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US 2026/0226192 A1Published application
Agents, methods and uses thereof
OwnerZahra JAWADinventor
Life of this patent
Estimating the term…
Abstract
The present invention relates to methods and conjugates to improve the penetrability of biological substances into the tumour microenvironment (TME) for therapeutic purposes, suitably the agent comprises at least: i. a therapeutic domain; ii. a cleavable domain; and iii. a stabilisation domain.
Claims31
1:
- An engineered agent comprising:
- i. a therapeutic domain;
- ii. a cleavable domain;
- and
- iii. a stabilisation domain
- wherein the cleavable domain is located in a hinge region and is positioned between the therapeutic domain and the stabilisation domain;
- wherein the stabilisation domain is a Fc region;
- wherein the cleavable domain comprises a tumour-specific protease cleavage site;
- and
- wherein the therapeutic domain is selected from any one or more of:
- i. an antigen-binding domain;
- ii. a Fab region;
- iii. a F(ab′)2 region;
- iv. a scFv region;
- v. a tandem scFv region;
- vi. a domain antibody;
- vii. a nanobody;
- viii. a diabody;
- ix. a monoclonal antibody;
- x. a polyclonal antibody;
- xi. triabody;
- xii. tetrabody;
- xiii. pentabody;
- xiv. hexabody;
- xv. an antibody drug conjugate;
- xvi. a bispecific peptide;
- and
- xvii. a multispecific peptide.
25 more elements
2:
- The agent according to claim 1 wherein the agent has a size which prevents it from penetrating the glomerular filtration barrier.
3:
- The agent according to claim 1 wherein the agent has:
- i. a size of at least 6 nanometres (nm);
- and/or
- ii. a molecular weight of at least 40 kilodaltons (kDa), at least 50 kDa, at least 70 kDa, at least 100 kDa.
1 more element
4:
- The agent according to claim 1, wherein the half-life of the agent in a biological system is:
- i. at least 10 hours;
- and/or
- ii. at least 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or at least 15 times longer than the half-life of the therapeutic domain when present in isolation from a) the cleavable domain and the stabilisation domain;
- or b) the stabilisation domain in said biological system.
2 more elements
5:
- The agent according to claim 1 wherein the therapeutic domain is a domain that, when present in isolation from the cleavable domain and the stabilisation domain, in a biological system, has a half-life of less than 10 hours, less than 9 hours, less than 8 hours, less than 7 hours, less than 6 hours, or less than 5 hours.
6:
- The agent according to claim 1 wherein the ability of:
- i. the agent to penetrate a solid tumour is decreased relative to the ability of the therapeutic domain when present in isolation from a) the cleavable domain and the stabilisation domain;
- or b) the stabilisation domain;
- and/or
- ii. the therapeutic domain when present in isolation from a) the cleavable domain and the stabilisation domain;
- or b) the stabilisation domain, to penetrate a solid tumour is increased relative to the ability of the agent, optionally wherein the increase is at least a 5-fold increase, at least a 10-fold increase, at least a 15-fold increase, at least a 20-fold increase.
3 more elements
7:
- The agent according to claim 1 wherein the tumour uptake level of the therapeutic domain when present in isolation from a) the cleavable domain and the stabilisation domain;
- or b) the stabilisation domain is at least 10% ID/g.
8:
- The agent according to claim 1 wherein the domain antibody is a single domain antibody (sdAb);
- and/or
- the bispecific peptide is a bispecific antibody;
- and/or
- the multispecific peptide is a multispecific antibody.
2 more elements
9:
- The agent according to claim 1, wherein the cleaved therapeutic domain has a molecular weight of no more than 50 kDa, no more than 40 kDa, no more than 30 kDa, no more than 25 kDa, no more than 20 kDa, no more than 20 kDa, no more than 15 kDa.
10:
- The agent according to claim 1, wherein the agent is:
- i. a monoclonal antibody;
- ii. a polyclonal antibody;
- iii. diabody;
- iv. triabody;
- v. tetrabody;
- vi. pentabody;
- vii. hexabody;
- viii. an antibody drug conjugate;
- ix. a bispecific peptide, such as a bispecific antibody;
- and/or
- x. a multispecific peptide, such as a multispecific antibody,
- preferably i. a monoclonal antibody.
10 more elements
11:
- The agent according to claim 1, wherein the therapeutic domain is a specific binding partner of an entity:
- i. expressed by a target cell or a target tissue;
- and/or
- ii. expressed by and/or associated with unwanted cells.
1 more element
12:
- The agent according to claim 1, wherein the therapeutic domain binds to an antigen selected from a list comprising Her2, VEGF, PD-1, PMSA, CEA, CTLA-4, EGFR or PDL1;
- and/or wherein the agent or the therapeutic domain is a Trastuzumab-derived fragment, a Bevacizumab-derived fragment, a Pembrolizumab-derived fragment, a Cetuximab-derived fragment, a M5A-derived fragment, or an Ipilimumab-derived fragment.
(canceled)
14:
- The agent according to claim 1, wherein the cleavable domain does not interfere with the binding of the therapeutic domain to its binding partner.
(canceled)
16:
- The agent according to claim 1, wherein the therapeutic domain binds its target with an IC50 of from 0.2 to 1.4 nM, such as from 0.22 to 0.36 nM and/or has a KD of from 3 to 4.5 nM.
(canceled)
(canceled)
19:
- The agent according to claim 1, wherein the Fc region is an IgG, IgE, IgM, IgD or IgA family Fc region or a bispecific Fc region.
20:
- The agent according to claim 1, wherein the tumour-specific protease site is cleavable by u plasminogen activator (upA), Napsin A, ADAM10, fibroblast activation protein (FAP), matriptase, legumain, MT-SP1, cysteine proteases, serine proteases, metalloproteases, or a combination thereof.
(canceled)
(canceled)
23:
- The agent according to claim 1 wherein the cleavable domain is located in the upper hinge or in the lower hinge, preferably wherein the cleavable domain is located in the upper hinge.
24:
- The agent according to claim 1, wherein where the agent is a protein or polypeptide, the stabilisation domain comprises a Fc region and a hinge region and the cleavable domain is located:
- i. N-terminal to the hinge region and after the therapeutic domain;
- or
- ii. C-terminal to the hinge region and before the CH2 domain of the Fc region.
1 more element
(canceled)
(canceled)
27:
- A method of treating or preventing cancer, wherein the method comprises administering one or more agents according to claim 1.
(canceled)
(canceled)
30:
- A method of improving the penetrability of a therapeutic domain into a tissue or tumour, wherein the method comprises engineering an agent comprising:
- i) a therapeutic domain;
- ii) a cleavable domain;
- and
- iii) a stabilisation domain;
- wherein the cleavable domain is located in a hinge region and is positioned between the therapeutic domain and the stabilisation domain;
- wherein the stabilisation domain is a Fc region;
- wherein the cleavable domain comprises a tumour-specific protease cleavage site;
- and
- wherein the therapeutic domain is selected from any one or more of:
- i. an antigen-binding domain;
- ii. a Fab region;
- iii. a F(ab′)2 region;
- iv. a scFv region;
- v. a tandem scFv region;
- vi. a domain antibody;
- vii. a nanobody;
- viii. a diabody;
- ix. a monoclonal antibody;
- x. a polyclonal antibody;
- xi. triabody;
- xii. tetrabody;
- xiii. pentabody;
- xiv. hexabody;
- xv. an antibody drug conjugate;
- xvi. a bispecific peptide;
- and
- xvii. a multispecific peptide.
25 more elements
(canceled)
Dependencies are inferred from the claim text.