Anti-CD93 constructs and uses thereof

Abstract

The present application provides anti-CD93 constructs (e.g., anti-CD93 antibodies) that bind to CD93, nucleic acid molecules encoding the amino acid sequence of anti-CD93, vectors containing the nucleic acid molecules, host cells containing the vectors, methods for preparing anti-CD93 constructs, pharmaceutical compositions containing anti-CD93 constructs, and methods for using anti-CD93 constructs or compositions. CD93 (cluster of differentiation 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.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 058,359, filed July 29, 2020, U.S. Provisional Application No. 63 / 084,474, filed September 28, 2020, and International Application No. PCT / US2021 / 035542, filed June 2, 2021, the contents of which are incorporated by reference in their entirety for all purposes.

[0002] Technical Field The present disclosure relates to anti-CD93 constructs (such as anti-CD93 antibodies) and uses thereof.

[0003] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (Filename: 193852000243SEQLIST.TXT, Recorded: July 28, 2021, Size: 185KB). [Background technology]

[0004] Background of the Application CD93 (cluster of differentiation 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. CD93 was initially thought to be a receptor for C1q but is now thought to be involved instead in cell-cell adhesion and clearance of apoptotic cells. The intracellular cytoplasmic tail of this protein contains two highly conserved domains that may be involved in CD93 function. Indeed, the highly charged juxtamembrane domain has been found to interact with moesin, a protein known to link transmembrane proteins to the cytoskeleton and to play a role in cytoskeletal remodeling. This process appears to be crucial for adhesion, migration, and phagocytosis.

[0005] The disclosures of all publications, patents, patent applications and published patent applications mentioned herein are hereby incorporated by reference in their entirety. Summary of the Invention [Means for solving the problem]

[0006] BRIEF SUMMARY OF THE APPLICATION The following summary is illustrative only and is not intended to be in any way limiting. That is, the following summary is provided to introduce highlights, benefits, and advantages of novel molecules and their uses. As such, the following summary is not intended to identify essential features of the claimed subject matter, nor is it intended for use in determining the scope of the claimed subject matter.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0026] In some embodiments of any of the above anti-CD93 constructs, the antibody portion is an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a bispecific antibody, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab' fragment, a F(ab'), an Fv fragment, a disulfide-stabilized Fv fragment (dsFv), a (dsFv), an Fv-Fc fusion, an scFv-Fc fusion, an scFv-Fv fusion, a diabody, a tribody, and a tetrabody. 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 portion comprises an Fc fragment selected from the group consisting of Fc fragments derived from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some embodiments, the Fc fragment is selected from the group consisting of Fc fragments derived from 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 has an extended serum half-life. In some embodiments, the Fc fragment has a reduced serum half-life.

[0028] In some embodiments of any of the above anti-CD93 constructs, the antibody portion blocks 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 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) binding of CD93 to IGFBP7 and / or b) binding of CD93 to MMRN2.

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

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

[0033] In another aspect, the present application provides an isolated nucleic acid encoding any of the above anti-CD93 constructs.

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

[0035] In another aspect, the application provides an isolated host cell comprising any of the above-described isolated nucleic acids or vectors.

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

[0037] In another aspect, the present application provides a method of producing an anti-CD93 construct, the method comprising: a) culturing the isolated host cell of claim 25 under conditions effective to express the anti-CD93 construct; and b) obtaining the expressed anti-CD93 construct from the host cell.

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

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

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

[0041] [Figure 3-1]3A-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] 3A-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] 4A-4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to controls. [Figure 4-2] 4A-4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to controls. [Figure 4-3] 4A-4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to controls. [Figure 4-4] 4A-4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to controls.

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

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

[0045] [Figure 7]Figures 7A and 7B show alignments of VH and VL CDRs according to Kabat numbering. From top to bottom, the sequences in Figure 7A are SEQ ID NOs: 393 to 406, and the sequences in Figure 7B are SEQ ID NOs: 407 to 420.

[0046] [Figure 8] Figures 8A and 8B show alignments of VH and VL CDRs determined by the VBASE2 tool. From top to bottom, the sequences in Figure 8A are SEQ ID NOs: 393 to 406, and the sequences in Figure 8B are SEQ ID NOs: 407 to 420.

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

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

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

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

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

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

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

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

[0055] [Figure 17] FIG. 17 shows tumor volumes in mice treated with exemplary anti-CD93 constructs.

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

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

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

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

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

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

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

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

[0064] [Figure 27] FIG. 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] FIG. 28 shows the binding of an exemplary humanized 17B10 antibody to mouse CD93 cell surface-expressing HEK cells as determined by a fluorescence-activated cell sorting (FACS) assay.

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

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

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

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

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

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

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

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

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

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

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

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

[0078] [Figure 41] FIG. 41 shows a characterization of the binding kinetics of exemplary 16E4 and 7F3 antibodies to hCD93.

[0079] [Figure 42] FIG. 42 shows the characterization of the binding kinetics of an exemplary humanized 16E4 antibody to hCD93.

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

[0081] [Figure 44] Figure 44 shows a 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 effect of humanized 16E4 and 7F3 antibodies on MMRN2 binding to CHO-hCD93 cells.

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

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

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

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

[0087] [Figure 51] Figure 51 provides a summary of the properties of exemplary anti-CD93 antibodies. DETAILED DESCRIPTION OF THE INVENTION

[0088] Detailed Description of the Invention The present application provides novel anti-CD93 constructs that specifically bind to CD93 (e.g., anti-CD93 monoclonal or multispecific antibodies), methods for preparing the anti-CD93 constructs, and methods for using the constructs (e.g., methods for treating a disease or condition).

[0089] Anti-CD93 antibodies (e.g., anti-CD93 antibodies that block the interaction between CD93 and IGFBP7) can effectively treat tumors or cancers, block aberrant tumor angiogenesis, normalize immature and leaky tumor vessels, promote a functional vascular network 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 promote the delivery of a second agent. See, e.g., 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 the tumor to a second treatment or facilitate the delivery of a second agent.

[0090] I. Definition The term "antibody" is used in its broadest sense and 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 antigen-binding fragments thereof, so long as they exhibit the desired antigen-binding activity. The term "antibody portion" refers to a full-length antibody or an antigen-binding fragment thereof.

[0091] A full-length antibody comprises 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) (light chain (LC) CDRs, including LC-CDR1, LC-CDR2, and LC-CDR3, and heavy chain (HC) CDRs, including HC-CDR1, HC-CDR2, and HC-CDR3). The CDR boundaries of the antibodies 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 interposed between adjacent stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops. The constant regions of the heavy and light chains are not involved 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 chains. 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] The term "antigen-binding fragment" as used herein refers to antibody fragments, including, for example, diabodies, Fab, Fab', F(ab'), Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv), bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (ds diabodies), single-chain Fvs (scFv), scFv dimers (bivalent diabodies), multispecific antibodies formed from portions of an antibody containing one or more CDRs, camelid single-domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment that binds to an antigen but does not comprise the complete antibody structure. An antigen-binding fragment can bind to the same antigen as bound by the parent antibody or parent antibody fragment (e.g., the parent scFv). In some embodiments, the antigen-binding fragment can contain one or more CDRs from a particular human antibody grafted onto framework regions from a different human antibody.

[0093] An "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and binding site. This fragment consists of a dimer of one heavy-chain variable region domain and one light-chain variable region domain in tight, non-covalent association. The folding of these two domains results in six hypervariable loops (three loops from each heavy and light chain) 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 an Fv containing only three antigen-specific CDRs) has the ability to recognize and bind antigen, although often with lower affinity than the entire binding site.

