodiments, the K on of the binding between the antibody portion and CD93 is about 10 3 M -1 s -1 、 10 4 M -1 s -1 、 10 5 M -1 s -1 、 106 M -1 s -1 、 10 7 M -1 s -1 or 10 8 M -1 s -1 or less than any one of these. In some embodiments, CD93 is human CD93.

[0329] In some embodiments, the K of the binding between the antibody portion and CD93 off is about 1 s -1 ~ about 10 -6 s -1 、 about 1 s -1 ~ about 10 -2 s -1 、 about 10 -2 s -1 ~ about 10 -3 s -1 、 about 10 -3 s -1 ~ about 10 -4 s -1 、 about 10 -4 s -1 ~ about 10 -5 s -1 、 about 10 -5 s -1 ~ about 10 -6 s -1 、 about 1 s -1 ~ about 10 -5 s -1 、 about 10 -2 s -1 ~ about 10 -6 s -1 、 about 10 -3 s -1 ~ about 10 -6 s -1 、 about 10 -4 s -1 ~ about 10 -6 s -1 、 about 10 -2 s -1 ~ about 10 -5 s -1 、 or about 10 -3 s -1 ~ about 10 -5 s -1In some embodiments, the binding between the antibody moiety and CD93 is K off It takes at least about 1 second -1 , 10 -2 s -1 , 10 -3 s -1 , 10 -4 s -1 , 10 -5 s -1 or 10 -6 s -1 It is one of the following. In some embodiments, CD93 is human CD93.

[0330] In some embodiments, the binding affinity of the anti-CD93 antibody moiety or anti-CD93 construct is higher than that of existing anti-CD93 antibodies (e.g., anti-human CD93 antibodies, e.g., MM01) (e.g., K D (The value is smaller.)

[0331] b) Chimeric antibody or humanized antibody In some embodiments, the anti-CD93 antibody portion is a chimeric antibody. Specific chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and in Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In some embodiments, the chimeric antibody includes a non-human variable region (e.g., a mouse-derived variable region) and a human constant region. In some embodiments, the chimeric antibody is a “class-switched” antibody in which the class or subclass is changed from that of the parent antibody. The chimeric antibody includes its antigen-binding fragment.

[0332] In some embodiments, the anti-CD93 antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce its immunogenicity against humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody contains one or more variable domains, where HVR, e.g., CDR (or a portion thereof), is derived from the non-human antibody, and FR (or a portion thereof) is derived from the human antibody sequence. The humanized antibody also optionally contains at least a portion of the human constant region. In some embodiments, some FR residues in the humanized antibody are replaced with corresponding residues from the non-human antibody (e.g., the antibody from which the HVR residues are derived) to restore or improve the specificity or affinity of the antibody, for example.

[0333] Humanized antibodies and methods for their production are outlined, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, for example, in: Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patents No. 5,821,337, No. 7,527,791, No. 6,982,321, and No. 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describes SDR(a-CDR) grafts); Padlan, Mol.Immunol.28:489-498 (1991) (describes "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describes "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br.J.Cancer,83:252-260 (2000) (describes the "guide selection" approach to FR shuffling).

[0334] Human framework regions that may be used for humanization include, but are not limited to, the following: framework regions selected using the “best fit” method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); framework regions derived from consensus sequences of human antibodies of specific subgroups of light chain variable regions or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human maturation (somatic mutation) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening of FR libraries (e.g., Baca et al. See al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996).

[0335] It is understood that the humanization of mouse-derived antibodies is a common and routine technique. Therefore, it is understood that any and all humanized formats of the anti-CD93 antibodies disclosed in the sequence listing can be used in preclinical or clinical settings. When any humanized format of a referenced anti-CD93 antibody or its antigen-binding region is used in such preclinical or clinical settings, the humanized format is expected to have the same or similar biological activity and profile as the original non-humanized format.

[0336] c) Human antibodies In some embodiments, the anti-CD93 antibody portion is a human antibody (known as a human domain antibody or human DAb). Human antibodies can be produced using various techniques known in the art. Human antibodies are generally produced by van Dijk and van This is described in de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001), Lonberg, Curr. Opin. Immunol. 20:450-459 (2008), and Chen, Mol. Immunol. 47(4):912-21 (2010). Transgenic mice or rats capable of producing fully human single-domain antibodies (or DAbs) are known in the art. See, for example, US20090307787A1, U.S. Patent No. 8,754,287, US20150289489A1, US20100122358A1, and WO2004049794.

