Anti-PGDH antibodies

Abstract

Isolated antibodies which bind and inhibit 15-PGDH protein are described. Related nucleic acids, cells and therapeutic uses are also described.

Description

[0001] Anti-PGDH antibodies

[0002] This application claims priority from US 63 / 879208 filed 10 / 09 / 2025, GR 20250100471 filed 25 / 06 / 2025, and PCT / IB2024 / 000732 filed 20 / 12 / 2024, the contents and elements of each of which are herein incorporated by reference for all purposes.

[0003] Field of the Disclosure

[0004] The present disclosure relates to antibodies capable of binding and inhibiting 15-PGDH and particularly, although not exclusively, to novel therapeutic antibodies. Methods for using anti-PGDH antibodies in therapy, including for the treatment of Parkinson’s Disease and inflammatory conditions, muscle atrophy and / or dystrophy, or a disease or disorder associated with muscle atrophy and / or dystrophy, are also described.

[0005] Background

[0006] Parkinson’s Disease (PD) is a progressive neurodegenerative disease. It is an age-dependent disease characterised by a progressive loss of dopaminergic neurons in the substantia nigra, locus coeruleus, and other neuronal populations that leads to a broad spectrum of non-motor and motor symptoms. Non-motor symptoms include rapid eye movement sleep behaviour disorder (RBD), anosmia, constipation, depression, dementia, and psychosis. Motor symptoms include tremor, stiffness, impaired posture, slowness of movement, falls, freezing, and muscle cramps (Jankovic et al., 2020). RBD has emerged as one of the most specific predictors of the synuclein-mediated neurodegenerative diseases including Parkinson's disease. It is now estimated that up to 90% of patients with RBD will eventually develop one of the a-synucleinopathies, although the delay from RBD to diagnosis of PD is variable (Roguski et al., 2020). The neuropathological hallmark of PD is the abnormal accumulation and aggregation of alpha synuclein protein (a-Syn) in the form of Lewy bodies and Lewy neurites. Pathological aggregation of a-Syn is a common feature of PD and other diseases referred to as alpha-synucleinopathies, such as dementia with Lewy bodies (Lewy body disease), and multiple-system atrophy (MSA). Chronic neuroinflammation is an important driver in the pathogenesis of PD, and prostaglandins have been implicated in this process (Tansey et al., 2010; Corwin et al., 2018). Prostaglandins are generated from arachidonic acid (AA) that is liberated from membrane phospholipids catalysed by phospholipase A2. The AAs are subsequently oxygenated to form prostaglandin H2 (PGH2) by cyclooxygenase-1 and 2 (COX1 , 2). PGH2 is transformed into PGE2, PGF2a, PGD2, and PGI2 via terminal prostaglandin synthases (PGES, PGFS, PGDS and PGIS respectively for each prostaglandin) that differ in their cell type distribution (Smyth et al., 2009). Different prostaglandins have different context-dependent effects. For example, while PGD2 is neurotoxic and has been shown to promote neurodegeneration, PGE2 (also referred to as PGE2) signalling reduces inflammatory neurodegeneration (Corwin et al., 2018; Liu et al., 2019). Further, whether PGD2 or PGE2 is beneficial or not is dependent on disease state and spatial (tissue and cell-type) and temporal factors (acute vs. chronic).PGE2 acts through four downstream G-protein-coupled prostaglandin E receptors: EP1 ; EP2; EP3; and EP4. The effect of PGE2 signalling depends on the expression of each EP receptor and the strength of each EP signal. EP1 (couple to Gq) and EP3 (couple to Gi) mediate PGE2-induced intracellular calcium mobilization. The EP2 and EP4 receptors coupled to Gs activate adenylate cyclase (AC) and increase cAMP production, whereas the EP3 receptor inhibits cAMP signalling (Cheng et al., 2021). The PGE2 signalling pathway has been implicated in neuroinflammation, mitochondrial function, oxidative stress, apoptosis, tissue regeneration, and neuronal signalling (Funk et al., 2001 ; Ho et al., 2017; Montalban et al., 2022; Palla et al. ,2021). In addition, reduced PGE2 signalling contributes to muscle wasting in sarcopenia, an age-related skeletal muscle wasting disease. These findings therefore implicate PGE2 in peripheral ageing-associated diseases (Palla et al., 2021 ; Guo et al., 2022). EP4 signalling has been shown to have a neuroprotective effect in a model of Parkinson’s disease (Pradhan et al. 2016).

[0007] 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is an enzyme responsible for the biological inactivation of eicosanoids such as prostaglandins, in particular prostaglandin E2 (PGE2). 15-PGDH negatively regulates the PGE2 signalling pathway and degrades PGE2 by catalysing its NAD-i-dependent dehydrogenation into 15-keto-PGE2 which is unable to bind prostaglandin receptors (Tai et al., 2002). 15-PGDH is mostly an intracellular protein, however small concentrations have been found in the extracellular space as well. Notably, inhibition of 15-PGDH promotes mitochondrial function and autophagy through increased PGE2 signalling, and this increased muscle mass and strength in aged mice (Palla et al., 2021). Small molecule inhibitors of 15-PGDH have been described for the treatment of inflammatory conditions and peripheral ageing-associated diseases (Zhang et al., 2015; Antczak et al., 2017, Huang et al., 2023). WO 2023 / 009618 describes bicyclic PGDH inhibitors and methods of using these in a range of conditions.

[0008] Summary of the Disclosure

[0009] The present inventors have shown that the antibody repertoire of resilient individuals can be used to identify disease-specific antibody sequences. In the present work, the inventors sought to identify candidate protective antibodies from patients resilient to Parkinson’s disease (PD). A proteome-wide interaction study of serum derived from PD patients revealed strong reactivity against 15-PGDH in patients resilient to PD and PD patients without cognitive impairment. These findings indicate that 15-PGDH autoreactivity has a protective role in PD pathology. Mass spectrometry-based proteomics of serum antibodies and phage display of antibody repertoires subsequently identified five monoclonal antibodies derived from these patients that bind and inhibit 15-PGDH. 15-PGDH-binding antibodies for research purposes have previously been described (see, for example, Kahnt et al., 2022 and Tai et al., 1990). However, these research antibodies are non-human (rabbit and mouse). They are not suitable for use as therapeutic antibodies, have no demonstrated therapeutic or potentially therapeutic effect, nor is there any teaching in these documents in relation to adapting these antibodies for a therapeutic purpose.

[0010] Palla et al., 2021 reported that 15-PGDH is elevated in aged tissues, including skeletal muscle tissues. Similarly, muscle transcriptome time-course profiles of mice analysed in Boersch et al., 2021 showed that expression of 15-PGDH increases in aged mice (data accessible at sarcoatlas.scicore.unibas.ch / , genesymbol: Hpgd). 15-PGDH degrades Prostaglandin E2 (PGE2), and the resulting reduction in PGE2 signalling is a major contributor to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells within muscle (Palla et al., 2021). Palla et al. demonstrated that inhibition of 15-PGDH, by targeted genetic knockdown or a small molecule inhibitor, increases aged muscle mass, strength, and exercise performance in mice.

[0011] The present inventors have demonstrated that treatment of aged mice with a family of antibodies as described herein that specifically bind to and inhibit PGDH had a more profound effect in improving gait and stability than was achieved by the small molecule inhibitor of 15-PGDH (Figure 21). The inventors also observed that the elevation in 15-PGDH levels is not just seen in aged tissues, identifying that the levels of 15-PGDH are also upregulated in young mice with an immobilised limb (a limb immobilisation model of disuse atrophy described in Wu et al., 2023), suggesting that 15-PGDH is also a contributor to disuse atrophy, for example disuse atrophy caused by immobilisation. Furthermore, using the same limb immobilisation model of disuse atrophy the inventors demonstrated that treatment with antibodies of the disclosure significantly increased muscle strength and function following short term (e.g. 2 weeks) limb immobilisation, despite no observable increase in muscle mass in this model (Figure 30).

[0012] In a first aspect, the present disclosure provides an isolated antibody that specifically binds and inhibits 15-PGDH.

[0013] Antibodies according to the present aspect may have any one or more of the following optional features.

[0014] The antibody may comprise a heavy chain variable domain with the following CDRs:

[0015] CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL_7819; ATL 7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL 7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL 7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL_7921 ; ATL 7922; ATL_7923; ATL_7924); SEQ ID NO: 12 (ATL_6027); SEQ ID NO: 13 (ATL_6058; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 14 (ATL_6074); SEQ ID NO: 15 (ATL_6075); SEQ ID NO: 112 (ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL 7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932) or SEQ ID NO: 191 (ATL_7471); CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955); SEQ ID NO: 16 (ATL_6026; ATL_7925; ATL_7450; ATL_7819; ATL_7824; ATL 7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL 7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7919; ATL_7920; ATL_7923); SEQ ID NO: 17 (ATL_6027); SEQ ID NO: 18 (ATL_6058; ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 19 (ATL_6074); SEQ ID NO: 20 (ATL_6075); SEQ ID NO: 96 (ATL_7952; ATL_7917; ATL_7918; ATL_7921 ; ATL_7922; ATL_7924); SEQ ID NO: 97 (ATL_7953); SEQ ID NO: 154 (ATL_7820); SEQ ID NO: 155 (ATL_7821); SEQ ID NO: 156 (ATL_7822); or SEQ ID NO: 157 (ATL_7823), andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953; ATL_7829); SEQ ID NO: 21 (ATL_6026; ATL 7925; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL 7825; ATL_7826; ATL_7827; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895 ATL 7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7918; ATL_7919; ATL_7921 ; ATL_7924); SEQ ID NO: 22 (ATL_6027); SEQ ID NO: 23 (ATL_6058; ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 24 (ATL_6074); SEQ ID NO: 25 (ATL_6075); or SEQ ID NO: 162 (ATL_7917; ATL_7920; ATL_7922; ATL_7923);

[0016] or a set of CDRs containing one to six (for example one, two, or three) amino acid mutations, compared with the above set of CDRs. The mutations may be substitutions compared with the above set of CDRs.

[0017] In a second aspect, the disclosure provides an isolated antibody that specifically binds and inhibits 15-PGDH comprising a heavy chain variable domain with the following CDRs:

[0018] CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955; ATL_6026; ATL_7925 ATL_7952; ATL_7953);

[0019] CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955); SEQ ID NO: 16 (ATL_6026; ATL_7925); SEQ ID NO: 96 (ATL_7952); or SEQ ID NO: 97 (ATL_7953); and

[0020] CDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953); or SEQ ID NO: 21 (ATL_6026; ATL_7925);

[0021] or a set of CDRs containing one to six, or one to three amino acid mutations compared with the above set of CDRs. The mutations may be substitutions compared with the above set of CDRs. The mutation may be at position 62, for example N62A or N62Q; and / or at position 63, for example G63A; and / or at position 64, for example N64A; and / or at position 65, for example T65A or T65S; and / or at position 111C, for example D111 CE; and / or at position 112D, for example S112DA.