[0094] A "single-chain Fv" (also abbreviated as "sFv" or "scFv") is a VFv that is linked to a single polypeptide chain. H and V L In some embodiments, the scFv polypeptide is an antibody fragment containing a V domain that enables the scFv to form the desired structure for antigen binding. H Domains and V LIt further comprises a polypeptide linker between the domains. For a review of scFvs, 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 term "CDR" or "complementarity determining region" is intended to mean the discontinuous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. These specific regions were identified by Kabat et al., J.Biol.Chem.252:6609-6616(1977);Kabat et 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.,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 Pluckthun, J. Mol. Biol., 309:657-670 (2001), wherein the definitions include overlapping or subsets of amino acid residues when compared with each other. Nevertheless, application of either definition to refer to the CDR of an antibody or grafted antibody or variant thereof is intended to be within the scope of the term as defined and used herein. The amino acid residues encompassing the CDRs defined by each of the above-cited references are set forth in Table 1 below for comparison. CDR prediction algorithms and interfaces are 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., 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 possible inclusion in one or more claims herein. In some embodiments, the CDR sequences provided herein are based on the IMGT definition. For example, CDR sequences can be determined by the VBASE2 tool (http: / / www.vbase2.org / vbase2.php; see also Retter I, Althaus HH, Munch R, Muller W: VBASE2, an integrated V gene database. Nucleic Acids Res. 2005 Jan 1;33 (Database Issue):D671-4, incorporated herein by reference in its entirety). [Table 1]

[0096] The phrases "Kabat variable domain residue numbering" or "Kabat amino acid position numbering" and variations thereof refer to the numbering system used for the heavy or light chain variable domains of the antibody compilation of Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortening or insertion of the FR or hypervariable region (HVR) of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues 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 the "standard" Kabat numbered sequence at the regions of homology.

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

[0098] "Framework" or "FR" residues are those variable domain residues other than the CDR residues as herein defined.

[0099] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. Most commonly, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired antibody specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. In general, humanized antibodies comprise substantially all of at least one, and typically two, variable domains, with all or substantially all of the hypervariable loops corresponding to those of a non-human immunoglobulin and all or substantially all of the FRs being those of a human immunoglobulin sequence. Humanized antibodies also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a 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 that of an antibody produced by a human and / or produced using any of the techniques for producing human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies containing 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). Also available for preparing human monoclonal antibodies are methods 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 antigen to transgenic animals, e.g., immunized xenogeneic animals, that have been engineered to produce such antibodies in response to antigen challenge but whose endogenous gene loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™). See also Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006), regarding human antibodies generated via human B cell hybridoma technology.

[0101] "Percent (%) amino acid sequence identity" or "homology" with respect to the polypeptide and antibody sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the polypeptide being compared, after aligning the sequences and taking into account any conservative substitutions as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, 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 alignment, including any algorithms required to achieve maximum alignment across the entire length of the sequences being compared. However, for purposes of this specification, % amino acid sequence identity values ​​are generated using the sequence comparison computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5(1):113, 2004).

[0102] "Homologous" refers to sequence similarity or sequence identity between two polypeptides or two nucleic acid molecules. If both positions in two compared sequences 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 molecules are homologous at that position. The percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences multiplied by 100, divided by the number of positions compared. For example, if 6 out of 10 positions in two sequences are matching or homologous, the two sequences are 60% homologous. As an example, the protein sequences SGTSTD and TGTSDA share 50% homology. Generally, comparisons are performed when two sequences are aligned to maximize homology.

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

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

[0105] The "CH1 domain" (also called "C1" for "H1" domain) typically spans from about amino acid 118 to about amino acid 215 (EU numbering system).

[0106] The "hinge region" is generally defined as the region in IgG corresponding to Glu216 to Pro230 of 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 inter-heavy chain S—S bonds in the same positions.

[0107] The "CH2 domain" (also called the "C2" domain) of the human IgG Fc region typically extends from about amino acid 231 to about amino acid 340. The CH2 domain is unique in that it is not tightly paired with another domain. Rather, two N-linked branched carbohydrate chains are sandwiched between the two CH2 domains in intact, native IgG molecules. It has been speculated that the carbohydrates may provide a surrogate for domain-domain pairing and help stabilize the CH2 domain. Burton, Molec Immunol. 22:161-206 (1985).

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

[0109] The terms "Fc region" or "fragment crystallizable region" are used herein to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226 or the amino acid residue at position 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 recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition can include an antibody population in which all K447 residues have been removed, an antibody population in which the K447 residue has not been removed, and an antibody population having a mixture of antibodies with and without the K447 residue. 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. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, FcRN, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. (See M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997). FcRNs are important for the recycling of antibodies to the blood, allowing for an increased serum half-life of the antibody. FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein.

[0111] As used herein, the term "epitope" refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. Two antibodies or antibody portions 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 thereof "competes" with a second antibody or fragment thereof for binding to a target antigen if the first antibody or fragment thereof inhibits target antigen binding of the second antibody or fragment thereof by at least about 50% (e.g., at least about any one of 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, or vice versa. A high-throughput process for antibody "binning" based on cross-competition is described in PCT Publication No. WO 03 / 48731.

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

[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 and IGFBP7 or MMRN2 by occupying at least a portion of the binding site on CD93 that is involved in IGFBP7 or MMRN2 binding, the anti-CD93 constructs described herein may block the binding of CD93 and IGFBP7 or MMRN2 by altering the structure of CD93 so that CD93 and IGFBP7 / MMRN2 cannot bind.

[0115] An "isolated" or "purified" antibody (or construct) is one that has been identified, separated and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is free of association with all other components from its production environment.

[0116] An "isolated" nucleic acid molecule encoding a construct, antibody, or antigen-binding fragment thereof described herein is a nucleic acid molecule that has been identified and separated from at least one contaminant nucleic acid molecule with which it is normally associated in the environment in which it is produced. Preferably, an isolated nucleic acid is not associated with all components associated with the production environment. An isolated nucleic acid molecule encoding a polypeptide or antibody described herein is in a form other than the form or setting in which it is found in nature. Thus, an isolated nucleic acid molecule is distinct from a nucleic acid encoding a polypeptide or antibody described herein that naturally occurs in a cell. Isolated nucleic acid includes a nucleic acid molecule contained in a cell that normally contains the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location different from its natural chromosomal location.

[0117] The term "control sequence" refers to a DNA sequence necessary for the expression of an operably linked coding sequence in a particular host organism. Control sequences suitable for prokaryotes include, for example, a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0118] A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to promote translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers need not be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adapters or linkers are used in accordance with 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 linked. The term includes vectors as self-replicating nucleic acid structures as well as vectors that are integrated into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0120] As used herein, the terms "transfected" or "transformed" or "transduced" refer to the process by which exogenous nucleic acid is transferred or introduced into a host cell. A "transfected" or "transformed" or "transduced" cell is one that has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny.

[0121] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0122] The term "immunoconjugate" includes reference to the covalent attachment of a therapeutic agent or detectable label to an antibody, such as an antibody portion described herein. The attachment can be direct or indirect, such as via a linker (such as a peptide linker).

[0123] As used herein, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms attributable to the disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the progression of the disease), preventing or slowing the spread of the disease (e.g., metastasis), preventing or slowing the recurrence of the disease, slowing or slowing the progression of the disease, improving the disease state, providing remission (partial or total) of the disease, reducing the dose of one or more other medications required to treat the disease, slowing the progression of the disease, increasing or improving quality of life, increasing weight gain, and / or extending survival. Reduction in the pathological consequences of cancer (e.g., tumor volume, etc.) is also encompassed by "treatment." The methods of the present application contemplate any one or more of these aspects of treatment.

[0124] In the context of cancer, the term "treating" includes any or all of inhibiting cancer cell growth, inhibiting cancer cell replication, reducing overall tumor burden, and ameliorating one or more symptoms associated with the disease.

[0125] The term "inhibition" or "inhibiting" refers to the reduction or cessation of any phenotypic trait, or the reduction or cessation of the incidence, degree, or likelihood of that trait. "Reducing" or "inhibiting" refers to the decrease, reduction, or cessation of an activity, function, and / or amount compared to a reference. In certain embodiments, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 20% or more. In other embodiments, "reducing" or "inhibiting" refers to the ability to cause an overall reduction of 50% or more. In yet other embodiments, "reducing" or "inhibiting" refers to 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 comparison purposes. The reference can be obtained from a healthy and / or non-disease sample. In some examples, the reference can be obtained from an untreated sample. In some examples, the reference is obtained from a non-disease or non-treated sample of an individual. In some examples, the reference is obtained from one or more healthy individuals who are not individuals or patients.