[0337] Human antibodies (e.g., human DAbs) can be prepared by administering immunogens to transgenic animals modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of a human immunoglobulin locus, either substituted for the endogenous immunoglobulin locus, located extrachromosomally, or randomly incorporated into the animal's chromosomes. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 (describes XENOMOUSE® technology); U.S. Patent No. 5,770,429 (describes HuMab®); U.S. Patent No. 7,041,870 (describes KM MOUSE®); and U.S. Patent Application No. 2007 / 0061900 (describes VelociMouse®). Human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining them with different human constant regions.

[0338] Human antibodies (e.g., human DAbs) can also be produced by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described (see, for example, 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 produced via human B-cell hybridoma technology have also been described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Further methods include, for example, those described in U.S. Patent No. 7,189,826 (production of monoclonal human IgM antibody from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (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).

[0339] Human antibodies (e.g., human DAbs) can also be produced by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0340] d) Antibodies derived from the library The anti-CD93 antibody portion described herein can be isolated by screening a combinatorial library for antibodies having one or more desired activities. For example, various methods for preparing phage display libraries and screening such libraries for antibodies having desired binding properties are known in the art. Such methods are, for example, described in Hoogenboom et al.'s Methods in Molecular Biology 178:1-37 (O'Brien et al.). This is outlined in (al., ed., Human Press, Totowa, NJ, 2001), and further, see, for example, McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J.Mol.Biol.222:581-597 (1992); Marks and Bradbury, in Methods. in Molecular Biology 248:161-175(Lo,ed.,Human Press,Totowa,NJ,2003);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Lee et al. This is described in al., J.Mol.Biol.340(5):1073-1093(2004);Fellouse, Proc.Natl.Acad.Sci.USA 101(34):12467-12472(2004); and Lee et al., J.Immunol.Methods 284(1-2):119-132(2004). Methods for constructing single-domain antibody libraries are described; see, for example, U.S. Patent No. 7,371,849.

[0341] In a certain phage display method, V H and V LGenetic repertoires can be separately cloned by polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for antigen-binding phages as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). The phages typically present antibody fragments as either scFv or Fab fragments. Libraries from immunized sources provide high-affinity antibodies against immunogens without the need to construct hybridomas. Alternatively, naive repertoires (e.g., human-derived) can be cloned without any immunization (as described in Griffiths et al., EMBO J, 12:725-734 (1993)) to provide a single antibody source against a wide range of non-self and self-antigens. Finally, as described by Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992), naive libraries can also be synthetically constructed by cloning an unreorganized V gene segment from stem cells, encoding a highly variable CDR3 region using PCR primers containing random sequences, and achieving rearrangement in vitro. Examples of patent publications describing human antibody phage libraries include U.S. Patent No. 5,750,373, and U.S. Patent Application Publications 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0342] Antibodies or antibody fragments isolated from a human antibody library are considered human antibodies or human antibody fragments in this specification.

[0343] e) Substitutions, insertions, deletions, and modifications In some embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include HVR (or CDR) and FR. Conservative substitutions are shown in Table 2 under the heading "Preferred Substitutions." More substantial substitutions are provided in Table 2 under the heading "Exemplary Substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into antibodies of interest, and the products can be screened for desired activity, e.g., retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 2]

[0344] Amino acids can be grouped according to their general side-chain properties: (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues affecting chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

[0345] Non-conservative substitution involves swapping one member of one class with one of another.

[0346] One type of substitution variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized antibody or a human antibody). Generally, the resulting variant(s) selected for further study have been modified (e.g., improved) in specific biological properties (e.g., increased affinity, decreased immunogenicity) compared to the parent antibody, and / or substantially retain the specific biological properties of the parent antibody. Exemplary substitution variants are affinity-mature antibodies, which can be readily generated using phage display-based affinity maturation techniques, such as those described herein. Briefly, one or more HVR residues are mutated, the variant antibody is presented on a phage, and it is screened for specific biological activity (e.g., binding affinity).