[0022] The heavy chain variable domain (VH) may have the following CDRs: CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925 ATL_7952; ATL_7953); CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and CDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953); or a set of CDRs containing one to six, or one to three amino acid mutations, compared with the above set of CDRs. The mutations may be substitutions compared with the above set of CDRs. The substitution may be at position 62, for example N62A or N62Q; and / or at position 64, for example N64A; and / or at position 111 C, for example D111 CE. The isolated antibody may comprise a heavy chain variable domain with the following CDRs: CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925 ATL_7952; ATL_7953); CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and CDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944;ATL_8945; ATL_8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953); and a light chain variable domain (VL), with the following CDRs: CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL 8945; ATL_8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL 7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL 7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL 7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL_7921 ; ATL_7922; ATL_7923; ATL_7924); SEQ ID NO: 27 (ATL_6027); CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955; ATL_7925; ATL_7952; ATL_7953; ATL_7900; ATL_7919; ATL_7923); and CDRL3 comprising an amino acid sequence of SEQ ID NO: 207 (ATL_8946).

[0023] The heavy chain variable domain (VH) may have the following framework sequences: HFWR1 of SEQ ID NO: 41 (ATL_6026) or SEQ ID NO: 95 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL 7952; ATL_7953; ATL_7955); HFWR2 of SEQ ID NO: 42 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7955); HFWR3 of SEQ ID NO: 43 (ATL_6026); SEQ ID NO: 99 (ATL_7925; ATL_7953); SEQ ID NO: 100 (ATL_7952); or SEQ ID NO: 101 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and HFWR4 of SEQ ID NO: 44 (ATL_6026); or SEQ ID NO: 103 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955); or framework sequences with one to nine or one to six mutations (e.g. one, two, three, four, five or six mutations) compared with the framework sequences above. The mutations may be substitutions compared with the above set of framework sequences. The mutation may be at position 5, for example Q5V; and / or at position 53, for example M53A; and / or at position 78, for example M78I or M78A; and / or at position 81 , for example D81 E; and / or at position 89, for example M89A; and / or at position 97, for example D97E; and / or at position 98, for example D98E; and / or at position 99, for example T99A; and / or at position 123, for example M123T.

[0024] The antibody may bind to an epitope in 15-PGDH comprising one or more of, or all of, the following residues: Leu 39, Glu40, Val43, Gln44, Lys46, Ala47, Leu59, Phe60, Ile61 , Gln62, Cys63, Gln70, Asp73, Thr74, Arg76, Lys77, Asp80, H is81 of 15-PDGH, provided as SEQ ID NO: 82. Antibody ATL_6026 of the disclosure has been shown by X-ray crystallography to bind 15-PGDH at those residues. Therefore any antibody according to the disclosure including at least any antibody with the VH sequence of ATL_6026 and / or the VH CDRs of ATL_6026, and any antibody sequence derived therefrom (e.g. any antibody with the VH and / or the VH CDRs or any of ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL 7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL 7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7925; ATL_7952; ATL_7953; ATL_7955; ATL_8944; ATL_8945; ATL_8946; ATL_8947) may bind to an epitope as defined above.

[0025] The antibody may have a heavy chain variable domain with the following CDRs: CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and CDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955).The antibody may have a heavy chain variable domain with the following framework sequences: HFWR1 of SEQ ID NO: 95 (ATL_8944; ATL_8945; ATL_8946;ATL_8947; ATL_7955); HFWR2 of SEQ ID NO: 42 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); HFWR3 of SEQ ID NO: 101 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and HFWR4 of SEQ ID NO: 103 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955).

[0026] In a third aspect, the disclosure provides an isolated antibody that specifically binds and inhibits 15-PGDH wherein the antibody binds to an epitope in 15-PGDH comprising one or more of, or all of, the following residues: Leu 39, Glu40, Val43, Gln44, Lys46, Ala47, Leu59, Phe60, Ile61 , Gln62, Cys63, Gln70, Asp73, Thr74, Arg76, Lys77, Asp80, His81 of 15-PDGH, provided as SEQ ID NO: 82.

[0027] In a fourth aspect, the disclosure provides an isolated antibody that specifically binds and inhibits 15-PGDH comprising a heavy chain variable domain with the following CDRs:

[0028] CDRH1 comprising an amino acid sequence of SEQ ID NO: 13 (ATL_6058); or SEQ ID NO: 112 (ATL_7933; ATL_7956);

[0029] CDRH2 comprising an amino acid sequence of SEQ ID NO: 18 (ATL_6058; ATL_7933; ATL_7956); and

[0030] CDRH3 comprising an amino acid sequence of SEQ ID NO: 23 (ATL_6058; ATL_7933; ATL_7956);

[0031] or a set of CDRs containing one, two, or three amino acid mutations compared with the above set of CDRs. The mutations may be substitutions. The substitution may be at position 28, for example D28E and / or at position 29, for example S29A. The heavy chain variable domain (VH) may comprise the following framework sequences: HFWR1 of SEQ ID NO: 57 (ATL_6058; ATL_7933; ATL_7956); HFWR2 of SEQ ID NO: 58 (ATL_6058) or SEQ ID NO: 113 (ATL_7933; ATL_7956); HFWR3 of SEQ ID NO: 59 (ATL_6058) or SEQ ID NO: 114 (ATL_7933; ATL_7956); and HFWR4 of SEQ ID NO: 60 (ATL_6058; ATL_7933) or SEQ ID NO: 115 (ATL_7956); or framework sequences with one to eight, for example one to six (e.g. one, two, three, four, five, or six) mutations, compared with the framework sequences above. The mutations may be substitutions compared with the framework sequences above. The mutation may be at position 40, for example A40S; and / or at position 49, for example R49G; and / or at position 66, for example S66N; and / or at position 78, for example M78I; and / or at position 81 , for example D81 E; and / or at position 85, for example K85N; and / or at position 92, for example T92S; and / or at position 122, for example M122T. The antibody may bind to an epitope that comprises one or more (or all of) residues Asp221 ; Leu224; Asn227; Thr231 ; Asp235; Ala237; Leu238; Thr246; Thr247; Ser248; Lys249; Gly250; Ile251 ; His252; Phe253; Asp255 of 15 PGDH, provided as SEQ ID NO: 82. The antibody may have a heavy chain variable domain with the following CDRs: CDRH1 comprising an amino acid sequence of SEQ ID NO: 112 (ATL_7933); CDRH2 comprising an amino acid sequence of SEQ ID NO: 18 (ATL_7933); and CDRH3 comprising an amino acid sequence of SEQ ID NO: 23 (ATL_7933).

[0032] The antibody may have a heavy chain variable domain (VH) with the following framework sequences: HFWR1 of SEQ ID NO: 57 (ATL_7933); HFWR2 of SEQ ID NO: 113 (ATL_7933); HFWR3 of SEQ ID NO: 114 (ATL_7933); and HFWR4 of SEQ ID NO: 60 (ATL_7933).

[0033] Embodiments of any of the above aspects may have any one or more of the following optional features.The antibody may comprise a heavy chain variable domain (VH) with the following framework sequences: HFWR1 of SEQ ID NO: 41 (ATL_6026); SEQ ID NO: 49 (ATL_6027); SEQ ID NO: 57 (ATL_6058; ATL 7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL 7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 65 (ATL_6074); SEQ ID NO: 73 (ATL_6075); or SEQ ID NO: 95 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL 7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL 7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL 7918; ATL_7919; ATL_7920; ATL_7921 ; ATL_7922; ATL_7923; ATL_7924);

[0034] HFWR2 of SEQ ID NO: 42 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_6026; ATL_7925; ATL 7952; ATL_7953; ATL_7955; ATL_7450; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL 7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL 7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL 7921 ; ATL_7922; ATL_7923; ATL_7924); SEQ ID NO: 50 (ATL_6027); SEQ ID NO: 58 (ATL_6058; ATL_7469; ATL_7927); SEQ ID NO: 66 (ATL_6074); SEQ ID NO: 74 (ATL_6075); SEQ ID NO: 113 (ATL_7933; ATL_7956; ATL_7467; ATL_7468; ATL_7470; ATL_7471 ; ATL_7472; ATL_7473; ATL_7926; ATL 7930; ATL_7931 ; ATL_7932); or SEQ ID NO: 153 (ATL_7819); SEQ ID NO: 192 (ATL_7928); or SEQ ID NO: 193 (ATL_7929);

[0035] HFWR3 of SEQ ID NO: 43 (ATL_6026; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL 7823; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL 7900; ATL_7901 ; ATL_7902; ATL_7922); SEQ ID NO: 51 (ATL_6027); SEQ ID NO: 59 (ATL_6058; ATL_7469); SEQ ID NO: 67 (ATL_6074; ATL_7472); SEQ ID NO: 75 (ATL_6075); SEQ ID NO: 99 (ATL_7925; ATL_7953; ATL_7919); SEQ ID NO: 100 (ATL_7952; ATL_7917; ATL_7920; ATL_7921); SEQ ID NO: 101 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); SEQ ID NO: 114 (ATL_7933; ATL 7956; ATL_7926; ATL_7928; ATL_7929); SEQ ID NO: 158 (ATL_7824); SEQ ID NO: 159 (ATL_7825; ATL 7918; ATL_7923; ATL_7924); SEQ ID NO: 160 (ATL_7826); SEQ ID NO: 161 (ATL_7827); SEQ ID NO: 194 (ATL_7931); SEQ ID NO: 195 (ATL_7932); SEQ ID NO: 196 (ATL_7467; ATL_7468; ATL_7470; ATL_7471); SEQ ID NO: 197 (ATL_7473); SEQ ID NO: 198 (ATL_7927); or SEQ ID NO: 199 (ATL_7930); and

[0036] HFWR4 of SEQ ID NO: 44 (ATL_6026); SEQ ID NO:52 (ATL_6027); SEQ ID NO: 60 (ATL_6058; ATL 7933; ATL_7469; ATL_7927); SEQ ID NO: 68 (ATL_6064); SEQ ID NO: 76 (ATL_6075); SEQ ID NO: 103 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955; ATL 7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL 7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL 7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL_7921 ; ATL_7922; ATL 7923; ATL_7924); or SEQ ID NO: 115 (ATL_7956; ATL_7467; ATL_7468; ATL_7470; ATL_7471 ; ATL_7472; ATL_7473; ATL_7926; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932)

[0037] or framework sequences with one to nine or one to five mutations (e.g. one, two, or three mutations), compared with the framework sequences above. The mutations may be substitutions compared with the framework sequences above. The mutations may be at position 5, for example Q5V; and / or at position 53, for example M53A; and / or at position 78, for example M78I or M78A; and / or at position 81 ; for example D81 E; and / or at position 89, for example M89A; and / or at position 97, for example D97E; and / or at position98, for example D98E; and / or at position 98, for example D98E; and / or at position 99, for example T99A, and / or at position 123, for example M123T. Compared with the framework sequences for ATL_6026, the mutations may be at position 78, for example M78I or M78A; and / or at position 81 ; for example D81 E; and / or at position 97, for example D97E; and / or at position 98, for example D98E; and / or at position 98, for example D98E; and / or at position 99, for example T99A. Compared with the framework sequences for ATL_6058, the mutations may be at position 78, for example M78I; and / or at position 81 ; for example D81 E.