[0127] As used herein, "delaying the onset of disease" means postponing, hindering, slowing, preventing, stabilizing, inhibiting, and / or postponing the onset of a disease (such as cancer). This delay can be of various lengths of time, 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 can, in effect, encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the development of metastases, can be delayed.

[0128] "Preventing" as used herein includes providing protection against the occurrence or recurrence of a disease in an individual who may have a predisposition to the disease, but who has not yet been diagnosed with the disease.

[0129] As used herein, "inhibiting" a function or activity refers to decreasing the function or activity when compared to conditions that are otherwise the same except for the condition or parameter of interest, or when compared to another condition. For example, an antibody that inhibits 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 a mammal, including, but not limited to, a human, bovine, equine, feline, canine, rodent, or primate. In some embodiments, the individual is a human.

[0131] An "effective amount" of a drug refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. The specific dose may vary depending on one or more of 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 to be imaged, and the physical delivery system in which it is carried.

[0132] A "therapeutically effective amount" of a substance / molecule, agonist, or antagonist of the present application can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule, agonist, or antagonist to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the substance / molecule, agonist, or antagonist are outweighed by the therapeutically beneficial effects. A therapeutically effective amount can be delivered in one or more administrations.

[0133] A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, although not necessarily, the prophylactically effective amount will be less than the therapeutically effective amount, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease.

[0134] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that allows the biological activity of the active ingredient(s) to be effective and that does not contain additional components that are unacceptably toxic to the individual to whom the formulation is administered. Such formulations may be sterile.

[0135] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation aid or carrier conventional in the art for use with therapeutic agents that together comprise a "pharmaceutical composition" for administration to an individual. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations used and is compatible with the other ingredients of the formulation. A pharmaceutically acceptable carrier is appropriate for the formulation being used.

[0136] A "sterile" preparation is aseptic or essentially free of living microorganisms and their spores.

[0137] Administration "in combination with" one or more further 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 where at least a portion of the administration overlaps in time or where the administration of one therapeutic agent falls within a short period of time relative to the administration of the other therapeutic agent. For example, the two or more therapeutic agents are administered within a time interval of about 60 minutes or less, e.g., about any of 30, 15, 10, 5, or 1 minute or less.

[0139] The term "sequentially" is used herein to refer to the administration of two or more therapeutic agents, where administration of one or more agents is continued after discontinuing administration of one or more other agents. For example, the administration of the two or more therapeutic agents is separated by a time interval of more than about 15 minutes, e.g., about 20, 30, 40, 50, or 60 minutes, 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month or more.

[0140] As used herein, "in combination with" refers to the administration of one treatment modality in addition to another treatment modality. Thus, "in combination with" refers to the administration of one treatment modality before, during, or after the administration of another treatment modality to an individual.

[0141] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information regarding the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings regarding the use of such therapeutic product.

[0142] An "article of manufacture" is any article of manufacture (e.g., package or container) or kit that includes at least one reagent, e.g., a pharmaceutical agent for treating a disease or disorder (e.g., cancer), or a probe for specifically detecting a biomarker described herein. In certain embodiments, the article of manufacture or kit is promoted, distributed, or sold as a unit for performing the methods described herein.

[0143] It is understood that embodiments of the present application described herein include "consisting of" and / or "consisting essentially of."

[0144] Reference herein to "about" a value or parameter includes (and accounts for) the variation that surrounds the value or parameter itself. For example, a statement of "about X" includes the statement "X."

[0145] As used herein, reference to a value or parameter "is not" generally means and describes a value or parameter "other than." For example, "the method is not used to treat cancer of type X" means that the method is used to treat cancers other than type X.

[0146] Here, "about X to Y" is synonymous with "about X to about Y."

[0147] As used in this specification and the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0148] II. Anti-CD93 Constructs The present application provides anti-CD93 constructs comprising an anti-CD93 antibody portion that specifically binds to CD93 as described herein.

[0149] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6.

[0150] In some embodiments, V Hcomprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 6, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 7, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 8, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 9, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 10, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 12, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

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

[0152] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 13. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region, and V having the sequence shown in SEQ ID NO: 14. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0153] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 13, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0154] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

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

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

[0157] In some embodiments, the antibody portion has a V sequence set forth in any of SEQ ID NOs: 29 and 307-312. H HC-CDR1, HC-CDR2 and HC-CDR3 containing the amino acid sequences of CDR1, CDR2 and CDR3, respectively, in the chain region, and V having the sequence shown in any of SEQ ID NOs: 30 and 313 to 318. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0158] In some embodiments, V H includes variants 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 to any one of the amino acid sequences of SEQ ID NOs: 29 and 307 to 312; L These include variants comprising an amino acid sequence of any one of SEQ ID NOs: 30 and 313 to 318, or an amino acid sequence having at least about 80% sequence identity (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%).

[0159] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 35,L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 36, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38.

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

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

[0162] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:45. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence shown in SEQ ID NO: 46 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0163] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 45, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0164] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 49, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 51, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54.

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

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

[0167] In some embodiments, the antibody portion has a V H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region, and V having the sequence shown in SEQ ID NO: 62 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0168] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 61, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0169] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 65, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 66, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 68, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 69, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 70.

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

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

[0172] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 77. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region, and V having the sequence shown in SEQ ID NO: 78 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0173] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 77, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0174] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (VH-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 84, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 85, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 86.

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

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

[0177] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO:93. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence set forth in SEQ ID NO: 94 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0178] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 93, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0179] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102.

[0180] In some embodiments, V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 103, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 105, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; Lcomprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 106, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 107, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

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

[0182] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 109. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence set forth in SEQ ID NO: 110. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0183] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 109, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity;L includes variants comprising the amino acid sequence of SEQ ID NO: 110, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0184] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118.

[0185] In some embodiments, V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. Hcomprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 119, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 120, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 122, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 124, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

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

[0187] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 125. H HC-CDR1, HC-CDR2 and HC-CDR3 containing the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region, and V having the sequence set forth in SEQ ID NO: 126 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0188] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 125, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0189] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 129, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 131, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 132, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 133, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 134.

[0190] In some embodiments, V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 129, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 131, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; Lcomprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 132, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 133, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 134, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 135, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 136, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 137, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 138, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 139, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 140, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

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

[0192] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 141. HHC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence set forth in SEQ ID NO: 142 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0193] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 141, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0194] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 145, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 148, 355, or 358, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 149 or 356, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 150, 357, or 359.

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

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

[0197] In some embodiments, the antibody portion has a V sequence set forth in any of SEQ ID NOs: 157 and 360-362. H HC-CDR1, HC-CDR2 and HC-CDR3 each containing the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, and V having the sequence shown in any of SEQ ID NOs: 158 and 363 to 365. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0198] In some embodiments, V H includes variants 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 to any one of the amino acid sequences of SEQ ID NOs: 157 and 360 to 362; L These include variants comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to any one of the amino acid sequences of SEQ ID NOs: 158, and 363 to 365.

[0199] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 157, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

[0201] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 360, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V L includes variants comprising the amino acid sequence of SEQ ID NO: 364, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

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

[0204] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 361, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 364, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

[0206] In some embodiments, V Hincludes the amino acid sequence of SEQ ID NO: 362, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 363, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0207] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 362, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 364, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0208] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 362, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 365, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0209] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 162, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 163, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 164, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 165, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 166.

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

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

[0212] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 173. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence set forth in SEQ ID NO: 174. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0213] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 173, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

[0215] In some embodiments, V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 180 or 353, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181 or 354, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 180, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182. Hcomprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 183, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 184, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 185, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 186, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 187, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 188, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

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

[0217] In some embodiments, the antibody portion has a V sequence set forth in any of SEQ ID NOS: 189 and 347-349. H HC-CDR1, HC-CDR2 and HC-CDR3 each containing the amino acid sequences of CDR1, CDR2 and CDR3 in the chain region, and V having the sequence shown in any of SEQ ID NOs: 190 and 350 to 352. LThe chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0218] In some embodiments, V H includes variants 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 to any one of the amino acid sequences of SEQ ID NOs: 189 and 347 to 349; L The amino acid sequences of SEQ ID NOs: 190 and 350 to 352 include variants having an amino acid sequence with at least about 80% sequence identity (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%).