[0347] For example, modifications (e.g., substitutions) may be made to the HVR to improve antibody affinity. Such modifications may be made in the HVR "hotspots," i.e., residues encoded by codons that are frequently mutated during the somatic cell maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and / or SDR (a-CDR), resulting in the modified V H or V LThe binding affinity is tested. Affinity maturation by constructing and re-selecting a secondary library is described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into variable genes selected for maturation by one of various methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-specific mutagenesis). A secondary library is then constructed. The library is then screened to identify any antibody variants with the desired affinity or molecular behavior. Another method for introducing diversity involves an HVR-directed approach that randomizes several HVR residues (e.g., 4-6 residues at a time). HVR residues involved in antigen binding can be specifically identified using, for example, alanine or histidine scanning mutagenesis or modeling. In particular, HC-CDR3 and LC-CDR3 are often targeted.

[0348] In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such alterations do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative alterations that do not substantially reduce binding affinity (e.g., conservative substitutions provided herein) can be made in an HVR. Such alterations may be outside the HVR "hot spot" or CDR.

[0349] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, target residues or groups of charged residues (e.g., Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the antibody-antigen interaction is affected. Further substitutions can be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively, or even further, the crystal structure of the antigen-antibody complex can be used to identify contact points between the antibody and antigen. Such contact residues and adjacent residues can be targeted or excluded as candidates for substitution. Modifiers can be screened to determine whether they possess the desired properties of the antibody.

[0350] Amino acid insertions include amino-terminus and / or carboxyl-terminus fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of terminal insertion is an antibody with an N-terminal methionyl residue. Other insertion modifications of antibody molecules include fusion of the antibody to the N-terminus or C-terminus with enzymes that increase the serum half-life of the antibody (e.g., for ADEPT) or polypeptides.

[0351] f) Glycosylated variants In some embodiments, the anti-CD93 antibody moiety is modified to increase or decrease the degree to which the construct is glycosylated. The addition or deletion of glycosylation sites to the antibody can be conveniently achieved by modifying the amino acid sequence so that one or more glycosylation sites are created or removed.

[0352] If the antibody moiety includes an Fc region, the carbohydrate bound to it may be altered. Native antibodies produced by mammalian cells typically have a C in the Fc region. HThe oligosaccharides include branched oligosaccharides that are generally bound to the two-domain Asn297 by an N-bond. See, for example, Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose bound to GlcNAc in the "stem" of the branched oligosaccharide structure. In some embodiments, modification of the oligosaccharide in the antibody moiety may be performed to produce antibody variants with specific improved properties.

[0353] In some embodiments, the anti-CD93 antibody moiety has a carbohydrate structure lacking fucose (directly or indirectly) bound to the Fc region. For example, the amount of fucose in such an antibody may be 1%–80%, 1%–65%, 5%–65%, or 20%–40%. The amount of fucose is determined by calculating the average amount of fucose in the glycans at Asn297 relative to the total amount of all sugar structures bound to Asn297 (e.g., complex, hybrid, and high-mannose structures) as measured by MALDI-TOF mass spectrometry, as described, for example, in International Publication No. 2008 / 077546. Asn297 refers to the asparagine residue located at approximately position 297 of the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to slight sequence changes in the antibody. Such fucosylated variants may have improved ADCC function. For example, US Patent Application Publication Numbers US 2003 / 0157108 (Presta, L.); US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621; US ​​2004 / 0132140; US 2004 / 0110704;US 2004 / 0110282;US 2004 / 0109865;WO 2003 / 085119;WO 2003 / 084570;WO 2005 / 035586;WO 2005 / 035778;WO2005 / 053742;WO2002 / 031140;Okazaki et al.J.Mol.Biol.336:1239-1249(2004);Yamane-Ohnuki et al.Biotech.Bioeng.87:614(2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US 2003 / 0157108 A1, Presta, L; and WO 2004 / 056312 A1, Adams et al., particularly Example 11), and knockout cell lines, e.g., alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003 / 085107).