[0038] The antibody may have a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the with the amino acid sequence selected from the group consisting of: SEQ ID NO: 1 ; SEQ ID NO: 2; SEQ ID NO: 3; SEQ ID NO: 4; SEQ ID NO: 5; SEQ ID NO: 90; SEQ ID NO: 91 ; SEQ ID NO: 92; SEQ ID NO: 93; SEQ ID NO: 109; SEQ ID NO: 110; SEQ ID NO: 118; SEQ ID NO: 119; SEQ ID NO: 120; SEQ ID NO: 121 ; SEQ ID NO: 122; SEQ ID NO: 123; SEQ ID NO: 124; SEQ ID NO: 125; SEQ ID NO: 126; SEQ ID NO: 127; SEQ ID NO: 128; SEQ ID NO: 129; SEQ ID NO: 130; SEQ ID NO: 131 ; SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 178; SEQ ID NO: 179; SEQ ID NO: 180; SEQ ID NO: 181 ; SEQ ID NO: 182; SEQ ID NO: 183; SEQ ID NO: 184; SEQ ID NO: 185; SEQ ID NO: 186; SEQ ID NO: 187; and SEQ ID NO: 188. For example the antibody may have a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the with the amino acid sequence selected from the group consisting of: SEQ ID NO: 1 ; SEQ ID NO: 3; SEQ ID NO: 90; SEQ ID NO: 91 ; SEQ ID NO: 92; SEQ ID NO: 93; SEQ ID NO: 109; SEQ ID NO: 110. For example the antibody may have a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the with the amino acid sequence selected from the group consisting of: SEQ ID NO: 93 and SEQ ID NO: 109. For example the antibody may have a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the amino acid sequence of SEQ ID NO: 93

[0039] The antibody may have a heavy chain variable domain (VH) comprising CDRH1 , CDRH2, and CDRH3 within a human framework, and / or within a germline framework.

[0040] The antibody may comprise a light chain variable domain (VL), with the following CDRs:

[0041] CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL_7819; ATL_7820; ATL 7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL 7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL_7921 ; ATL_7922; ATL_7923; ATL_7924); SEQ ID NO: 27 (ATL_6027); SEQ ID NO: 28 (ATL_6058; ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL 7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 29 (ATL_6074); or SEQ ID NO: 30 (ATL_6075);

[0042] CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955; ATL_7925; ATL_7952; ATL_7953; ATL_7900; ATL_7919; ATL_7923); SEQ ID NO:31 (ATL_6026; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL 7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL 7896; ATL_7901 ; ATL_7902; ATL_7920); SEQ ID NO: 32 (ATL_6027); SEQ ID NO: 33 (ATL_6058; ATL 7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL 7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 34 (ATL_6074); SEQ ID NO: 35 (ATL_6075); SEQ ID NO: 166 (ATL_7917; ATL_7918); or SEQ ID NO: 167 (ATL_7899; ATL_7921 ; ATL_7922; ATL_7924); and

[0043] CDRL3 comprising an amino acid sequence of SEQ ID NO: 206 (ATL_8944); SEQ ID NO: 207 (ATL_8946); SEQ ID NO: 107 (ATL_7955; ATL_7925; ATL_7952; ATL_7953; ATL_7902; ATL_7917; ATL_7922; ATL 7923; ATL_7924); SEQ ID NO: 36 (ATL_8947; ATL_6026; ATL_7450; ATL_7819; ATL_7820; ATL 7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL 7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7918); SEQ ID NO: 37 (ATL_6027); SEQ ID NO: 38 (ATL_6058; ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL 7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 39 (ATL_6074); SEQ ID NO: 40 (ATL_6075); SEQ ID NO: 168 (ATL_8945; ATL_7901 ; ATL_7919; ATL_7921); or SEQ ID NO: 169 (ATL_7920);

[0044] or a set of CDRs containing one to four (e.g. one, two, three or four) amino acid mutations, such as substitutions, compared with the above set of CDRs. The mutation may be at position 57, for example N57A or N57Q; and / or at position 65, for example S65N or S65A; and / or at position 109, for example N109A or N109Q; and / or at position 113, for example S113N or S113A. Alternatively, the mutations in the light chain CDRs may not include a mutation at position 109 or position 113 in standard IMGT numbering, For example the mutations may not include a mutation in CDRL3.

[0045] The antibody may comprise a light chain variable domain (VL) with the following CDRs: CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and CDRL3 comprising an amino acid sequence of SEQ ID NO: 206 (ATL_8944); SEQ ID NO: 207 (ATL_8946); SEQ ID NO: 168 (ATL_8945; ATL_7901 ; ATL_7919; ATL_7921); SEQ ID NO: 36 (ATL_8947; ATL_6026); or SEQ ID NO: 107 (ATL_7955). The light chain variable domain (VL) may comprise the following framework sequences: LFWR1 of SEQ ID NO: 104 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); LFWR2 of SEQ ID NO: 46 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955); LFWR3 of SEQ ID NO: 106 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and LFWR4 of SEQ ID NO: 108 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955).

[0046] The antibody may comprise a light chain variable domain (VL) with the following CDRs: CDRL1 comprising an amino acid sequence of SEQ ID NO: 28 (ATL_6058; ATL_7933; ATL_7956); CDRL2 comprising an amino acid sequence of SEQ ID NO: 33 (ATL_6058; ATL_7933; ATL_7956); and CDRL3 comprising an amino acid sequence of SEQ ID NO: 38 (ATL_6058; ATL_7933; ATL_7956); or a set of CDRs containing one, two, or three amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs. The light chain variable domain (VL) may comprise the following framework sequences: LFWR1 of SEQ ID NO: 61 (ATL_6058; ATL_7933; ATL_7956); LFWR2 of SEQ ID NO: 62 (ATL_6058) or SEQ ID NO: 116 (ATL_7933; ATL_7956); LFWR3 of SEQ ID NO: 63 (ATL_6058) or SEQID NO: 117 (ATL_7933; ATL_7956); and LFWR4 of SEQ ID NO: 64 (ATL_6058; ATL_7933; ATL_7956); or framework sequences with one to four mutations compared with the framework sequences above. The mutations may be substitutions, optionally wherein the substitution is at position 49, optionally wherein the substitution is P49A; and / or at position 52, optionally wherein the substitution is R52L; and / or at position 74, optionally wherein the substitution is G74D; and / or at position 90, optionally wherein the substitution is S90T.

[0047] The antibody may comprise a light chain variable domain (VL) with the following CDRs: CDRL1 comprising an amino acid sequence of SEQ ID NO: 28 (ATL_7933); CDRL2 comprising an amino acid sequence of SEQ ID NO: 33 (ATL_7933); and CDRL3 comprising an amino acid sequence of SEQ ID NO: 38 (ATL_7933); and wherein the light chain variable domain (VL) comprises the following framework sequences: LFWR1 of SEQ ID NO: 61 (ATL_7933); LFWR2 of SEQ ID NO: 116 (ATL_7933) ; LFWR3 of SEQ ID NO: 117 ( ATL_7933) ; and LFWR4 of SEQ ID NO: 64 (ATL_7933).

[0048] The antibody may comprise a light chain variable domain (VL) with the following framework sequences: LFWR1 of SEQ ID NO: 45 (ATL_6026; ATL_0007450; ATL_0007819; ATL_0007820; ATL_0007821 ; ATL 0007822; ATL_0007823; ATL_0007824; ATL_0007825; ATL_0007826; ATL_0007827; ATL 0007829; ATL_0007892; ATL_0007893; ATL_0007899; ATL_0007900; ATL_0007901 ; ATL 0007902; ATL_0007917); SEQ ID NO: 53 (ATL_6027); SEQ ID NO: 61 (ATL_6058; ATL_7933; ATL 7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 69 (ATL_6074); SEQ ID NO: 77 (ATL_6075); SEQ ID NO: 104 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL 7952; ATL_7953; ATL_7955; ATL_0007896; ATL_0007920; ATL_0007921 ; ATL_0007922) ; SEQ ID NO: 163 (ATL 0007889; ATL_0007895; ATL_0007919; ATL_0007924) ; or SEQ ID NO: 164 (ATL 0007890; ATL_0007918; ATL_0007923);

[0049] LFWR2 of SEQ ID NO: 46 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_6026; ATL_7925; ATL 7952; ATL_7953; ATL_7955; ATL_0007450; ATL_0007819; ATL_0007820; ATL_0007821 ; ATL 0007822; ATL_0007823; ATL_0007824; ATL_0007825; ATL_0007826; ATL_0007827; ATL 0007829; ATL_0007889; ATL_0007890; ATL_0007892; ATL_0007893; ATL_0007896; ATL 0007899; ATL_0007900; ATL_0007901 ; ATL_0007902; ATL_0007920); SEQ ID NO: 54 (ATL_6027); SEQ ID NO: 62 (ATL_6058; ATL_7468); SEQ ID NO: 70 (ATL_6074); SEQ ID NO: 78 (ATL_6075); SEQ ID NO: 116 (ATL_7933; ATL_7956; ATL_7467; ATL_7469; ATL_7470; ATL_7471 ; ATL_7472; ATL_7473; ATL 7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932); SEQ ID NO: 165 (ATL_0007895; ATL 0007917; ATL_0007918; ATL_0007919; ATL_0007921 ; ATL_0007922; ATL_0007923; ATL 0007924); SEQ ID NO: 200 (ATL_7927); or SEQ ID NO: 201 (ATL_7926);

[0050] LFWR3 of SEQ ID NO: 47 (ATL_6026; ATL_0007450; ATL_0007819; ATL_0007820; ATL_0007821 ; ATL 0007822; ATL_0007823; ATL_0007824; ATL_0007825; ATL_0007826; ATL_0007827; ATL 0007829; ATL_0007889; ATL_0007890; ATL_0007893; ATL_0007899; ATL_0007900; ATL 0007901 ; ATL_0007902; ATL_0007921); SEQ ID NO: 55 (ATL_6027); SEQ ID NO: 63 (ATL_6058; ATL_7468); SEQ ID NO: 71 (ATL_6074); SEQ ID NO: 79 (ATL_6075); SEQ ID NO: 106 (ATL_8944; ATL 8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955; ATL_0007892; ATL 0007895; ATL_0007896; ATL_0007917; ATL_0007918; ATL_0007919; ATL_0007920;ATL 0007922; ATL_0007923; ATL_0007924) ; or SEQ ID NO: 117 (ATL_7933; ATL_7956; ATL_7470; ATL 7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7469; ATL_7472; ATL_7473); and

[0051] LFWR4 of SEQ ID NO: 48 (ATL_6026; ATL_0007450; ATL_0007819; ATL_0007820; ATL_0007821 ; ATL 0007822; ATL_0007823; ATL_0007824; ATL_0007825; ATL_0007826; ATL_0007827; ATL 0007829; ATL_0007889; ATL_0007890; ATL_0007892; ATL_0007899; ATL_0007900; ATL 0007901 ; ATL_0007902; ATL_0007922); SEQ ID NO: 56 (ATL_6027); SEQ ID NO: 64 (ATL_6058; ATL 7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL 7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 72 (ATL_6074; ATL_0007893; ATL_0007895; ATL_0007896; ATL_0007917; ATL_0007918; ATL_0007919; ATL 0007920; ATL_0007921 ; ATL_0007923; ATL_0007924); SEQ ID NO: 80 (ATL_6075); or SEQ ID NO: 108 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955); or framework sequences with one, two, or three mutations, such as substitutions, compared with the framework sequences above.