[0219] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 189, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 190, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0220] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 347, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0221] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 347, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 351, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0222] In some embodiments, V H includes any of the amino acid sequences of SEQ ID NO: 347, or variants thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising an amino acid sequence of any of SEQ ID NO: 352, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0223] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 348, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0224] In some embodiments, V Hincludes the amino acid sequence of SEQ ID NO: 348, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 351, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0225] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 348, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 352, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0226] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 349, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 350, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0227] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 349, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity;L includes variants comprising the amino acid sequence of SEQ ID NO: 351, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0228] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 349, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 352, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0229] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 193, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 194, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 195, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 196, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 197, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 198.

[0230] In some embodiments, V Hcomprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 193, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 194, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 195, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 196, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 197, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 198, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 199, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 200, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 201, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 202, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 203, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 204, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

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

[0232] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 205. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence set forth in SEQ ID NO: 206 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0233] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 205, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0234] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 209, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 210, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 211, L-2comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 212, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 213, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 214.

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

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

[0237] In some embodiments, the antibody portion has the sequence set forth in SEQ ID NO: 221. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence set forth in SEQ ID NO: 222 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0238] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 221, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants 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 any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0239] In some embodiments, the anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of CD93, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 289, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 290, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 291, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 292, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 293, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 294.

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

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

[0242] In some embodiments, the antibody portion has a V sequence set forth in any of SEQ ID NOs: 287 and 319-321. H HC-CDR1, HC-CDR2 and HC-CDR3 each containing the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, and V having the sequence shown in any of SEQ ID NOs: 288 and 322 to 324. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0243] In some embodiments, V H includes variants 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 to any one of the amino acid sequences of SEQ ID NOs: 287 and 319 to 321; L These include variants comprising an amino acid sequence of any of SEQ ID NOs: 288 and 322 to 324, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0244] In some embodiments, the antibody portion comprises a V having a sequence set forth in any of SEQ ID NOs: 287, and 319-321. HHC-CDR1, HC-CDR2 and HC-CDR3 each containing the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, and V having the sequence shown in any of SEQ ID NOs: 288 and 322 to 324. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0245] In some embodiments, V H includes a variant 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 to any one of the amino acid sequences of SEQ ID NOs: 319 to 321; L includes variants comprising the amino acid sequence of any one of SEQ ID NOs: 322 to 324, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

[0247] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 319, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising the amino acid sequence of SEQ ID NO: 323, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

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

[0250] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 320, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 323, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

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

[0253] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 321, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 323, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0254] In some embodiments, V Hincludes the amino acid sequence of SEQ ID NO: 321, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 324, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

[0256] In some embodiments, V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17 or 304, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18 or 305, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; Lcomprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

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

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

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

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

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

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

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

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

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

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

[0267] In some embodiments, the antibody portion comprises a V having a sequence set forth in any of SEQ ID NOs: 29, and 307-312. H HC-CDR1, HC-CDR2 and HC-CDR3 containing the amino acid sequences of CDR1, CDR2 and CDR3, respectively, in the chain region, and V having the sequence shown in any of SEQ ID NOs: 30 and 313 to 318. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0268] In some embodiments, V H includes a variant comprising an amino acid sequence of any one of SEQ ID NOs: 307 to 312, 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; V L includes variants comprising the amino acid sequence of any one of SEQ ID NOs: 313 to 318, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0269] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 307, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 313, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0270] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 307, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 314, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0271] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 307, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 315, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0272] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 307, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0273] In some embodiments, V Hincludes the amino acid sequence of SEQ ID NO: 307, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 317, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0274] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 307, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 318, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0275] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 308, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 313, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0276] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 308, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity;L includes variants comprising the amino acid sequence of SEQ ID NO: 314, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0277] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 308, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 315, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0278] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 308, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0279] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 308, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising the amino acid sequence of SEQ ID NO: 317, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0280] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 308, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 318, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0281] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 309, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 313, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0282] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 309, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 314, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0283] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 309, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 315, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0284] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 309, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0285] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 309, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 317, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0286] In some embodiments, V Hincludes the amino acid sequence of SEQ ID NO: 309, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 318, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0287] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 310, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 313, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0288] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 310, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 314, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0289] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 310, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity;L includes variants comprising the amino acid sequence of SEQ ID NO: 315, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0290] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 310, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0291] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 310, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 317, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0292] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 310, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; Lincludes variants comprising the amino acid sequence of SEQ ID NO: 318, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0293] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 311, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 313, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0294] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 311, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 314, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0295] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 311, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 315, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0296] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 311, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0297] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 311, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 317, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0298] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 311, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 318, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0299] In some embodiments, V Hincludes the amino acid sequence of SEQ ID NO: 312, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 313, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

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

[0302] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 312, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity;L includes variants comprising the amino acid sequence of SEQ ID NO: 316, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

[0304] In some embodiments, V H includes the amino acid sequence of SEQ ID NO: 312, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 318, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0305] In some embodiments, the antibody moiety comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V Hcomprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, ii) an HC-CDR2 comprising the amino acid sequence RIFPGDGDX1X2YX3GKFKG (SEQ ID NO: 233) (wherein X1X2 is AN or TD, and / or X3 is N or D), and iii) an HC-CDR3 comprising the amino acid sequence of TGAAYX1FDPFPY (SEQ ID NO: 234) (wherein X1 is D or E); V L comprises i) an LC-CDR1 comprising the amino acid sequence SSX1KSLLHSX2GX3TYLY (SEQ ID NO: 235), where X1 is S or T, X2 is N or S, and / or X3 is V or I, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 37, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38.

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

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

[0308] In some embodiments, the antibody moiety comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including VH comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 1, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 3, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of KASQX1VX2TX3VX4 (SEQ ID NO: 245), where X1 is N or D, X2 is G or S, X3 is N or A, and / or X4 is A or V; ii) an LC-CDR2 comprising the amino acid sequence of SASYRX1X2 (SEQ ID NO: 246), where a) X1 is F or Y and X2 is I or T, or b) X1X2 is F1 or YT; and iii) an LC-CDR3 comprising the amino acid sequence QQX1X2X3X4PX5T (SEQ ID NO: 247), where X1X2X3X4 is YNRN or HYST, and / or X5 is I or F. In some embodiments, the LC-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6, 118, or 214. In some embodiments, the LC-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6.

[0309] In some embodiments, the antibody moiety comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; Lcomprises i) an LC-CDR1 comprising the amino acid sequence of KASQX1VX2TX3VX4 (SEQ ID NO: 245), where X1 is N or D, X2 is G or S, X3 is N or A, and / or X4 is A or V; ii) an LC-CDR2 comprising the amino acid sequence of SASYRX1X2 (SEQ ID NO: 246), where a) X1 is F or Y and X2 is I or T, or b) X1X2 is F1 or YT; and iii) an LC-CDR3 comprising the amino acid sequence QQX1X2X3X4PX5T (SEQ ID NO: 247), where X1X2X3X4 is YNRN or HYST, and / or X5 is I or F. In some embodiments, the LC-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6, 118, or 214. In some embodiments, the LC-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 118.

[0310] In some embodiments, the antibody moiety comprises a heavy chain variable region (V H ) and the light chain variable region (V L ), including V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 209, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 210, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 211, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; Lcomprises i) an LC-CDR1 comprising the amino acid sequence of KASQX1VX2TX3VX4 (SEQ ID NO: 245), where X1 is N or D, X2 is G or S, X3 is N or A, and / or X4 is A or V; ii) an LC-CDR2 comprising the amino acid sequence of SASYRX1X2 (SEQ ID NO: 246), where a) X1 is F or Y and X2 is I or T, or b) X1X2 is F1 or YT; and iii) an LC-CDR3 comprising the amino acid sequence QQX1X2X3X4PX5T (SEQ ID NO: 247), where X1X2X3X4 is YNRN or HYST, and / or X5 is I or F. In some embodiments, the LC-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 6, 118, or 214. In some embodiments, the LC-CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 214.