[0354] In some embodiments, the anti-CD93 antibody moiety has a bifid oligosaccharide, for example, a bifid oligosaccharide bound to the Fc region of the antibody that is bifid by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and U.S. 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide bound to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).

[0355] g) Fc region variant In some embodiments, the anti-CD93 antibody portion includes an Fc fragment.

[0356] The terms “Fc region,” “Fc domain,” “Fc fragment,” or “Fc” refer to the C-terminal non-antigen-binding region of an immunoglobulin heavy chain that contains at least a portion of the constant region. This term includes both native and modified Fc regions. In some embodiments, the human IgG heavy chain Fc region extends from Cys226 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present without affecting the structure or stability of the Fc region. Unless otherwise specified herein, the numbering of amino acid residues in IgG or the Fc region follows the EU numbering system for antibodies, also known as 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.

[0357] In some embodiments, the Fc fragment is derived from an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some embodiments, the Fc fragment is derived from an immunoglobulin selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof.

[0358] In some embodiments, the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment (e.g., reduced effector function by at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, or 95%, as measured by the level of antibody-dependent cell-mediated cytotoxicity (ADCC)).

[0359] In some embodiments, the Fc fragment is an IgG1 Fc fragment. In some embodiments, the IgG1 Fc fragment contains the L234A mutation and / or the L235A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment containing the S228P, F234A, and / or L235A mutation. In some embodiments, the Fc fragment contains the N297A mutation. In some embodiments, the Fc fragment contains the N297G mutation.

[0360] In some embodiments, one or more amino acid modifications can be introduced into the Fc region of the antibody moiety to generate an Fc region variant. The Fc region variant may include a human Fc region sequence (e.g., human IgG1, IgG2, IgG3, or IgG4 Fc region) that includes amino acid modifications (e.g., substitutions) at one or more amino acid positions.

[0361] In some embodiments, Fc fragments possess some, but not all, effector functions, making them desirable candidates for applications where the half-life of the antibody portion in vivo is important, but certain effector functions (such as complement and ADCC) are unnecessary or detrimental. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / depletion of CDC and / or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcγR binding (and therefore likely lacks ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 2 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). A non-limiting example of an in vitro assay for evaluating the ADCC activity of a target molecule is U.S. Patent No. 5,500,362 (e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA). See 83:7059-7063 (1986) and Hellstrom, I et al. This is described in al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (see, for example, ACTI® non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA) and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or in addition, the ADCC activity of the target molecule can be measured in vivo, for example, in Clynes et al. Proc. Nat'l Acad. Sci. USA It can be evaluated in animal models such as those disclosed in 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q and therefore lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in International Publication Nos. 2006 / 029879 and International Publication Nos. 2005 / 100402. A CDC assay can be performed to evaluate complement activation (e.g., Gazzano-Santoro See et al., J.Immunol.Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004). The determination of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, for example, Petkova, S B et al., Int'l.Immunol. 18(12):1759-1769 (2006)).

[0362] Antibodies with reduced effector function include those with one or more substitutions of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc variants include the so-called "DANA" Fc variant (U.S. Patent No. 7,332,581) in which residues 265 and 297 are substituted with alanine, and Fc variants having two or more substitutions of amino acid positions 265, 269, 270, 297, and 327. In some embodiments, the Fc fragment includes the N297A mutation. In some embodiments, the Fc fragment includes the N297G mutation.

[0363] Certain antibody variants with improved or reduced binding to FcR have been described. (See, for example, U.S. Patent No. 6,737,056; International Publication No. 2004 / 056312; and Shields et al., J. Biol. Chem. 9(2):6591-6604(2001).)

[0364] In some embodiments, the Fc fragment is an IgG1 Fc fragment. In some embodiments, the IgG1 Fc fragment contains the L234A mutation and / or the L235A mutation. In some embodiments, the IgG1 Fc fragment contains the L235A mutation and / or the G237A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment containing the S228P, F234A, and / or L235A mutation.

[0365] In some embodiments, the antibody moiety includes an Fc region having one or more amino acid substitutions that improve ADCC, for example, substitutions at positions 298, 333 and / or 334 of the Fc region (residue EU numbering).