[0052] The antibody may comprise a light chain variable domain (VL) with the following framework sequences: LFWR1 of SEQ ID NO: 45 (ATL_6026) or SEQ ID NO: 104 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL 7925; ATL_7952; ATL_7953; ATL_7955); LFWR2 of SEQ ID NO: 46 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7955); LFWR3 of SEQ ID NO: 47 (ATL_6026) or SEQ ID NO: 106 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL 7953; ATL_7955); and LFWR4 of SEQ ID NO: 48 (ATL_6026) or SEQ ID NO: 108 (ATL_8944; ATL 8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955); or framework sequences with one to five mutations (e.g. one, two, three, four, or five mutations), compared with the framework sequences above. The mutations may be substitutions compared with the framework sequences above. The mutation may be at position 2, for example A2S; and / or at position 8, for example S8P; and / or at position 52, for example P52L; and / or at position 90, for example V90A; and / or at position 124, for example V124L. Alternatively, the mutation may be at a position other than position 52, that is, P52 may be maintained. The antibody may have a light chain variable domain (VL) with the following CDRs: CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and CDRL3 comprising an amino acid sequence of SEQ ID NO: 206 (ATL_8944); SEQ ID NO: 207 (ATL_8946); SEQ ID NO: 168 (ATL_8945; ATL_7901 ; ATL_7919; ATL_7921); SEQ ID NO: 36 (ATL_8947; ATL_6026); or SEQ ID NO: 107 (ATL_7955). The antibody may have a light chain variable domain (VL) comprising the following framework sequences: LFWR1 of SEQ ID NO: 104 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); LFWR2 of SEQ ID NO: 46 (ATL_8944; ATL 8945; ATL_8946; ATL_8947; ATL_7955); LFWR3 of SEQ ID NO: 106 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); and LFWR4 of SEQ ID NO: 108 (ATL_8944; ATL_8945; ATL_8946; ATL 8947; ATL_7955).

[0053] The antibody may comprise a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the amino acid sequence selected from the group consisting of: SEQ ID NO:6; SEQ ID NO: 7; SEQ ID NO: 8; SEQ ID NO: 9; SEQ ID NO: 10 SEQ ID NO: 94; SEQ ID NO: 111 ; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141 ; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151 ; SEQ ID NO: 152; SEQ ID NO: 189; SEQ ID NO: 190; SEQ ID NO: 202; SEQ ID NO: 203; SEQ ID NO: 204; and SEQ ID NO: 205; optionally the group consisting of: SEQ ID NO: 6; SEQ ID NO: 8; SEQ ID NO: 94; SEQ ID NO: 111 ; SEQ ID NO: 202; SEQ ID NO: 203; SEQ ID NO: 204; and SEQ ID NO: 205; optionally the group consisting of: SEQ ID NO: 94;SEQ ID NO: 111 ; SEQ ID NO: 202; SEQ ID NO: 203; SEQ ID NO: 204; and SEQ ID NO: 205; optionally the group consisting of SEQ ID NO: 202; SEQ ID NO: 203; SEQ ID NO: 204; and SEQ ID NO: 205; optionally wherein the antibody comprises a light chain variable domain (VL) comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 202; SEQ ID NO: 203; SEQ ID NO: 204; and SEQ ID NO: 205.

[0054] The antibody may comprise:

[0055] (a) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 1 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 6; or (b) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 2 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 7; or (c) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 3 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 8; or (d) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 4 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 9; or (e) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 5 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 10 or (f) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 90 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or (g) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 91 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or(h) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 92 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or (i) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or (j) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 109 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 111 ; or (k) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 110 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 111 (l) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 202; or

[0056] (m) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 203; or

[0057] (n) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 204; or

[0058] (o) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 205.

[0059] The antibody may comprise a light chain variable domain (VL) comprising CDRL1 , CDRL2, and CDRL3 within a human framework, and / or within a germline framework.

[0060] The antibody may bind 15-PGDH at an allosteric site. The antibody may bind to and inhibit 15-PGDH through allosteric inhibition. The antibody may bind to one or more residues of 15-PGDH that are involvedin cofactor (NAD+) binding to 15-PGDH. The antibody may bind to one or more residues of 15-PGDH that are involved in promoting cofactor (NAD+) binding to 15-PGDH. The antibody may bind to and / or obstruct one or more residues in the cofactor entry site of 15-PGDH. The antibody may interfere with and / or block the cofactor entry site of 15-PGDH. The antibody may prevent or inhibit closure of the lid domain of 15-PGDH. The lid domain of 15-PGDH may be defined as domain comprising residues187-219 of 15-PGDH (as numbered according to SEQ ID NO: 82) or corresponding residues in another 15-PGDH sequence. For example, prevention or inhibition of closure of the lid domain of 15-PGDH may be determined a lack of density of residues 187-219 of 15-PGDH (as numbered according to SEQ ID NO: 82) in the X-ray crystal structure of the antibody bound to 15-PGDH. The antibody may prevent binding of NAD+ to 15-PGDH. Antibody ATL_6026 of the disclosure has been shown by X-ray crystallography to bind 15-PGDH in this way. Therefore any antibody according to the disclosure including at least any antibody with the VH sequence of ATL_6026 and / or the VH CDRs of ATL_6026, and any antibody sequence derived therefrom (e.g. any antibody with the VH and / or the VH CDRs or any of ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL 7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL 7892; ATL_7893; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7925; ATL_7952; ATL_7953; ATL_7955; ATL_8944; ATL_8945; ATL_8946; ATL_8947) may bind to 15-PGDH in the manner described above.

[0061] The antibody may be a monoclonal antibody. The antibody may be an IgG 1 , or a modified version thereof, such as a LALA IgG 1 , for example a LALA IgG 1 variant according to SEQ ID NO: 87. The antibody may be a human antibody.

[0062] The antibody may bind human 15-PGDH, wherein the antibody binds human 15-PGDH with a Kd of at most 106M, 107M, 108M, 109M, preferably at most 109M, as measured by ELISA, and / or wherein the antibody binds human 15-PGDH with an EC50 below 100 nM, below 50 nM, or below 10nM as measured by titration ELISA. The antibody may inhibit 15-PGDH as determined using a 15-PGDH enzyme activity assay. In embodiments, the antibody inhibits human 15-PGDH with an IC50 below 200 nM or below 150 nM. The antibody may bind human 15-PGDH, wherein the antibody binds human PGDH with a KD of at most 1 E-06M, at most 1 E-07M, at most 1 E-08M, at most 1 E-09M, at most 5E-10M, at most 3E-10M, at most 2.5E-10M, at most 2E-10M, preferably at most 2E-10M, as measured by biolayer interferometry (BLI).

[0063] The antibody may alter PGE2 levels in an in vitro cell culture. The antibody may alter one or more of autophagy, neuronal activity, oxidative stress, and apoptosis of dopaminergic neurons in vitro. The antibody may alter microglia inflammatory state in vitro. The antibody may reduce inflammation, optionally neuroinflammation, in an in vitro cell culture, optionally wherein a reduction in inflammation is determined by measuring the levels of one or more pro-inflammatory cytokines. The pro-inflammatory cytokines may include IL-6, IL-1 p, and / or TNFa. An in vitro cell culture may comprise cells exposed to a proinflammatory condition, optionally comprising exposure to aSyn fibrils. The antibody may alter the levels of circulating PGE2 in vivo. The antibody may alter 15-PGDH levels in an in vitro cell culture. The antibody may alter phospho-aSyn129 levels in an in vitro cell culture comprising cells exposed to aSyn fibrils. The antibody may alter mitochondrial function in an in vitro cell culture, optionally wherein an alteration in mitochondrial function is determined by measuring the mitochondrial membrane potential (MMP) comprising cellsexposed to aSyn fibrils. The antibody may decrease the levels of one or more pro-inflammatory cytokines in vivo. The pro-inflammatory cytokines may include IL-6, IL-1 p, and / or TNFa. The antibody may decrease the levels of one or more pro-inflammatory cytokines in an animal model and / or in a subject exposed to pro-inflammatory conditions, optionally comprising exposure to LPS.

[0064] The antibody may preserve or increase muscle strength and / or muscle function. For example, the antibody may preserve or increase muscle strength and / or muscle function of a disused muscle or muscle group. The antibody may preserve or increase muscle strength and / or muscle function of a muscle or muscle group subjected to immobilisation in an animal model and / or in a subject. Muscle strength and / or muscle function may be determined by measuring the isometric force generated by muscle contraction induced by electrical stimulation. The antibody may preserve or increase muscle strength and / or muscle function without preserving or increasing muscle mass. The antibody may preserve or increase muscle strength and / or muscle function following immobilisation for a predetermined period of time without preserving or increasing muscle mass. The predetermined period of time may be a period of time such that muscle anabolism is not expected in the absence of treatment with the antibody. The predetermined period of time may be 1 , 2, 3 or 4 weeks.

[0065] The antibody may be an isolated VH domain according to any embodiment of any preceding embodiment or any embodiment described herein. The antibody may be an isolated Fragment antigen-binding (Fab) antibody according to any embodiment of any preceding embodiment or any embodiment described herein.

[0066] In a fifth aspect, the disclosure provides an isolated nucleic acid comprising a nucleotide sequence encoding an antibody according to the first, second, third or fourth aspect.

[0067] In a sixth aspect, the disclosure provides a vector or set of vectors comprising the nucleic acid according to the fifth aspect.