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

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

[0313] In some embodiments, the construct comprises an antibody portion, such as a full-length antibody, a diabody, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab' fragment, a F(ab'), an Fv fragment, a disulfide-stabilized Fv fragment (dsFv), a (dsFv), a V H H, Fv-Fc fusion, scFv-Fc fusion, scFv-Fv fusion, diabody, tribody, and tetrabody, or an antigen-binding fragment thereof.

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

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

[0316] In some embodiments, the anti-CD93 antibody portion 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 portion 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 has been altered to have increased serum half-life compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has been altered to have decreased serum half-life compared to the corresponding wild-type Fc fragment.

[0317] In some embodiments, the antibody portion comprises a humanized version of any of the antibody portions described herein.

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

[0319] In some embodiments, the anti-CD93 construct comprises 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 binding of CD93 to IGFBP7. In some embodiments, the IGFBP7 is human IGFBP7. In some embodiments, 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 dose of the anti-CD93 antibody and CD93 is in a ratio of about 1:10, 1:6, 1:3, 1:1.5, 1:1, 4:3, 2:1, or 5:1. In some embodiments, 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 an anti-CD93 antibody at a concentration of about 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 and MMRN2. In some embodiments, the MMRN2 is human MMRN2. In some embodiments, the MMRN2 is MMRN2 495-674In some embodiments, the anti-CD93 antibody is a fragment of the CD93 construct. In some embodiments, 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 the anti-CD93 antibody with CD93 or CD93-expressing cells. In some embodiments, the anti-CD93 construct does not block binding of CD93 to MMRN2.

[0323] In some embodiments, the anti-CD93 construct blocks CD93 binding 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, the CD93 is human CD93.

[0326] a) Antibody affinity The binding specificity of an antibody moiety can be determined experimentally by methods known in the art, including, but not limited to, Western blot, ELISA, RIA, ECL, IRMA, EIA, BLI, BIACORE™ test, flow cytometry, and peptide scanning.

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

[0328] In some embodiments, the K of binding between the antibody moiety and CD93 on 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 10 6 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 of binding between the antibody moiety and CD93 is on 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 of binding between the antibody moiety and CD93 is on is about 10 3 M -1 s -1 , 10 4 M -1 s -1 , 10 5 M -1 s -1 , 10 6 M-1 s -1 , 10 7 M -1 s -1 or 10 8 M -1 s -1 In some embodiments, the CD93 is human CD93.

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

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

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

[0332] In some embodiments, the anti-CD93 antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which the HVRs, e.g., CDRs (or portions thereof), are derived from a non-human antibody and the FRs (or portions thereof) are derived from human antibody sequences. Optionally, the humanized antibody also comprises at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve the specificity or affinity of the antibody.

[0333] Humanized antibodies and methods for their production are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing SDR (a-CDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing a "guided selection" approach to FR shuffling).

[0334] Human framework regions that can be used for humanization include, but are not limited to, 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 particular 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 mature (somatically mutated) 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 (see, e.g., Baca et al. al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

[0335] It is understood that humanization of mouse-derived antibodies is a common and routinely used 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 a humanized format of any of the referenced anti-CD93 antibodies or their antigen-binding regions 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 described in van Dijk and van 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 that have been engineered 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 that replaces the endogenous immunoglobulin locus, is present extrachromosomally, or is randomly integrated 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, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 (describing XENOMOUSE™ technology); U.S. Pat. No. 5,770,429 (describing HuMab®); U.S. Pat. No. 7,041,870 (describing KM MOUSE®), and U.S. Patent Application No. 2007 / 0061900 (describing VelociMouse®). The human variable regions from intact antibodies produced by such animals can be further modified, for example, by combining 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 are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Further methods include those described, for example, in U.S. Patent No. 7,189,826 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (which describes 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 generated by isolating Fv clone variable domain sequences selected from a human-derived phage display library. 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) Library-derived antibodies The anti-CD93 antibody portions described herein can be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, various methods are known in the art for generating phage display libraries and screening such libraries for antibodies with the desired binding characteristics. Such methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and further described, for example, in 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. 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 have been described, see, e.g., U.S. Patent No. 7,371,849.

[0341] In certain phage display methods, V H and V LGene repertoires can be separately cloned by polymerase chain reaction (PCR) and randomly recombined in phage libraries, which can then be screened for antigen-binding phages as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments as either scFv fragments or Fab fragments. Libraries from immunized sources provide high-affinity antibodies to immunogens without the need to construct hybridomas. Alternatively, naive repertoires can be cloned (e.g., from humans) without any immunization, providing a single source of antibodies against a wide range of non-self and self antigens, as described in Griffiths et al., EMBO J, 12:725-734 (1993). Finally, naive libraries can also be generated synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode highly variable CDR3 regions and achieve rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Pat. No. 5,750,373, and U.S. Patent Application Publication Nos. 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 herein.

[0343] e) Substitutions, insertions, deletions and variants In some embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include HVRs (or CDRs) and FRs. Conservative substitutions are shown in Table 2 under the heading of "preferred substitutions." More substantial changes are provided in Table 2 under the heading of "exemplary substitutions" and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into an antibody of interest, and the products can be screened for a desired activity, such as retained / improved antigen binding, reduced immunogenicity, or improved ADCC or CDC. [Table 2]

[0344] Amino acids can be grouped according to 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 that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

[0345] Non-conservative substitutions involve exchanging a member of one of these classes for another class.

[0346] One type of substitution variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have altered (e.g., improved) specific biological properties (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and / or will substantially retain specific biological properties of the parent antibody. An exemplary substitution variant is an affinity-matured antibody, which can be conveniently generated using, for example, phage-display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated, and the variant antibodies are displayed on phage and screened for a specific biological activity (e.g., binding affinity).

[0347] For example, alterations (e.g., substitutions) may be made in HVRs to improve antibody affinity. Such alterations may be made in residues encoded by HVR "hotspots," i.e., codons that undergo frequent mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or in SDRs (a-CDRs), to improve the affinity of the resulting variant V. H or V LThe antibodies are tested for binding affinity. Affinity maturation by constructing and reselecting a secondary library is described, for example, by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some affinity maturation embodiments, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. 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, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified using, for example, alanine- or histidine-scanning mutagenesis or modeling. In particular, the HC-CDR3 and LC-CDR3 are often targeted.

[0348] In some embodiments, substitutions, insertions, or deletions can occur within one or more HVRs, so long as such changes do not substantially reduce the antibody's ability to bind to antigen. For example, conservative changes (e.g., conservative substitutions provided herein) can be made in HVRs that do not substantially reduce binding affinity. Such changes can be outside of HVR "hotspots" or CDRs.

[0349] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," described in Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or groups of target residues (e.g., charged residues such as 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 interaction between the antibody and antigen is affected. Further substitutions can be introduced at amino acid positions that demonstrate functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of the antigen-antibody complex can be used to identify contact points between the antibody and antigen. Such contact and adjacent residues can be targeted or eliminated as candidates for substitution. Variants can be screened to determine whether they contain the desired antibody properties.

[0350] Amino acid sequence insertions include amino- and / or carboxyl-terminal 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 a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of antibody molecules include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0351] f) Glycosylation variants In some embodiments, the anti-CD93 antibody portion is altered to increase or decrease the extent to which the construct is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0352] If the antibody portion comprises an Fc region, the carbohydrate attached thereto can be altered. Native antibodies produced by mammalian cells typically contain the C of the Fc region. HThe antibody fragments typically contain biantennary oligosaccharides linked by an N-linkage to Asn297 in the 2 domain. See, e.g., Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharides may contain various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose linked to GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharides of the antibody moiety may be made to generate antibody variants with specific improved properties.

