Granted Patent
B2
US 12,297,222 · App. 18/664,971 · Granted May 13, 2025
CD206 targeted drug delivery vehicles carrying novel bisphosphonate drug payloads via a degradable linker
Assignee:
Navidea Biopharmaceuticals, Inc.
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Abstract
Provided are novel compounds containing a polymeric carbohydrate backbone, one or more mannose-binding C-type lectin receptor targeting moieties, and a nitrogenous bisphosphonate compound coupled to the backbone via a thiol-maleimide conjugation, in addition to pharmaceutical compositions, methods of synthesizing, and methods of use. The thiol-maleimide conjugation of a bisphosphonate to a polymeric carbohydrate backbone provides for methods of using the compounds and compositions thereof for releasing the therapeutic payload when internalized into a mannose-binding C-type lectin receptor-expressing cell, such as tumor associated macrophages (TAMs) for the treatment of various diseases, including, cancer, autoimmune diseases, and inflammatory disorders.
Claims (21)
1. A bisphosphonate compound of Formula (II):
wherein
R 1 are each independently H, a positively-charged counter ion, a substituted or unsubstituted, linear or branched C 1 -C 6 alkyl group, or an acyloxyalkyl group;
X 1 is H or a C 1 alkyl group;
Y is NH or absent; and
W is an imidazole or a thiazole substituted with a C 1 alkyl group, wherein W is further substituted with a carbonyl group that is either a ketone group, or the carbonyl group is combined with an acylhydrazide to form a bisphosphonate compound modified with a hydrazone moiety.
2. The compound of claim 1 , wherein W is an imidazole, the carbonyl group is a ketone group, Y is absent, and X 1 is a C 1 alkyl group.
3. A bisphosphonate compound of Formula (III):
4. The compound of claim 1 , wherein the compound has the following formula (IV):
5. The compound of claim 1 , wherein the carbonyl group is combined with an acylhydrazide to form a bisphosphonate compound modified with a hydrazone moiety.
6. The compound of claim 5 , wherein the acylhydrazide has the following structure:
NH 2 —NH—C(O)—R 2 .
7. The compound of claim 5 , wherein the hydrazone moiety has the following structure:
8. The compound of claim 7 , wherein R 2 comprises —R 4 —SH, wherein R 4 is a substituted or unsubstituted, linear or branched C 1 -C 12 alkyl, alkenyl, alkynyl, or aromatic group.
9. The compound of claim 7 , wherein R 2 comprises —(CH 2 ) 2 SH.
10. The compound of claim 5 , wherein the compound has the following formula (V):
wherein R 2 comprises —R 4 —SH, wherein R 4 is a substituted or unsubstituted, linear or branched C 1 -C 12 alkyl, alkenyl, alkynyl, or aromatic group.
11. The compound of claim 10 , wherein R 2 comprises —(CH 2 ) 2 SH.
12. The compound of claim 5 , wherein the compound has the following formula (VI):
wherein R 2 comprises —R 4 —SH, wherein R 4 is a substituted or unsubstituted, linear or branched C 1 -C 12 alkyl, alkenyl, alkynyl, or aromatic group.
13. The compound of claim 12 , wherein R 2 comprises —(CH 2 ) 2 SH.
Assignments (4)
US BANKRUPTCY COURT SALE ORDER DATED JAN. 30, 2026 TO RELEASE SECURITY INTEREST RECORDED AT 069165 / 0332
Recorded Feb 12, 2026
From: SCOTT, JOHN KIM, JR.
To: NAVIDEA BIOPHARMACEUTICALS, INC.
Reel/Frame 074831/0644 →
CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY INFORMATION PREVIOUSLY RECORDED ON REEL 68711 FRAME 393. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY AGREEMENT.
Recorded Sep 27, 2024
From: NAVIDEA BIOPHARMACEUTICALS, INC.
To: SCOTT, JOHN KIM, JR.
Reel/Frame 069165/0332 →
SECURITY INTEREST
Recorded Sep 26, 2024
From: NAVIDEA BIOPHARMACEUTICALS, INC.
To: NAVIDEA BIOPHARMACEUTICALS, INC.
Reel/Frame 068711/0393 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 15, 2024
From: RALPH, DAVID A.; ARNOLD, JEFFREY SCOTT
To: NAVIDEA BIOPHARMACEUTICALS, INC.
Reel/Frame 067423/0223 →
Continuity (4)
Provisional Application
63352324
· Jun 15, 2022
Provisional Application
63344134
· May 20, 2022
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