[0068] In a seventh aspect, the disclosure provides a host cell comprising the vector or set of vectors according to the sixth aspect, or a host cell in vitro transformed with a nucleic acid according to the fifth aspect.

[0069] In an eighth aspect, the disclosure provides a composition comprising the antibody or fragment thereof according to the first, second, third or fourth aspect, and at least one additional component, optionally comprising a pharmaceutically acceptable excipient, vehicle or carrier.

[0070] In a ninth aspect, the disclosure provides antibody according to the first, second, third or fourth aspect, or a composition according to the eighth aspect, for use as a therapeutic. For example, the disclosure provides an antibody according to the first, second, third or fourth aspect, or a composition according to the eighth aspect, for use in the treatment or prevention of muscle atrophy and / or dystrophy, or in the treatment or prevention of muscle function and / or muscle strength loss in a subject in need thereof. As another example, the disclosure provides an antibody according to the first, second, third or eighth aspect, or a composition according to the eighth aspect, for use in the treatment or prevention of a disease or disorder associated with inflammation and / or neuroinflammation.In a tenth aspect, the disclosure provides antibody according to the first, second, third or fourth aspect, or a composition according to the eighth aspect, for use in the treatment or prevention of a disease or disorder. The disease may be associated with inflammation and / or neuroinflammation. In embodiments, the disease is a synucleinopathy or a synuclein-mediated neurodegenerative disease. The disease may be selected from Parkinson’s Disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Alzheimer’s Disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). The disease may be Parkinson’s Disease. The disease or disorder may be associated with muscle atrophy and / or dystrophy. The disease or disorder may be disuse atrophy. The disease or disorder may be aging related muscle atrophy. In embodiments, the disease is a myopathy. The disease or disorder may be selected from aging related muscle atrophy, spinal muscular atrophy (SMA), sarcopenia, sarcopenic obesity, Duchenne’s muscular dystrophy, cachexia, inflammatory myopathy, drug-induced myopathy, or disuse atrophy. The inflammatory myopathy may be muscle atrophy associated with an acute or chronic inflammatory disease or disorder. The drug-induced myopathy may be a myopathy associated with treatment with an incretin therapy. The incretin therapy may be a GIP and / or GLP (e.g. GLP-1) agonist. The disuse atrophy may be caused by a bone fracture, for example a hip fracture, a nerve injury, for example a spinal cord injury (SCI), immobilisation, bed rest, and / or obesity. The immobilisation may be immobilisation of a bone fracture, for example an immobilisation of a bone fracture by splinting and / or casting.

[0071] In an eleventh aspect, the disclosure provides a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition according to the eighth aspect, or an antibody according to the first, second, third or fourth aspect. The subject may have or may be at risk of developing a disease associated with inflammation and / or neuroinflammation, optionally wherein the disease is a synucleinopathy or a synuclein-mediated neurodegenerative disease. The disease may be selected from Parkinson’s Disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Alzheimer’s Disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). The disease may be Parkinson’s Disease. The subject may have or may be at risk of developing muscle atrophy and / or dystrophy and / or muscle function and / or muscle strength loss or a disease or disorder associated with muscle atrophy and / or dystrophy and / or muscle function and / or muscle strength loss. The method may be a method of treating or preventing muscle atrophy and / or dystrophy and / or muscle function and / or muscle strength loss, or a disease or disorder associated with muscle atrophy and / or dystrophy, in a subject in need thereof. The subject may have or be at risk of developing disuse atrophy. The subject may have or be at risk of developing aging related muscle atrophy. In embodiments, the disease is a myopathy. The disease or disorder may be selected from aging related muscle atrophy, spinal muscular atrophy (SMA), sarcopenia, sarcopenic obesity, Duchenne’s muscular dystrophy, cachexia, inflammatory myopathy, drug-induced myopathy, or disuse atrophy. The inflammatory myopathy may be muscle atrophy associated with an acute or chronic inflammatory disease or disorder. The drug-induced myopathy may be a myopathy associated with treatment with an incretin therapy. The incretin therapy may be a GIP and / or GLP (e.g. GLP-1) agonist. The disuse atrophy may be caused by a bone fracture, for example a hip fracture, a nerve injury, for example a spinal cord injury (SCI),immobilisation, bed rest, and / or obesity. The immobilisation may be immobilisation of a bone fracture, for example immobilisation of a bone fracture by splinting and / or casting.

[0072] In a twelfth aspect, the disclosure provides the use of an antibody according to the first, second, third or fourth aspect in the manufacture of a medicament. The medicament may be for the treatment of a disease associated with inflammation and / or neuroinflammation, optionally wherein the disease is a synucleinopathy or a synuclein-mediated neurodegenerative disease. The disease may be selected from Parkinson’s Disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Alzheimer’s Disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). The disease may be Parkinson’s Disease. The medicament may be for the treatment or prevention of muscle atrophy and / or dystrophy and / or muscle function and / or muscle strength loss, or a disease or disorder associated with muscle atrophy and / or dystrophy and / or muscle function and / or muscle strength loss. The disease or disorder may be disuse atrophy. The disease or disorder may be aging related muscle atrophy. In embodiments, the disease is a myopathy. The disease or disorder may be selected from aging related muscle atrophy, spinal muscular atrophy (SMA), sarcopenia, sarcopenic obesity, Duchenne’s muscular dystrophy, cachexia, inflammatory myopathy, drug-induced myopathy, or disuse atrophy. The inflammatory myopathy may be muscle atrophy associated with an acute or chronic inflammatory disease or disorder. The drug-induced myopathy may be a myopathy associated with treatment with an incretin therapy. The incretin therapy may be a GIP and / or GLP (e.g. GLP-1) agonist. The disuse atrophy may be caused by a bone fracture, for example a hip fracture, a nerve injury, for example a spinal cord injury (SCI), immobilisation, bed rest and / or obesity. The immobilisation may be immobilisation of a bone fracture, for example immobilisation of a bone fracture by splinting and / or casting.

[0073] The invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.

[0074] Summary of the Figures

[0075] Embodiments and experiments illustrating the principles of the disclosure will now be discussed with reference to the accompanying figures in which:

[0076] Figure 1 shows the results of high-throughput proteome screening for autoreactivity in PD subject. The figure shows the hit fold change for autoreactive proteins to each subject sample. Points highlighted in green represent autoreactivity to 15-PGDH within subject SU_478 sample. All other data points in black and across all patient samples represent autoreactivity to a diverse range of human proteins.

[0077] Figure 2 shows 15-PGDH activity measured in the presence of 15-PGDH reactive and non-reactive serum. Plot shows fluorescence signal over time, where the fluorescence signal is generated by reduction of a fluorescent probe upon oxidation of NADH generated by 15-PGDH mediated substrate oxidisation. The activity of 15-PGDH is proportional to the fluorescent signal (fluorescence signal proportional to NADH concentration).Figure 3 shows the results of serum and plasma screening by ELISA across a panel of Parkinson’s Disease and healthy control patients (subjects). Fig. 3A shows raw absorbances demonstrating the level of binding to 15-PGDH across these patient samples. Fig.3B shows z-scores demonstrating the level of autoreactivity to 15-PGDH across these patient samples. Z-score is calculated as [raw signal - mean signal] / Standard deviation (SD). Dotted line at y=1 .5. Lysozyme was included as negative control. 15-PGDH antigen was an in-house recombinant human 15-PGDH with additional C-terminal Avi and hexahistidine tag (rhPGDH-Avi-His). 84 serum or plasma samples were screened for binding to 15-PGDH. Subjects SU1271 (healthy, no prodromal PD), SU478 (late onset at 90 years old with severe motor progression but no cognitive impairment ), SU1238 (resilient, RBD 7 years no progression to PD), SU1242 (resilient, RBD 12 years, no progression to PD), and SU1264 (healthy, no prodromal PD) are the top 5 subjects and with clear higher z-scores, showing serum / plasma reactivity against at least one form of 15-PGDH. SU1286 (PD 6.8 years + RBD, no cognitive impairment) was also selected for further characterisation as it was just outside the threshold for determining reactivity, but found not to inhibit 15-PGDH during serum inhibition tests (Fig. 2). Figure 4 shows the principles and results of a PGDH inhibition assay. Fig. 4A shows a schematic of a 15-PGDH inhibition assay. 15-PGDH inactivation of PGE2 modulates inflammatory signalling. A biochemical assay was adapted to measure 15-PGDH inhibition following incubation with 15-PGDH reactive serum or 15-PGDH binding monoclonal antibodies. Fig. 4B shows results of experiments where diluted patient serum from PGDH-reactive subjects SU1238, SU1242, SU1264, SU478, and SU1286 and an age-matched control (SU477) was incubated with active recombinant 15-PGDH and then added to the reaction mix from a commercial fluorometric PGDH activity assay (ab273327). Mean increase in fluorescence at 587 nm across three replicate samples for each subject was measured at the endpoint of the assay. PGDH-reactive subject means were compared to the SU477 mean by ordinary one-way ANOVA.SU1286 sample did not show significant enzyme inhibition in this format, validating the z-score cutoff used to select serum for screening.

[0078] Figure 5 shows the results of a PGDH inhibition assay in the presence of the antibody ATL6058. Activity is reported as a percentage of activity in the presence of an equal concentration of isotype control antibody. Error bars show Standard Error of the Mean (SEM) for three technical replicates in one assay run. Data were fit using non-linear regression [inhibitor] vs response function in Graphpad Prism. ATL6058 was, identified from PD patient SU478 via serum proteomics.

[0079] Figure 6 shows the results of a single point ELISA for antibodies identified from PD patients SU1242 and SU1271 . Fig. 6A shows the raw absorbance data of antibodies ATL_0006026 and ATL_0006027 binding to 15-PGDH (rhPGDH-Avi-His). Fig. 6B) shows binding of antibodies ATL_0006026 and ATL_0006027 as fold change over lysozyme control. Both include anti-His antibody to confirm antigen coating and antihuman-15-PGDH (Goat IgG) as a positive control.

[0080] Figure 7 shows the results of a single point ELISA for antibodies identified from PD patients SU1238 and SU1286. Fig. 7A shows the raw absorbance of antibodies ATL_0006074, and ATL_0006075 binding to Neutravidin captured NLB-rhPGDH-Avi-His or plated PGDH (both full length). Fig. 7B shows the raw absorbance of ATL_0006058 binding to Neutravidin captured NLB-rhPGDH-Avi-His or plated PGDH (both full length). Fig. 7C shows binding of antibodies ATL_0006058 to Neutravidin-captured biotinylated PGDHor plated PGDH as fold change over background lysozyme binding. Fig. 7D shows binding of antibodies ATL_0006074, and ATL_0006075 to Neutravidin-captured biotinylated PGDH or plated PGDH as fold change over background lysozyme binding.