[0366] In some embodiments, modifications are made to the Fc region that result in alterations (i.e., either improvements or reductions) to C1q binding and / or complement-dependent cell injury (CDC), as described, for example, in U.S. Patent No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0367] In some embodiments, the antibody partial modifier includes a modified Fc region containing one or more amino acid substitutions that alter the half-life and / or alter the binding to the neonatal Fc receptor (FcRn). Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J.Immunol. 117:587 (1976) and Kim et al., J.Immunol. 24:249 (1994)), are described in US2005 / 0014934A1 (Hinton et al.). These antibodies include an Fc region having one or more substitutions that alter the binding of the Fc region to FcRn. Such Fc modifiers include those having one or more substitutions of Fc region residues (e.g., substitution of Fc region residue 434) (U.S. Patent No. 7,371,826).

[0368] See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94 / 29351 for other examples of Fc region variants.

[0369] h) Cysteine-modified antibody variant In some embodiments, it may be desirable to produce a cysteine-modified antibody moiety, e.g., “thioMAb”, in which one or more residues of the antibody are substituted with cysteine ​​residues. In certain embodiments, the substituted residues are located in an accessible site of the antibody. By substituting these residues with cysteine, the reactive thiol group is thereby positioned in an accessible site of the antibody and can be used to conjugate the antibody to another part, such as a drug moiety or a linker-drug moiety, as further described herein, to produce an immunoconjugate. In some embodiments, one or more of the following residues may be substituted with cysteine: A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. The cysteine-modified antibody moiety may be produced, for example, as described in U.S. Patent No. 7,521,541.

[0370] i) Antibody derivative In some embodiments, the antibody moieties described herein may be further modified to include further non-proteinoid moieties that are known in the art and readily available. Moieties suitable for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propropylene glycol homopolymers, prolipropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in production due to its stability in water. The polymers may have any molecular weight and may be branched or unbranched. The number of polymers that bind to an antibody can vary, and if more than one polymer binds, they may be the same or different molecules. In general, the number and / or types of polymers used in derivatization can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody being improved, and whether the antibody derivative will be used for diagnostic purposes under defined conditions.

[0371] In some embodiments, the antibody moiety may be further modified to include one or more biologically active proteins, polypeptides, or fragments thereof. “Bioactive” or “biologically active,” when used interchangeably herein, means exhibiting biological activity in the body to perform a particular function. For example, it may mean a combination with a specific biomolecule such as a protein or DNA, and then the promotion or inhibition of the activity of such biomolecule. In some embodiments, the biologically active protein or fragment thereof includes proteins and polypeptides administered to a patient as active drug substances for the prevention or treatment of a disease or condition, as well as proteins and polypeptides used for diagnostic purposes, such as enzymes used in diagnostic tests or in vitro assays, and proteins and polypeptides administered to a patient to prevent disease (such as vaccines).

[0372] Multispecific anti-CD93 construct In some embodiments, the anti-CD93 construct includes a multispecific (e.g., bispecific) anti-CD93 construct comprising an anti-CD93 antibody moiety comprising one of the anti-CD93 antibody moieties described herein and a second binding moiety (such as a second antibody moiety) that specifically recognizes a second antigen.

[0373] In some embodiments, the multispecific anti-CD93 molecule comprises an anti-CD93 antibody moiety and a second moiety (such as a second antibody moiety) that specifically recognizes a second antigen.

[0374] In some embodiments, the second antigen is an immune checkpoint molecule. In some embodiments, the second antigen is PD-1 or PD-L1.

[0375] In some embodiments, the second part is the extracellular domain (ECD) of PD-1 or PD-L1. In some embodiments, the second part is a PD-L1 trap or a PD-1 trap. See, for example, Nat Commun. 2018 Jun 8;9(1):2237.

[0376] In some embodiments, the second antigen is a tumor antigen.

[0377] In some embodiments, the second antigen is an angiogenic agent. In some embodiments, the angiogenic agent is a VEGF (e.g., human VEGF) antibody. In some embodiments, the angiogenic agent is a VEGF receptor. In some embodiments, the angiogenic agent is VEGFR1 (e.g., human VEGFR1). In some embodiments, the angiogenic agent is VEGFR2 (e.g., human VEGFR2).

