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Anti-peripheral lymph node addressin antibodies and uses thereof

A lymph node and antibody technology, applied in the direction of antibodies, anti-tumor drugs, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve the problem of lack of selective adverse reactions of immunosuppressants

Pending Publication Date: 2021-12-14
THE BRIGHAM & WOMEN S HOSPITAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of immunosuppressants is hampered by a lack of selectivity and the high number of often observed adverse drug reactions

Method used

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  • Anti-peripheral lymph node addressin antibodies and uses thereof
  • Anti-peripheral lymph node addressin antibodies and uses thereof
  • Anti-peripheral lymph node addressin antibodies and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0302] Example 1: MHA112 monoclonal antibody (mAb) recognizes HEV in mice and humans

[0303] sialylated Lewis X (sLeX)-type glycan CD34 Chinese hamster ovary (CHO) cell line was immunized with two GlcNAc6ST1 / 2 / 4 triple knockout (KO) mice lacking peripheral lymph node angioaddressin (PNAd). The MHA112 single hybridoma clone was identified by HEV immunofluorescent staining. Supernatants from MHA112 hybridoma cultures were collected and used to stain mouse lymph node (LN) and human tonsil sections. Figure 1A Low magnification images showing hyperendothelial venule (HEV) structures of mouse LNs recognized by MHA112 hybridoma supernatants. High magnification images ( Figure 1B ) shows MHA112-stained mouse and human HEV structures.

Embodiment 2

[0304] Embodiment 2: MHA112 mAb typing

[0305] Then, a typing enzyme-linked immunosorbent assay (ELISA) was performed to identify the immunoglobulin (Ig) form of MHA112 mAb. Such as figure 2 As shown in A, MHA112 supernatants were positive in anti-IgM coated wells. These data suggest that the MHA112 isotype is mouse IgM.

Embodiment 3

[0306] Example 3: Transport of MHA112 mAb-conjugated NPs to LNs

[0307] MECA79 is a monoclonal ligand that recognizes all known L-selectin ligands on endothelial venules—PNAd, including CD34, GlyCAM-1, and a subset of MAdCAM-1 (Hemmerich, S., Butcher, E.C. & Rosen, S.D., J Exp Med 180, 2219-2226, 1994). MECA79 was produced by using collagenase-dispersed mesenteric and peripheral lymph node stromal elements as immunogens and selection based on selective staining of peripheral lymph node HEV (Streeter et al., J. Cell. Biol. 107:1853-1862, 1988) .

[0308] MHA112-conjugated, MECA79-conjugated and non-conjugated particles (loaded with IR800 dye) were injected intravenously into mice. Analysis 24 hours after injection showed hyperintensities in the LNs of the MHA112-NP and positive control MECA79-NP groups compared to mice injected with non-conjugated IR800-NP ( Figure 3A ). Sections of axillary LNs were then stained to evaluate the internal LN distribution of NPs 24 hours af...

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Abstract

The present disclosure provides, inter alia, anti-peripheral lymph node addressin antibodies and antigen binding fragments thereof. The present disclosure also provides compositions comprising drug-containing polymeric particles that mimic lymphocyte migration in vivo and can specifically deliver immunosuppressive or immunoregulatory drugs to lymphoid tissues and sites of chronic inflammation where T-cell activation and T-cell mediated injury are occurring; such compositions comprise the antibodies or antigen-binding fragments thereof described in the disclosure. The present disclosure also comprises antibody-drug conjugates and compositions comprising the antibody-drug conjugates. Methods of preparing and using these antibodies, antigen-binding fragments thereof, and compositions thereof are also provided.

Description

[0001] priority statement [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 804,797, filed February 13, 2019. The entirety of the foregoing is hereby incorporated by reference. technical field [0003] The present invention relates to anti-peripheral lymph node addressin (PNAd) antibodies, antigen-binding fragments thereof, conjugates thereof, and uses thereof. Background technique [0004] Peripheral lymph node addressin (PNAd) is a tissue-specific endothelial cell antigen constitutively expressed on high endothelial cell venules (HEVs) in both mice and humans. PNAd are a group of endothelial sialomucins—CD34, podocalixin, glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1), and 200 kDa sialylated glycoprotein (sgp200)—all of which include sulfate Lysialylation-Lewis X (sLeX)-like motif (von Andrian, U.H. & Mackay, C.R., N Engl J Med 343:1020-1034, 2000). PNAd is expressed on peripheral lymph nodes, tonsils, and ven...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K16/30
CPCA61P35/00A61K47/6929A61K47/6849C07K16/2854C07K16/30A61K2039/505C07K2317/76C07K2317/92C07K2317/73A61K47/65A61P3/10C07K2317/24
Inventor R·阿布迪
Owner THE BRIGHAM & WOMEN S HOSPITAL INC
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