[0081] Figure 8 shows the results of a multipoint ELISA binding of IgG to 15-PGDH, either plated (ATL_0006026, ATL_0006027, ATL_0005338 (isotype control) or Neutravidin captured 15-PGDH (ATL_0006058, ATL_0006074, ATL_0006075). EC50s shown calculated using non-linear regression (curve fit) function on GraphPad Prism.

[0082] Figure 9 shows the results of a PGDH inhibition assays in the presence of anti-PGDH antibodies identified using phage display. Fig. 9A shows the percentage of activity for ATL6026. Fig. 9B shows the percentage of activity for ATL6027. Fig. 9C shows the percentage of activity for ATL6074. Fig. 9D shows the percentage of activity for ATL6075. Activity is reported as a percentage of activity in the presence of an equal concentration of isotype control antibody. Error bars show SEM for three technical replicates in one assay run. Data were fit using non-linear regression [inhibitor] vs response function in Graphpad Prism.

[0083] Figure 10 shows the results of a kinetics analysis of 15-PGDH binding antibodies using biolayer interferometry (BLI). Figs. 10A-E show binding to human 15-PGDH; and Fig. F-J show binding to mouse 15-PGDH. Each plot shows BLI raw data collected for each antibody concentration (represented by different colours) and 1 :1 binding fit shown in red. Figs. 10A and F show results for ATL_6026. Figs. 10B and G show results for ATL_6027. Figs. 10C and H show results for ATL_6058. Figs. 10D and I show results for ATL_6074. Figs. 10E and J show results for ATL_6075.

[0084] Figure 11 shows the results of kinetic analysis of 15-PGDH binding antibodies using surface plasmon response (SPR). Fig. 11 A shows binding of ATL6026 to human 15-PGDH. Fig. 11 B shows binding of ATL6027 (B) to human 15-PGDH. Fig. 11C shows binding of ATL6058 to human 15-PGDH. Fig. 11D shows binding of ATL6074 to human 15-PGDH. Fig. 11E shows binding of ATL6075 to human 15-PGDH. Each plot shows SPR raw data collected for each antigen concentration (represented by different colours) and 1 :1 binding fit shown in red. For antibodies other than ATL6027 (shown in B) data shown were collected at two sensor locations at four capture densities. For ATL6027 data shown were collected at two sensor locations at the highest capture density only.

[0085] Figure 12 shows the results of a thermal stability assay for the indicated antibodies tested on freshly thawed material over a temperature gradient. FF= Full spectrum fluorescence; SLS= Static light scattering; Tm1 = Unfolding at 50%; Tonset = unfolding at 10%.

[0086] Figure 13 shows sequence alignments showing antibodies of the disclosure aligned using the IMGT sequence numbering. Fig. 13A shows VH sequences. Fig. 13B shows VL sequences.

[0087] Figure 14 shows in silica predicted protein structure of (A) ATL6026 and (B) ATL6058 and their binding to a PGDH dimer. Fig. 14A shows predicted binding of ATL6026 to the active site via its CDR3 loop. Fig. 14B shows predicted binding of ATL6058 to a different epitope, suggesting allosteric inhibition.

[0088] Figure 15 shows the experimental design of an aSynuclein fibrils-induced model. This is used to determine the effects of antibodies of the disclosure on IL6 production and PGDH activity upon exposure ofdopaminergic neurons, astrocytes and microglia to aSynuclein fibrils. IL-6 in the CNS is secreted by astrocytes, microglia, oligodendrocytes, neurons, and endothelial cells. Each of these cell types can contribute to the overall IL-6 levels in response to various stimuli, playing roles in both normal physiology and in pathological conditions.

[0089] Figure 16 shows results demonstrating effective target engagement, with ATL-6026 specifically inhibiting 15-PGDH and subsequently eliciting significant anti-inflammatory effects in an alpha-synuclein-induced model. The figure shows the results of an ELISA for 15-PGDH and IL-6 at day 11 of the aSynuclein fibrils-induced PD-model. Fig. 16A shows the concentration of 15-PGDH in cell lysates obtained from the triculture. Bars show mean + / - standard error of the mean. 3 wells per condition. Fisher’s LSD pairwise comparisons versus isotype (ATL5338) control with aSynuclein preformed fibrils (aSyn PFFs), *p<0.05.

[0090] Fig. 16B shows the concentration of 15-PGDH in cell culture supernatants obtained from the triculture. Bars show mean + / - standard error of the mean. 3 wells per condition. Fig. 16C shows the concentration of IL-6 in the cell culture supernatants obtained from the triculture. Bars show mean + / - standard error of the mean for two experiments. Each data point represents mean of 3-4 wells from each experiment. Two way ANOVA with Tukey’s multiple comparisons comparing all means with each other, *p<0.05, **p<0.01 .

[0091] Figure 17 shows results demonstrating the restoration of mitochondrial function by ATL-6026 and ATL-605. The figure shows the results of an experiment measuring the red / green fluorescence intensity ratio using JC-1 dye to indicate mitochondrial membrane potential (MMP) of the aSynuclein fibrils-induced PD-model. Bars show mean + / - standard error of the mean for each well. 4 wells per condition each with 3-4 fields of view. Two way ANOVA with Tukey’s multiple comparisons versus Isotype control (ATL5338) with aSynuclein preformed fibrils (aSyn PFFs), **p<0.01 , ****p<0.0001 .

[0092] Figure 18 shows data demonstrating effective reduction of aSyn seeding by ATL-6026. The figure shows the results of immunostaining the aSynuclein fibrils-induced PD-model. Fig. 18A shows images obtained using DAPI nuclear stain, immunostaining with MAP2 antibody, and immunostaining with Phospho-aSyn129 antibody. Fig. 18B shows the quantification of the images in Fig. 18A. Bars show mean + / -standard error of the mean for each well. 3 wells per condition each with 3-4 fields of view. Two way ANOVA with Tukey’s multiple comparisons versus Isotype control (ATL5338) with aSynuclein preformed fibrils (aSyn PFFs), *p<0.05, ****p<0.0001 .

[0093] Figure 19 shows the results of an experiment measuring the cytokine levels in plasma and brain samples obtained from a LPS-induced mouse model of inflammation treated with isotype control (ATL5338; white), ATL6026 (dark grey) or positive control SW033291 small molecule inhibitor of 15-PGDH (SW; light grey). Results are shown as bar graphs of indicated cytokine concentrations showing mean + / - standard error of the mean (SEM) for 5-8 mice per group. Fig. 19A shows data for IL-6. Fig. 19B shows data for IL-1 p. Fig.

[0094] 19C shows data for TNF-a.

[0095] Figure 20 shows the results of an experiment measuring the gait and postural stability of aged mice treated with isotype control (ATL5338), ATL6026, positive control SW033291 , or vehicle control. Kinematic parameters measured were: (A) speed, (B) hind stance time, (C) diagonal interlimb coordination, (D) double support, (E) maximum knee angle, and (F) peak hind leg swing speed. Mean + / - SEM for n=12-13 miceper group. *p-value=0.0262 ATL5338 vs ATL6026 using an unpaired t test. Fig.20A shows the results for speed measurements. Fig.20B shows the results for hind stance time measurements. Fig.20C shows the results for diagonal interlimb coordination measurements. Fig. 20D shows the results for double support measurements. Fig. 20E shows the results for maximum knee angle measurements. Fig. 20F shows the results for peak hind leg swing speed measurements.

[0096] Figure 21 shows overall gait score obtained by combining the above kinematic parameters of Figure 20A-F. Fig. 21 A shows gait score results for mice treated with ATL6026 vs vehicle. Fig.21 B shows gait score results for mice treated with a small molecule inhibitor of 15-PGDH (SW033291) vs vehicle. The results show mice treated with (A) ATL6026 have a more profound effect in gait and stability vs isotype control than (B) the small molecule inhibition of 15-PGDH vs vehicle. Pairwise comparison using Unpaired t test with Welch’s correction, *p<0.05, **p<0.01.

[0097] Figure 22 shows sequence alignments showing antibodies of the disclosure aligned using the IMGT sequence numbering. Fig.22A. VH sequences. Fig.22B. VL sequences.

[0098] Figure 23 shows the results of a kinetics analysis of 15-PGDH binding antibodies using biolayer interferometry (BLI). (A-H) binding to human 15-PGDH. Each plot shows BLI raw data collected for each antibody concentration (each line representing a different concentration as indicated below the graph). Fig.

[0099] 23A shows results for ATL_6058. Fig. 23B shows results for ATL_7956. Fig. 23C shows results for ATL_7933. Fig. 23D shows results for ATL_6026. Fig. 23E shows results for ATL_7953. Fig. 23F shows results for ATL_7952. Fig. 23G shows results for ATL_7955. Fig.23H shows results for ATL_7925.

[0100] Figure 24 shows the results of a fluorescence-based enzyme inhibition assay testing the inhibition of 15-PGDH binding antibodies as measured by the reduction in fluorescence intensity (RFU). Fig. 24A shows results of a four-point 10-fold dilution series of antibodies ATL_6026, ATL_7925, ATL_7952, ATL_7953, and ATL_7955 compared to isotype control (ATL_5338) (one point per antibody, one set of points on the x-axis for each dilution series). Fig.24B-F show fluorescence intensity data across time shown for dilution series of 15-PGDH binding antibodies (each data series corresponding to a different dilution of the antibody on the specific plot). Fig. 24B shows results for ATL_5338. Fig. 24C: shows results for ATL_6026. Fig.

[0101] 24D shows results for ATL_7925. Fig. 24E shows results for ATL_7952. Fig. 24F shows results for ATL_7953. Fig.24G shows results for ATL_7955.

[0102] Figure 25 shows the results of a fluorescence-based enzyme inhibition assay testing the inhibition of 15-PGDH binding antibodies as measured by the reduction in fluorescence intensity (RFU). A-C: fluorescence intensity data across time shown for a dilution series of 15-PGDH binding antibodies (each data series corresponding to a different dilution of the antibody on the specific plot). Fig. 25A shows results for ATL_6058. Fig. 25B shows results for ATL_7933. Fig.25C shows results for ATL_7956.

[0103] Figure 26 shows sequence alignments showing antibodies of the disclosure aligned using the IMGT sequence numbering. Fig.26A: HFWR1 and HCDR1 sequences. Fig.26B: HFWR2 and HCDR2 sequences. Fig.26C: HFWR3 sequences Fig.26D: HCDR3 and HFWR4 sequences. Fig.26E: LFWR1 and LCDR1 sequences. Fig.26F: LFWR2 and LCDR2 sequences. Fig.26G: LFWR3 sequences Fig.26H:

[0104] LCDR3 and LFWR4 sequences.Figure 27 shows sequence alignments showing VL sequences of antibodies of the disclosure aligned using the IMGT sequence numbering.