[0378] In some embodiments, the second portion includes the extracellular domain (ECD) of the VEGF receptor. In some embodiments, the second portion includes the ECD of VEGFR1 and / or VEGFR2. In some embodiments, the second portion includes a VEGF trap. See, for example, Proc Natl Acad Sci USA. 2002 Aug 20;99(17):11393-8.

[0379] In some embodiments, the second antibody moiety and the anti-CD93 antibody moiety are fused to each other via a linker, such as any linker described herein, in any operable form that allows for proper functioning of the binding moiety. In some embodiments, the linker is a GS linker. In some embodiments, the linker is selected from the group consisting of SEQ ID NOs: 225-232 and 338.

[0380] In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising: a) an anti-CD93 antibody moiety comprising any one of the anti-CD93 antibody moieties described herein; and b) a second antibody moiety (anti-PD-L1 antibody moiety) that specifically recognizes PD-L1.

[0381] In some embodiments, the anti-CD93 construct is a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (VL A multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody containing ) and b) an anti-PD-L1 antibody moiety (such as any of the antibody moieties described herein) fused to at least one or both of the heavy chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD-L1 antibody moiety is fused to the N-terminus of both heavy chains. In some embodiments, the anti-PD-L1 antibody moiety is fused to the C-terminus of both heavy chains.

[0382] In some embodiments, the anti-CD93 construct is an anti-PD-L1 antibody moiety comprising a full-length antibody including two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-L1 antibody moiety containing (b) an anti-PD-L1 antibody moiety (such as any of the anti-CD93 antibody moieties described herein) fused to at least one or both of the heavy chains of a full-length anti-PD-L1 antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of both heavy chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of both heavy chains.

[0383] In some embodiments, the anti-CD93 construct is a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody containing ) and b) an anti-PD-L1 antibody moiety (such as any of the antibody moieties described herein) fused to at least one or both of the light chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD-L1 antibody moiety is fused to the N-terminus of both light chains. In some embodiments, the anti-PD-L1 antibody moiety is fused to the C-terminus of both light chains.

[0384] In some embodiments, the anti-CD93 construct is an anti-PD-L1 antibody moiety comprising a full-length antibody including two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-L1 antibody moiety containing a) and b) an anti-CD93 antibody moiety (such as any of the antibody moieties described herein) fused to at least one or both of the light chains of the full-length anti-PD-L1 antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of both light chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of both light chains.

[0385] In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising: a) an anti-CD93 antibody moiety comprising any one of the anti-CD93 antibody moieties described herein; and b) a second antibody moiety (anti-PD-1 antibody moiety) that specifically recognizes PD-1.

[0386] In some embodiments, the anti-CD93 construct is a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody containing ) and b) an anti-PD-1 antibody moiety (such as any of the antibody moieties described herein) fused to at least one or both of the heavy chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD- antibody moiety is fused to the N-terminus of both heavy chains. In some embodiments, the anti-PD-1 antibody moiety is fused to the C-terminus of both heavy chains.

[0387] In some embodiments, the anti-CD93 construct is an anti-PD-1 antibody moiety comprising a full-length antibody including two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V LA multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-1 antibody moiety containing a) and b) an anti-CD93 antibody moiety (such as any of the anti-CD93 antibody moieties described herein) fused to at least one or both of the heavy chains of a full-length anti-PD-1 antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of both heavy chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of both heavy chains.

[0388] In some embodiments, the anti-CD93 construct is a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody containing ) and b) an anti-PD-1 antibody moiety (such as any of the antibody moieties described herein) fused to at least one or both of the light chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD-1 antibody moiety is fused to the N-terminus of both light chains. In some embodiments, the anti-PD-1 antibody moiety is fused to the C-terminus of both light chains.

[0389] In some embodiments, the anti-CD93 construct is an anti-PD-1 antibody moiety comprising a full-length antibody including two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-1 antibody moiety containing a) and b) an anti-CD93 antibody moiety (such as any of the antibody moieties described herein) fused to at least one or both of the light chains of a full-length anti-PD-1 antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of both light chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of both light chains.

[0390] In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising: a) an anti-CD93 antibody moiety comprising one of the anti-CD93 antibody moieties described herein; and b) a second binding moiety that specifically recognizes VEGF.