[0353] In some embodiments, the anti-CD93 antibody portion has a carbohydrate structure lacking fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such an antibody can be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan at Asn297 relative to the sum of all glycans attached to Asn297 (e.g., complex, hybrid, and high-mannose structures) as measured by MALDI-TOF mass spectrometry, e.g., as described in WO 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 variations in the antibody. Such fucosylated variants may have improved ADCC function. For example, US Patent Application Publication Nos. 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; 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, which are deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application No. US 2003 / 0157108 A1, Presta, L; and WO 2004 / 056312 A1, Adams et al., especially Example 11), and knockout cell lines, such as 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 WO 2003 / 085107).

[0354] In some embodiments, the anti-CD93 antibody portion has a bisected oligosaccharide, e.g., a biantennary oligosaccharide attached to the Fc region of the antibody is bisected 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 US 2005 / 0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide attached 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 variants In some embodiments, the anti-CD93 antibody portion comprises 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 containing at least a portion of the constant region. This term includes native and variant Fc regions. In some embodiments, a 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 be present or absent without affecting the structure or stability of the Fc region. Unless otherwise specified herein, the numbering of amino acid residues in an IgG or 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., at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, or 95% reduced effector function as measured by the level of antibody-dependent cellular cytotoxicity (ADCC)).

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

[0360] In some embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody portion, thereby generating an Fc region variant. The Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0361] In some embodiments, the Fc fragment retains some, but not all, effector functions, making it a desirable candidate for applications in which the in vivo half-life of the antibody portion is important, but certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / depletion of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and thus 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). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et 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, e.g., the ACTI™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (CellTechnology, Inc. Mountain View, CA); and the CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells.Alternatively, or in addition, the ADCC activity of a molecule of interest can be assessed in vivo, for example, in an animal model such as that disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody is unable to bind to C1q and therefore lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro 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)). Determination of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

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

[0363] Certain antibody variants with improved or diminished binding to FcRs have been described (see, e.g., U.S. Pat. No. 6,737,056; WO 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 comprises an L234A mutation and / or an L235A mutation. In some embodiments, the IgG1 Fc fragment comprises an L235A mutation and / or a 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 comprising an S228P, F234A, and / or L235A mutation.

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

[0366] In some embodiments, modifications are made to the Fc region that result in altered (i.e., either improved or decreased) C1q binding and / or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

[0367] In some embodiments, the antibody partial variant comprises a variant Fc region containing one or more amino acid substitutions that alter half-life and / or 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 maternal IgG transfer 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 comprise an Fc region with one or more substitutions that alter binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more Fc region residues (e.g., substitution at 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 ​​Engineered Antibody Modifications In some embodiments, it may be desirable to generate cysteine ​​engineered antibody moieties, e.g., "thioMAbs," in which one or more residues of an antibody are substituted with cysteine ​​residues. In certain embodiments, the substituted residues are located at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby placed at accessible sites of the antibody, which can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to generate immunoconjugates, as further described herein. In some embodiments, any one or more of the following residues can be substituted with cysteine: A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine ​​engineered antibody moieties can be generated, for example, as described in U.S. Pat. No. 7,521,541.

[0370] i) Antibody derivatives In some embodiments, the antibody moieties described herein may be further modified to include additional nonproteinaceous moieties known in the art and readily available. Moieties suitable for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include 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, propylene glycol homopolymer, propylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. Generally, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular property or function of the antibody to be improved, whether the antibody derivative will be used for diagnosis under defined conditions, etc.

[0371] In some embodiments, the antibody portion may be further modified to include one or more biologically active proteins, polypeptides, or fragments thereof. "Biological activity" or "biologically active," as used interchangeably herein, refers to exhibiting biological activity in the body to perform a specific function. For example, it may refer to combining with a specific biomolecule, such as a protein or DNA, and then promoting or inhibiting the activity of such a biomolecule. In some embodiments, biologically active proteins or fragments thereof include proteins and polypeptides administered to patients 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 patients to prevent disease (such as vaccines).

[0372] Multispecific anti-CD93 construct In some embodiments, the anti-CD93 construct comprises a multispecific (e.g., bispecific) anti-CD93 construct comprising an anti-CD93 antibody moiety according to any 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, a multispecific anti-CD93 molecule comprises an anti-CD93 antibody portion and a second portion (such as a second antibody portion) that specifically recognizes a second antigen.

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

[0375] In some embodiments, the second portion is the extracellular domain (ECD) of PD-1 or PD-L1. In some embodiments, the second portion is a PD-L1 trap or a PD-1 trap. See, e.g., 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 comprises the extracellular domain (ECD) of a VEGF receptor. In some embodiments, the second portion comprises the ECD of VEGFR1 and / or VEGFR2. In some embodiments, the second portion comprises a VEGF trap. See, e.g., Proc Natl Acad Sci USA. 2002 Aug 20;99(17):11393-8.

[0379] In some embodiments, the second antibody portion and the anti-CD93 antibody portion are fused to each other via a linker, such as any of the linkers described herein, in any operable form that allows for proper function of the binding moieties. 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 according to any one of the anti-CD93 antibody moieties described herein; and b) a second antibody moiety that specifically recognizes PD-L1 (an anti-PD-L1 antibody moiety).

[0381] In some embodiments, the anti-CD93 construct is a) an anti-CD93 full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (VL a) a full-length anti-CD93 antibody comprising: ...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 full-length anti-PD-L1 antibody moiety is fused to the N-terminus of both heavy chains; in some embodiments, the full-length anti-PD-L1 antibody moiety is fused to the C-terminus of both heavy chains.

[0382] In some embodiments, the anti-CD93 construct comprises: a) an anti-PD-L1 antibody portion comprising a full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L a) an anti-PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising:

[0383] In some embodiments, the anti-CD93 construct is a) an anti-CD93 full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L a) a full-length anti-CD93 antibody comprising: ...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 full-length anti-PD-L1 antibody moiety is fused to the N-terminus of both light chains; in some embodiments, the full-length anti-PD-L1 antibody moiety is fused to the C-terminus of both light chains.

[0384] In some embodiments, the anti-CD93 construct comprises: a) an anti-PD-L1 antibody portion comprising a full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L a) an anti-PD-L1 antibody portion comprising: a) an anti-PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising: a) a PD-L1 antibody portion comprising:

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

[0386] In some embodiments, the anti-CD93 construct is a) an anti-CD93 full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L a) a full-length anti-CD93 antibody comprising: a) a full-length anti-CD93 antibody comprising: a) 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; 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-1 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 comprises: a) an anti-PD-1 antibody portion comprising a full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V La) an anti-PD-1 antibody portion comprising: a) a nucleotide sequence encoding a nucleotide sequence encoding a nucleotide sequence of ...

[0388] In some embodiments, the anti-CD93 construct is a) an anti-CD93 full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L 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 anti-CD93 full-length 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 comprises: a) an anti-PD-1 antibody portion comprising a full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L and b) an anti-CD93 antibody portion (such as any of the antibody portions described herein) fused to at least one or both of the light chains of an anti-PD-1 full-length antibody. In some embodiments, the anti-CD93 antibody portion is fused to the N-terminus of both light chains. In some embodiments, the anti-CD93 antibody portion 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 according to any 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) an anti-CD93 full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L a) a full-length anti-CD93 antibody comprising: a) a second binding moiety that specifically recognizes VEGF fused to at least one or both of the heavy chains of the full-length anti-CD93 antibody; and b) a second binding moiety 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 moiety is fused to the N-terminus of both heavy chains. In some embodiments, the second binding moiety is fused to the C-terminus of both heavy chains.

[0392] In some embodiments, the anti-CD93 construct comprises: a) an anti-VEGF antibody portion comprising a full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L and b) an anti-CD93 antibody portion (such as any of the anti-CD93 antibody portions described herein) fused to at least one or both heavy chains of an anti-VEGF full-length antibody. In some embodiments, the anti-CD93 antibody portion is fused to the N-terminus of both heavy chains. In some embodiments, the anti-CD93 antibody portion is fused to the C-terminus of both heavy chains.

[0393] In some embodiments, the anti-CD93 construct is a) an anti-CD93 full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V La) a full-length anti-CD93 antibody comprising: a) a second binding moiety that specifically recognizes VEGF fused to at least one or both of the light chains of the full-length anti-CD93 antibody; and b) a second binding moiety that specifically recognizes VEGF fused to at least one or both of the light chains of the full-length anti-CD93 antibody. In some embodiments, the second binding moiety is fused to the N-terminus of both light chains. In some embodiments, the second binding moiety that specifically recognizes VEGF is fused to the C-terminus of both light chains.