[0105] Figure 28 shows the results of a kinetics analysis of 15-PGDH binding antibodies using biolayer interferometry (BLI). (A-E) binding to human 15-PGDH. Each plot shows BLI raw data collected for each antibody concentration (each line representing a different concentration as indicated below the graph). Fig.

[0106] 28A shows results for ATL_7955. Fig. 28B shows results for ATL_8944. Fig. 28C shows results for ATL_8945. Fig. 28D shows results for ATL_8946. Fig. 28E shows results for ATL_8947.

[0107] Figure 29 shows the results of a fluorescence-based enzyme inhibition assay testing the inhibition of 15-PGDH binding antibodies as measured by the reduction in fluorescence intensity (RFU). Fig.29A-E show fluorescence intensity data across time shown for 15-PGDH binding antibodies (each antibody at the concentration indicated on the specific plot). Fig. 29A shows results for ATL_7955. Fig. 29B shows results for ATL_8944 (Y2846). Fig. 29C shows results for ATL_8945 (Y2848). Fig. 29D shows results for ATL 8946 (Y2847). Fig. 29E shows results for ATL_8947 (Y2849).

[0108] Figure 30 shows the results of an experiment testing the effects of ATL7955 treatment in an in vivo limb immobilisation model of disuse atrophy. Fig.30A shows read counts for Hpgd RNA transcripts from reanalysis of bulk transcriptomics on gastrocnemius muscles of young male C57BL6 mice (eight-week-old) reported in Wu et al., 2023. Transcripts are reported as Transcripts per million (TPM). Fig.30B-C shows measurements of force generated per gram of body weight after the limb has been stimulated at the indicated frequencies for all animals. Each data point represents the mean and standard error of the mean for all mice with the same treatment (Fig30B = day 21 measurements; Fig30C = day 28 measurements).

[0109] Fig.30D shows day 21 measurements for the maximum force generated per gram of body weight after the limb has been stimulated for all animals. Each bar represents the mean and standard error of the mean for all mice with the same treatment. Analysis: l-way ANOVA with Holm-Sidak’s correction for multiple comparisons, *, p<0.05; **, p<0.01 . Fig.30E shows day 21 measurements of force generated per gram of body weight after the limb has been stimulated at the indicated frequencies for all animals. Each data point represents the mean and standard error of the mean for all mice with the same treatment. Analysis 2-way ANOVA with Dunnett’s correction for multiple comparisons. Ns, not significant; p< <0.0001. Fig.30F shows gastrocnemius muscle weight measurements of the casted left limb vs non-casted right limb for the different treatment groups. Analysis 2-way ANOVA with Holm-Sidak’s correction for multiple comparisons. Only showing p-values <0.05. ****, p<0.0001 .

[0110] Figure 31 shows the X-ray crystal structure of two Fab fragments of ATL_6026 bound to a dimer of human 15-PGDH. Fig. 31 A shows a cartoon view of the full Fab-15-PGDH complex. Figs. 31B to 31 F show closeup views of the specific interactions between ATL_6026 and 15-PDGH as shown in Fig. 31 A. Fig. 31 G shows a protein alignment of human 15-PGDH (SEQ ID NO: 82) against orthologs of 15-PGDH found in Macaca fascicularis “MacFa” (SEQ ID NO: 84), mouse (SEQ ID NO: 86), and rat (SEQ ID NO: 171). The residues which the greatest interaction with ATL_6026 (<4 A) as determined by X-ray crystallography are indicated in boxes and highlighted in blue.Figure 32 shows the results of an experiment testing the effects of ATL_7955 treatment on motor function in an in vivo mouse model of Parkinson’s disease. Fig.32A shows a study outline (Y2490 is a murine version of ATL7955). Fig.32B shows the results of a Rotarod experiment testing motor coordination and balance. The graph shows the time to fall. Analysis with one-way ANOVA with Dunnett’s correction for multiple comparisons, *p<0.05. Fig.32C shows the estimated population of aSyn positive cells at ipsilateral (Ipsi) and contralateral (Contra) sections of the Substantia Nigra pars compacta (SNpc) of mouse brains following treatment, analysis using a 2 way ANOVA with Dunnett’s correction for multiple comparisons, ““ p<0.0001 , ns not significant; “TA”= test article (murine version of ATL_7955). Fig.32D shows a plot of overall score for gait after principal component analysis, each point represents one animal. PGDHi mAb = Y2490. Analysis with one-way ANOVA with Dunnett’s correction for multiple comparisons, ***p<0.001 , *p<0.05.

[0111] Detailed Description of the Disclosure

[0112] Aspects and embodiments of the present invention will now be discussed with reference to the accompanying figures. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0113] The present disclosure refers to antibodies described herein using references specified as “ATL_000xxxx”, “ATL_xxxx”, “ATLxxxx” or “xxxx”, where “xxxx” is a four digits reference number specific to an antibody described herein. All of the above notations are used interchangeably to refer to the same antibody or a portion thereof (e.g. a VH, VL or part thereof, of the antibody). For example, antibody ATL_0006026 is interchangeably referred to herein as ATL_6026, ATL6026 and 6026. Unless otherwise specified, reference to a position within an antibody domain refers to the position according to IMGT numbering.

[0114] Disclosed herein are antibodies and fragments thereof that are capable of specifically binding to 15-hydroxyprostaglandin dehydrogenase (15-PGDH) or a fragment thereof. As used herein, an antibody capable of specifically binding or specifically binding a target is one able to bind through the association of the epitope recognition site with an epitope within the target. It is distinct from non-specific binding, for example Fc mediated binding, ionic and / or hydrophobic interactions. In other words, an antibody which specifically binds a target recognised and binds to a specific protein structure within it rather than to proteins generally.

[0115] Binding to PGDH

[0116] The notations “15-PGDH” and “PGDH” are used interchangeably herein to refer to 15-hydroxyprostaglandin dehydrogenase or a fragment thereof. The fragment may include amino acids 3-266 of the human sequence of 15-hydroxyprostaglandin dehydrogenase, or equivalents in a homologous sequence such as the mouse 15-hydroxyprostaglandin dehydrogenase sequence or the cynomolgus monkey 15-hydroxyprostaglandin dehydrogenase sequence.

[0117] An antibody according to the present disclosure may bind human 15-PGDH. An antibody according to the present disclosure may bind human 15-PGDH as set out in SEQ ID NO: 82 (Uniprot ID P15428) or anantigen derived therefrom, such as e.g. as set out in SEQ ID NOs: 173, 83, and 81 . An antibody according to the present disclosure may bind orthologs of human 15-PGDH found in a non-human primate (e.g. Macaca fascicularis) and / or a rodent (e.g. mouse - Mus musculus and / or rat - Rattus norvegicus) species. For example, an antibody or fragment thereof may bind to one or more of: Macaca fascicularis 15-PGDH as set out in SEQ ID NO: 84 (Uniprot ID: Q8MJY8), or an antigen derived therefrom with the amino acid sequence set forth in SEQ ID NO: 170, Mus musculus 15-PGDH as set out in SEQ ID NO: 86 (Uniprot ID: Q8VCC1 ) or an antigen derived therefrom with the amino acid sequence set forth in SEQ ID NO: 85, and / or Rattus norvegicus 15-PGDH as set out in SEQ ID NO: 171 (Uniprot ID: 008699) or an antigen derived therefrom with the amino acid sequence set forth in SEQ ID NO: 172. Binding of an antibody of the disclosure to one or more of the above antigens may be determined by biolayer interferometry (BLI), such as e.g. as described in examples of the present disclosure. For example, cross-reactivity of an antibody as described herein binding human 15-PGDH with mouse 15-PGDH antigen may be determined by BLI, for example BLI performed as described herein (Materials and Methods).

[0118] Human 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is encoded by HPGD (NCBI gene ID: 3248).

[0119] 15-PGDH is located on chromosome 4 (4q34.1) and comprises 10 exons. Multiple transcript variants encoding different isoforms have been found for this gene. The PGDH protein is 266 amino acids in length, available under the Uniprot identifier P15428 and Ensembl ID ENSG00000164120. 15-PGDH is a member of the short-chain non-metalloenzyme alcohol dehydrogenase protein family and catalyses the NAD-dependent dehydrogenation (oxidation) of hydroxylated polyunsaturated fatty acids. These include prostaglandins (PGs; mainly PGE2, PGD2, and PGF2a), which function in a variety of physiologic and cellular processes such as inflammation (Sun et al., 2021).

[0120] The antibodies described herein inhibit 15-PGDH. As used herein, inhibition of 15-PGDH refers to the blocking, suppression or reduction of its enzymatic activity. In other words, the antibody according to the present disclosure may prevent or decrease the enzymatic activity of 15-PGDH, that is its NAD-dependent oxidation function may be reduced or abolished by binding to a binding site on 15-PGDH, compared with unbound 15-PGDH. The skilled person will be familiar with assays for measuring 15-PGDH activity, such as assays measuring the oxidation of a substrate as described in Tai, 1976. Inhibition of 15-PGDH may be determined using any assay known in the art, such as e.g. assays used in examples of the present disclosure. For example, inhibition of 15-PGDH may be determined using an assay based on the conversion of non-fluorescent NAD+ to fluorescent NADH catalyzed by 15-PGDH in the presence of substrate PGE2. Inhibition of 15-PGDH (e.g. mouse and / or human PGDH) may be assessed by measuring the half-maximal inhibitory concentration (IC50). Antibodies described herein may inhibit 15-PGDH with an IC50 below 1 .5E-07 M, below 2.5E-07 M, below 5 E-07 M, or below 1 E-08 M. In some embodiments, the IC50 is about 1 E-08 M, about 1 E-09 M, about 3 E-09 M about 4 E-09 M. In some embodiments, the IC50 below 1 E-09 M. Antibodies described herein may bind 15-PGDH (e.g. mouse and / or human) with high affinity. High affinity binding may be assessed by measuring the EC50 value, the concentration at which the antibody produces a half-maximal binding, for example via titration ELISA, as described herein. For example, affinity of the antibody may be assessed by binding to plate-bound recombinant human 15-PGDH as described herein.High affinity as referred to herein means an EC50 value of at most 1 E-06 M, at most 2E-06 M, at most 3E-06M, at most 4E-06, at most 5E-06 M, at most 6E-06 M, at most 7E-06, at most 8E-06 M, at most 9E-06 M, at most 1 E-07 M, at most 5E-07 M, at most 1 E-08 M, at most 2 E-08 M, at most 3 E-08 M, at most 4 E-08 M, at most 5 E-08 M, at most 6 E-08 M, at most 7 E-08 M, at most 8 E-08 M, at most 9 E-08 M, at most 1 E-09 M, at most 2 E-09 M, at most 3 E-09 M, at most 4 E-09 M, at most 5E-09 M, at most 6 E-09 M, at most 7 E-09 M; at most 8 E-09 M, at most 9 E-09 M, at most 1 E-10 M, at most 2 E-10 M, at most 3 E-10 M, at most 4 E-10 M, at most 5E-10 M, at most 6 E-10 M, at most 7 E-10 M. at most 8 E-10 M, at most 9 E-10 M, at most 1 E-11 M, at most 2 E-11 M, at most 3 E-11 M, at most 4E-11 M, at most 5 E-11 M , at most 6E-11 M, at most 7 E-11 M, at most 8 E-11 M, at most 9 E-11 M, at most 1 E-12M, at most 2 E-12M, at most 3 E-12M, at most 4 E-12M, 5E-12M, at most 6 E-12M, at most 7 E-12M, at most 8 E-12M, at most 9 E-12M or 1 E-13M.