[0391] In some embodiments, the anti-CD93 construct is a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody containing a) and a) a second binding site that specifically recognizes VEGF fused to at least one or both of the heavy chains of the full-length anti-CD93 antibody. In some embodiments, the second binding site is fused to the N-terminuses of both heavy chains. In some embodiments, the second binding site is fused to the C-terminuses of both heavy chains.

[0392] In some embodiments, the anti-CD93 construct is an anti-VEGF antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-VEGF antibody moiety containing (b) an anti-VEGF antibody moiety (a) fused to at least one or both of the heavy chains of the full-length anti-VEGF antibody (such as any of the anti-CD93 antibody moieties described herein). In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of both heavy chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of both heavy chains.

[0393] In some embodiments, the anti-CD93 construct is a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V LA multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody containing a) and a) a second binding site that specifically recognizes VEGF and is fused to at least one or both of the light chains of the full-length anti-CD93 antibody. In some embodiments, the second binding site is fused to the N-terminuses of both light chains. In some embodiments, the second binding site that specifically recognizes VEGF is fused to the C-terminuses of both light chains.

[0394] In some embodiments, the anti-CD93 construct is an anti-VEGF antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains is a heavy chain variable region (V H ) includes, and the two light chains each have a light chain variable region (V L A multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-VEGF antibody moiety containing a) and b) an anti-CD93 antibody moiety (such as any of the antibody moieties described herein) fused to at least one or both of the light chains of the full-length anti-VEGF antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of both light chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of both light chains.

[0395] In some embodiments, a) a full-length antibody that specifically recognizes CD93 comprising two heavy chains and two light chains, wherein the two heavy chains each comprise a heavy chain variable region (V) comprising HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291. H ) and the two light chains each contain a light chain variable region (V) containing LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294. LThe present invention provides an anti-CD93 construct comprising a) a full-length antibody and b) a VEGF-binding site comprising the amino acid sequence of SEQ ID NO: 325, wherein the VEGF-binding site is fused to one or both of the heavy chains of the full-length antibody. In some embodiments, the VEGF-binding site is fused to the C-terminus of both heavy chains of the full-length antibody. In some embodiments, the VEGF-binding site is fused to the full-length antibody via a linker. In some embodiments, the linker is a GS linker or selected from the group consisting of SEQ ID NOs: 225-232 and 338. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 338. In some embodiments, anti-CD93 V H This includes a variant containing one of the amino acid sequences of sequence numbers 287 and 319-321, or an amino acid sequence having at least approximately 80% (e.g., at least approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L This includes a modifier comprising one of the amino acid sequences of SEQ ID NO: 288 and 322-324, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the full-length antibody has an IgG1 isotype (such as a human IgG1 isotype). In some embodiments, the heavy chain comprises a modifier comprising the amino acid sequence of SEQ ID NO: 342, or an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the light chain includes the amino acid sequence of SEQ ID NO: 343, or a modified version having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0396] In some embodiments, anti-CD93 V HThis includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 1, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 2, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 3, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in HC-CDR, and is anti-CD93 V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 4, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 5, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 6, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0397] In some embodiments, anti-CD93 V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 17 or 304, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 18 or 305, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 19, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in HC-CDR, and is anti-CD93 V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 22, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0398] In some embodiments, anti-CD93 V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 289, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 290, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 291, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in HC-CDR, and anti-CD93 V LThis includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 292, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 293, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 294, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, anti-CD93 V H This includes i) HC-CDR1 containing the amino acid sequence of SEQ ID NO: 295, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO: 296, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO: 297, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in HC-CDR, and is anti-CD93 V L This includes i) LC-CDR1 containing the amino acid sequence of SEQ ID NO: 298, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO: 299, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO: 300, or a variant thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

[0399] In some embodiments, the above amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

[0400] Exemplary anti-PD-L1 antibody portion Exemplary anti-PD-L1 antibody moieties include, but are not limited to, those...

Claims

[Claim 1] A method for treating a disease or condition in an individual, or a method for modulating an immune response in an individual, the method comprising administering an anti-CD93 construct to the individual.

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