[0394] In some embodiments, the anti-CD93 construct comprises: a) an anti-VEGF antibody portion comprising a full-length antibody comprising two heavy chains and two light chains, each of the two heavy chains comprising a heavy chain variable region (V H ), and each of the two light chains contains a light chain variable region (V L and b) an anti-CD93 antibody portion (such as any of the antibody portions described herein) fused to at least one or both of the light chains of an anti-VEGF full-length antibody. In some embodiments, the anti-CD93 antibody portion is fused to the N-terminus of both light chains. In some embodiments, the anti-CD93 antibody portion is fused to the C-terminus of both light chains.

[0395] In some embodiments, a full-length antibody that specifically recognizes CD93 comprises: a) two heavy chains and two light chains, wherein the two heavy chains each comprise a heavy chain variable region (V) comprising an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 289, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 290, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 291. H ), and each of the two light chains comprises a light chain variable region (V) comprising an LC-CDR1 having the amino acid sequence of SEQ ID NO: 292, an LC-CDR2 having the amino acid sequence of SEQ ID NO: 293, and an LC-CDR3 having the amino acid sequence of SEQ ID NO: 294. Land b) a full-length antibody comprising the amino acid sequence of SEQ ID NO: 325, wherein the VEGF binding site is fused to one or both heavy chains of the full-length antibody. In some embodiments, the VEGF binding moiety is fused to the C-terminus of both heavy chains of the full-length antibody. In some embodiments, the VEGF binding moiety 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, the anti-CD93 V H includes variants 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 to any one of SEQ ID NOs: 287, and 319 to 321; L In some embodiments, the heavy chain comprises a variant comprising the amino acid sequence of SEQ ID NO: 342, or an amino acid sequence having at least about 80% sequence identity (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) to any one of SEQ ID NOs: 288, and 322-324. 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 variant comprising the amino acid sequence of SEQ ID NO: 342, or an amino acid sequence having at least about 80% sequence identity (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) to any one of SEQ ID NOs: 342. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 343, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

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

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

[0398] In some embodiments, anti-CD93 V H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 289, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 290, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 291, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; Lcomprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 292, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 293, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 294, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR. H comprises i) an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 295, ii) an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 296, and iii) an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 297, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; L comprises i) an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 298, ii) an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 299, and iii) an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 300, or a variant thereof comprising 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 the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0400] Exemplary Anti-PD-L1 Antibody Moieties Exemplary anti-PD-L1 antibody portions include, but are not limited to, those described in WO2019228514A1, WO2019227490A1, and WO2020019232A1.

[0401] In some embodiments, the anti-PD-L1 antibody portion (such as an scFv) used in the multispecific anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of PD-L1, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said VH-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 251, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 252, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 253, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 254, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 255, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 256.

[0402] In some embodiments, the anti-PD-L1 moiety comprises a V having a sequence set forth in SEQ ID NO: 281, 282, or 283. H HC-CDR1, HC-CDR2 and HC-CDR3 containing the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region, and V having the sequence set forth in SEQ ID NO: 284, 285 or 286. L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0403] In some embodiments, the anti-PD-L1 antibody portion (such as an scFv) used in a multispecific anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) including a) V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 251, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 252, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 253, or a variant thereof comprising up to about 5, 4, 3, 2, or 1 total amino acid substitutions in the HC-CDRs; b) V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 254, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NO: 255, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NO: 256, or a variant thereof comprising a total of up to about 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0404] In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0405] In some embodiments, V H includes variants comprising an amino acid sequence of SEQ ID NO: 281, 282, or 283, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L In some embodiments, V includes a variant comprising an amino acid sequence of SEQ ID NO: 284, 285, or 286, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. H includes the amino acid sequence of SEQ ID NO: 281, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes a variant comprising an amino acid sequence of SEQ ID NO: 284, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. H includes the amino acid sequence of SEQ ID NO: 282, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes a variant comprising an amino acid sequence of SEQ ID NO: 285, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. Hincludes the amino acid sequence of SEQ ID NO: 283, or a variant thereof having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; L includes variants comprising the amino acid sequence of SEQ ID NO: 286, or an amino acid sequence having at least about 80% (e.g., at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0406] In some embodiments, the second antibody moiety and the anti-CD93 antibody moiety are fused to each other via a linker, such as any of the linkers described herein, in any operable form that allows for proper function of the binding moieties.

[0407] Exemplary Anti-PD-1 Antibody Moieties Exemplary anti-PD-1 antibody portions include, but are not limited to, those described in WO2018133842 and WO2018133837.

[0408] In some embodiments, the anti-PD-1 antibody portion (such as an scFv) used in the multispecific anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of PD-1, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 257, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 258, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 259, L-2 comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 260, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 261, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 262.

[0409] In some embodiments, the anti-PD-1 moiety has the sequence set forth in SEQ ID NO:275. H HC-CDR1, HC-CDR2 and HC-CDR3, which contain the amino acid sequences of CDR1, CDR2 and CDR3 within the chain region, respectively, and V having the sequence set forth in SEQ ID NO: 276 L The chain regions include LC-CDR1, LC-CDR2, and LC-CDR3, which contain the amino acid sequences of CDR1, CDR2, and CDR3, respectively.

[0410] In some embodiments, the anti-PD-1 antibody portion (such as an scFv) used in the multispecific anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) including a) V H comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 257, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 258, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 259, or a variant thereof comprising up to about 5, 4, 3, 2, or 1 total amino acid substitutions in the HC-CDRs; b) V L comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 260, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 261, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 262, or a variant thereof comprising a total of up to about 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs. In some embodiments, the above amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of the present application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of the present application.

[0411] In some embodiments, the second antibody portion comprises a heavy chain variable region (V) comprising the amino acid sequence set forth in SEQ ID NO: 275. H ) and a light chain variable region (V L ) and a humanized antibody portion derived from a murine antibody comprising

[0412] In some embodiments, the anti-PD-1 antibody portion (such as an scFv) used in the multispecific anti-CD93 construct comprises a heavy chain variable region (V H ) and the light chain variable region (V L ) for a binding epitope of PD-1, and the antibody portion comprises a second heavy chain variable region (V H-2 ) and a second light chain variable region (V L-2 ) and competes with an antibody or antibody fragment comprising said V H-2 comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 263, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 264, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: ...

Claims

1. Heavy chain variable region (V Ｈ ) and the light chain variable region (V Ｌ ) wherein the V Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 289, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 290, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 291; Ｌ an anti-CD93 construct comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:

294.

2. An anti-CD93 construct comprising an antibody portion that specifically binds to CD93, the antibody portion having a sequence set forth in any of SEQ ID NOs: 287 and 319-321. Ｈ HC-CDR1, HC-CDR2 and HC-CDR3 containing the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain region, and V having the sequences set forth in any of SEQ ID NOs: 288, and 322-324. Ｌ An anti-CD93 construct comprising LC-CDR1, LC-CDR2 and LC-CDR3, which comprise the amino acid sequences of CDR1, CDR2 and CDR3, respectively, within the chain regions.

3. 2. The anti-CD93 construct of claim 1, (a) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 287, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 288, or an amino acid sequence having at least about 90% sequence identity; (b) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 319, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 322, or an amino acid sequence having at least about 90% sequence identity; (c) Said V Ｈ comprises the amino acid sequence of SEQ ID NO: 319, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 323, or an amino acid sequence having at least about 90% sequence identity; (d) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 319, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 324, or an amino acid sequence having at least about 90% sequence identity; (e) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 320, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 322, or an amino acid sequence having at least about 90% sequence identity; (f) Said V Ｈ comprises the amino acid sequence of SEQ ID NO: 320, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 323, or an amino acid sequence having at least about 90% sequence identity; (g) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 320, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 324, or an amino acid sequence having at least about 90% sequence identity; (h) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 321, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ includes a variant comprising the amino acid sequence of SEQ ID NO: 322, or an amino acid sequence having at least about 90% sequence identity; (i) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 321, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ comprises the amino acid sequence of SEQ ID NO: 323, or a variant comprising an amino acid sequence having at least about 90% sequence identity; or (j) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 321, or a variant comprising an amino acid sequence having at least about 90% sequence identity; Ｌ An anti-CD93 construct comprising the amino acid sequence of SEQ ID NO: 324, or a variant comprising an amino acid sequence having at least about 90% sequence identity.

4. An anti-CD93 construct according to any one of claims 1 to 3, (a) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 287, Ｌ comprises the amino acid sequence of SEQ ID NO: 288; (b) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 319, Ｌ comprises the amino acid sequence of SEQ ID NO: 322; (c) Said V Ｈ comprises the amino acid sequence of SEQ ID NO: 319, Ｌ comprises the amino acid sequence of SEQ ID NO: 323; (d) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 319, Ｌ comprises the amino acid sequence of SEQ ID NO: 324; (e) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 320, Ｌ comprises the amino acid sequence of SEQ ID NO: 322; (f) Said V Ｈ comprises the amino acid sequence of SEQ ID NO: 320, Ｌ comprises the amino acid sequence of SEQ ID NO: 323; (g) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 320, Ｌ comprises the amino acid sequence of SEQ ID NO: 324; (h) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 321, Ｌ comprises the amino acid sequence of SEQ ID NO: 322; (i) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 321, Ｌ comprises the amino acid sequence of SEQ ID NO: 323; or (j) the V Ｈ comprises the amino acid sequence of SEQ ID NO: 321, Ｌ an anti-CD93 construct comprising the amino acid sequence of SEQ ID NO:

324.

5. The V Ｈ comprises the amino acid sequence of SEQ ID NO: 321, Ｌ The anti-CD93 construct of any one of claims 1 to 4, comprising the amino acid sequence of SEQ ID NO:

324.

6. The antibody portion may be a full-length antibody, a diabody, a single chain Fv (scFv) fragment, a Fab fragment, a Fab' fragment, a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv) ２ 6. The anti-CD93 construct of any one of claims 1 to 5, which is an antibody or antigen-binding fragment thereof selected from the group consisting of: an Fv-Fc fusion, an scFv-Fc fusion, an scFv-Fv fusion, a diabody, a tribody, and a tetrabody.

7. 7. The anti-CD93 construct of any one of claims 1 to 6, wherein the antibody portion has an Fc fragment selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof.

8. 8. The anti-CD93 construct of claim 7, wherein the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof.

9. 9. The anti-CD93 construct of claim 7 or claim 8, wherein the Fc fragment has a reduced effector function compared to the corresponding wild-type Fc fragment.

10. 9. The anti-CD93 construct of claim 7 or claim 8, wherein the Fc fragment has enhanced effector function compared to the corresponding wild-type Fc fragment.

11. The anti-CD93 construct of any one of claims 1 to 10, wherein the antibody portion blocks binding of CD93 to IGFBP7.

12. The anti-CD93 construct of any one of claims 1 to 11, wherein the antibody portion blocks binding of CD93 to MMRN2.

13. The anti-CD93 construct of any one of claims 1 to 6, wherein said CD93 is human CD93.

14. an anti-CD93 construct comprising a first portion that binds to CD93 and a second portion that binds to a second antigen, wherein the first portion is a heavy chain variable region (V Ｈ ) and the light chain variable region (V Ｌ ), and Ｈ comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291; Ｌ an anti-CD93 construct comprising an LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO:

294.

15. The anti-CD93 construct of claim 14, wherein the second antigen is PD-1, PD-L1, or VEGF.

16. 16. An anti-CD93 construct according to claim 14 or claim 15, a) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 287, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 288, or an amino acid sequence having at least about 90% sequence identity; b) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 319, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 322, or an amino acid sequence having at least about 90% sequence identity; c) Said V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 319, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 323, or an amino acid sequence having at least about 90% sequence identity; d) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 319, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 324, or an amino acid sequence having at least about 90% sequence identity; e) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 320, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 322, or an amino acid sequence having at least about 90% sequence identity; f) Said V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 320, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 323, or an amino acid sequence having at least about 90% sequence identity; g) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 320, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 324, or an amino acid sequence having at least about 90% sequence identity; h) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 321, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ includes a variant comprising the amino acid sequence set forth in SEQ ID NO: 322, or an amino acid sequence having at least about 90% sequence identity; i) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 321, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ comprises the amino acid sequence set forth in SEQ ID NO: 323, or a variant comprising an amino acid sequence having at least about 90% sequence identity; or j) the V Ｈ comprises the amino acid sequence set forth in SEQ ID NO: 321, or a variant comprising an amino acid sequence having at least about 90% sequence identity, Ｌ An anti-CD93 construct comprising the amino acid sequence set forth in SEQ ID NO: 324, or a variant comprising an amino acid sequence having at least about 90% sequence identity.

17. 17. The anti-CD93 construct of any one of claims 14 to 16, wherein the anti-CD93 antibody portion is a full-length anti-CD93 antibody comprising two heavy chains and two light chains, and the second portion is fused to the C-terminus of both heavy chains of the full-length anti-CD93 antibody.

18. 18. The anti-CD93 construct of claim 17, wherein the two heavy chains fused to the second portion each comprise the amino acid sequence set forth in SEQ ID NO: 342, or a variant thereof comprising an amino acid sequence with at least about 90% sequence identity, and the two light chains each comprise the amino acid sequence set forth in SEQ ID NO: 343, or a variant thereof comprising an amino acid sequence with at least about 90% sequence identity.

19. A pharmaceutical composition comprising an anti-CD93 construct according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier.

20. An isolated nucleic acid encoding the anti-CD93 construct of any one of claims 1 to 18.

21. A vector comprising the isolated nucleic acid of claim 20.

22. 22. An isolated host cell comprising the isolated nucleic acid of claim 20 or the vector of claim 21.

23. 19. An immunoconjugate comprising the anti-CD93 construct of any one of claims 1 to 18 linked to a therapeutic agent or a label.

24. 1. A method for producing an anti-CD93 construct, comprising: a) culturing the isolated host cell of claim 22 under conditions effective to express the anti-CD93 construct; b) obtaining said expressed anti-CD93 construct from said host cell.

25. A composition comprising an anti-CD93 construct according to any one of claims 1 to 18, or a pharmaceutical composition according to claim 19, for treating a disease or condition in an individual.

26. 26. The composition of claim 25, wherein the disease or condition is associated with abnormal vasculature.

27. 27. The composition of claim 25 or claim 26, wherein the disease or condition is cancer.

28. 28. The composition of claim 27, wherein the cancer is a solid tumor.

29. 29. The composition of claim 27 or claim 28, wherein the cancer comprises a) CD93+ endothelial cells, b) IGFBP7+ blood vessels, and / or c) MMRN2+ blood vessels.

30. 30. The composition of any one of claims 27 to 29, wherein the cancer is characterized by tumor hypoxia.

31. The composition of any one of claims 27 to 30, wherein the cancer is locally advanced or metastatic cancer.

32. 32. The composition of any one of claims 27 to 31, wherein 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, renal cancer, bladder cancer, gastric cancer, non-small cell lung cancer, melanoma, and pancreatic cancer.

33. The composition of any one of claims 25 to 32, wherein the anti-CD93 construct is administered to the individual parenterally.

34. The composition of any one of claims 25 to 33, which is administered in combination with a second treatment.

35. 35. The composition of claim 34, wherein the second treatment is selected from the group consisting of surgery, radiation, gene therapy, immunotherapy, bone marrow transplant, stem cell transplant, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and chemotherapy.

36. 36. The composition of claim 35, wherein the second treatment is an immunotherapy, and the immunotherapy comprises an immunomodulatory agent.

37. 37. The composition of claim 36, wherein the immunomodulatory agent is an immune checkpoint inhibitor, and the immune checkpoint inhibitor comprises an anti-PD-L1 antibody or an anti-PD-1 antibody.

38. The composition of any one of claims 25 to 37, wherein the individual is a human.

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