[0121] In some embodiments, the antibody binds 15-PGDH with an EC50 of at most 5E-09M, at most 9E-09M, at most 9.50E-09M, at most 1 E-10, at most 1.5E-10, at most 2E-10, at most 2.5E-10, at most 3 E-10, as measured by titration ELISA. In some embodiments, the antibody binds 15-PGDH with an EC50 below 1 E-07M, below 5E-07M, or below 1 E-08M by titration ELISA.

[0122] High affinity binding may also be assessed by measuring the Kd value (the dissociation constant) as described herein, for example via titration ELISA or BLI, as described herein. Accordingly, in some embodiments antibodies described herein may bind human PGDH with a Kd of at most 106M, 107M, 10’8M, 109M, preferably at most 109M, as measured by ELISA. Accordingly, in some embodiments antibodies described herein may bind human PGDH with a Kd of at most 1 E-6, 1 E-7, 1 E-8, 3E-9, 1 E-9, preferably at most 3E-9 or 1 E-9 as measured by BLI. In some embodiments antibodies described herein may bind human PGDH with a Kd of at most 1 E-06M, at most 1 E-07M, at most 1 E-08M, at most 1 E-09M, at most 5E-1 OM, at most 3E-1 OM, at most 2.5E-1 OM, at most 2E-1 OM, preferably at most 2E-1 OM, as measured by BLI. Antibodies described herein may bind to and inhibit 15-PGDH through allosteric inhibition. Antibodies described herein may inhibit 15-PGDH through binding directly to the active site of the enzyme. In other words, antibodies described herein may bind one or more residues in the active site of the enzyme. Antibodies described herein may also or instead block the substrate or cofactor entry sites of 15-PGDH.

[0123] 15-PGDH residues involved in cofactor binding and enzyme activity include Gly12; Ala13; Ala14; Gln15, Gly16; Ile17; Gly18; Arg19, Ala20, Asp36; Trp37; Asn38, Cys63, Asp64, Val65, Asn91 , Lys98, Asn 99, Lys102, Val186, Asn187, Thr188, Ala189, Glu198 of human 15-PGDH or homologous residues in homologous proteins. Accordingly, antibodies described herein may bind one or more, or all of the following 15-PGDH residues: Gly12; Ala13; Ala14; Gln15, Gly16; Ile17; Gly18; Arg19, Ala20, Asp36; Trp37; Asn38, Cys63, Asp64, Val65, Asn91 , Lys98, Asn 99, Lys102, Val186, Asn187, Thr188, Ala189, Glu198 of human 15-PGDH or corresponding residues in homologous proteins. The antibody may bind to an epitope that comprises one or more (or all of) residues Met143; Pro144; Val145; Ala146; Gln147; Phe185; Tyr206; Asp208; His209; Asp212; Met213; Lys215; Tyr216; Tyr217; Gly218; Thr246; Thr247; Ser248, Arg163; Leu167; Asn170; Leu171 ; Ala237; Asn239; Thr258; Thr259; Pro260; Phe261 ; Gln262 of 15 PGDH, provided as SEQ ID NO: 82. 15-PGDH residues involved in substrate binding (as well as enzyme activity) include Ser138; Leu139; Gln148; Phe185; Phe217. Accordingly, antibodies described herein may bind oneor more, or all of the following 15-PGDH residues: Ser138; Leu139; Gln148; Phe185; Tyr217 of human 15-PGDH or corresponding residues in homologous proteins. Antibodies described herein may inhibit 15-PGDH through binding to an allosteric site of the enzyme. Allosteric as used herein refers to a site other than the active site of the enzyme. Accordingly, antibodies described herein may inhibit 15-PGDH allosterically, e.g. by reducing substrate affinity. Antibodies of the present disclosure may bind one or more active site residues of 15-PGDH. The antibody may bind 15-PGDH in the active site. The antibody may prevent binding of one or more substrates of 15-PGDH to the active site of 15-PGDH. The one or more substrates may include PGE2 (Prostaglandin E2). The antibody may bind to and / or obstruct the substrate binding site of 15-PGDH. The antibody may compete with PGE2 for binding to the substrate binding site of 15-PGDH. Antibodies of the present disclosure may bind one or more or all of the residues in Table 8, or corresponding residues in homologous proteins, which were predicted by in silico modelling. This may be the case for e.g. antibodies having the VH CDRs of ATL6026 (and optionally also the VL CDRs or ATL6026) and variants and derivatives thereof, such as e.g. ATL_0007450, ATL_0007819, ATL_0007820, ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826 ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893 ATL 0007896, ATL 0007899, ATL 0007900, ATL_0007901 , ATL 0007902, ATL 0007925 ATL 0007952, ATL_0007953, ATL_0007955, ATL_008944, ATL_0008946, ATL_0008945, ATL_0008947. Antibodies described herein may prevent (e.g. inhibit or reduce) binding of a substrate of 15-PGDH to the substrate binding site of the enzyme. Antibodies described herein may compete with binding of PGE2 to 15-PGDH. Antibodies of the present disclosure may bind one or more residues of 15-PGDH outside of the active site of the protein (e.g. allosteric site residues). Antibodies of the present disclosure may bind one or more or all of the residues in Table 9, or corresponding residues in homologous proteins. This may be the case for e.g. antibodies having the VH CDRs of ATL6058 (and optionally also the VL CDRs or ATL6058) and variants and derivatives thereof, such as e.g. ATL_0007926, ATL_0007927, ATL_0007928, ATL 0007929, ATL_0007930, ATL_0007931 , ATL_0007932, ATL_0007933, ATL_0007956, ATL 0007467, ATL_0007468, ATL_0007469, ATL_0007470, ATL_0007471 , ATL_0007472, ATL_0007473. Antibodies described herein may bind to one or more residues of 15-PGDH that are involved in cofactor binding to 15-PGDH, for example Cys63. The antibody may bind to and / or obstruct one or more residues in the cofactor entry site of 15-PGDH. The antibody may interfere with and / or block the cofactor entry site of 15-PGDH. The antibody may prevent or inhibit closure of the lid domain of 15-PGDH. For example, prevention or inhibition of closure of the lid domain of 15-PGDH may be determined a lack of density of residues 187-219 of 15-PGDH (as numbered according to SEQ ID NO: 82) in the X-ray crystal structure of the antibody bound to 15-PGDH. Antibodies of the present disclosure may bind one or more or all of the residues in Table 21 , or corresponding residues in homologous proteins. The cofactor may be NAD+. This may be the case for e.g. antibodies having the VH CDRs of ATL6026 (and optionally also the VL CDRs or ATL6026) and variants and derivatives thereof, such as e.g. antibodies having the VH or VH CDRs of: ATL 0007450, ATL_0007819, ATL_0007820, ATL_0007821 , ATL_0007822, ATL_0007823, ATL 0007824, ATL_0007825, ATL_0007826, ATL_0007827, ATL_0007829, ATL_0007889, ATL 0007890, ATL_0007892, ATL_0007893, ATL_0007896, ATL_0007899, ATL_0007900,ATL 0007901 , ATL_0007902, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_008944, ATL 0008946, ATL_0008945, ATL_0008947.

[0124] As used herein, the term “PGDH” encompasses truncations, derivatives, and variants of the sequence of human PGDH provided herein as SEQ ID NO: 82 or a homolog thereof (such as e.g. mouse PGDH provided as SEQ ID NO: 86), and it may refer to any protein with at least 80%, at least 90%, or at least 95% sequence identity with said sequence. The protein may be a protein that has the stated sequence identity with 15-PGDH or homologue thereof, and that has the enzymatic activity of the 15-PGDH or homologue thereof. The PGDH sequence may be a human PGDH sequence. The term “PGDH” encompasses any protein that is a fragment of human 15-PGDH or a homologue thereof that maintains at least some of the enzymatic activity of the corresponding full protein, as well as any derivative thereof with at least 80%, at least 90%, or at least 95% sequence identity with the sequence of such a fragment, provided that the variant maintains at least some of the enzymatic activity of the fragment. The term “PGDH” encompasses any protein that is a fragment of human 15-PGDH or a homologue thereof that maintains the enzymatic activity of the corresponding full protein, as well as any derivative thereof with at least 80%, at least 90%, or at least 95% sequence identity with the sequence of such a fragment, provided that the variant maintains the enzymatic activity of the fragment.

[0125] Structural properties

[0126] Antibodies of the present disclosure may specifically bind to an epitope on 15-PGDH. The term epitope, also known as antigenic determinant, as used herein refers to any protein determinant capable of specific binding by an immunoglobulin or fragment thereof. Epitopic, or antigenic, determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. Antibodies described herein may bind to an epitope that comprises one or more of the following residues of 15-PGDH, provided as SEQ ID NO: 82: Met143; Pro144; Val145; Ala146; Gln147; Phe185; Tyr206; Asp208; His209; Asp212; Met213; Lys215; Tyr216; Tyr217; Gly218; Asp221 ; Leu224; Asn227; Thr231 ; Asp235; Ala237; Leu238; Thr246; Thr247; Ser248; Lys249; Arg163; Leu167; Asn170; Leu171 ; Ala237; Asn239; Gly250; Ile251 ; His252; Phe253; Asp255; Thr258; Thr259; Pro260; Phe261 ; Gln262, or corresponding residues in a homologous sequence. In some embodiments, the antibody binds to an epitope that comprises Thr246; Thr247; and Ser248.

[0127] In some embodiments, e.g. in instances where the antibody comprises the HCDR1-3 of ATL6026, the antibody binds to an epitope that comprises one or more (or all) of residues Met143; Pro144; Val145; Ala146; Gln147; Phe185; Tyr206; Asp208; His209; Asp212; Met213; Lys215; Tyr216; Tyr217; Gly218; Thr246; Thr247; Ser248, Arg163; Leu167; Asn170; Leu171 ; Ala237; Asn239; Thr258; Thr259; Pro260; Phe261 ; Gln262 of 15 PGDH, provided as SEQ ID NO: 82, or corresponding residues in a homologous sequence. In some embodiments, e.g. in instances where the antibody comprises the HCDR1-3 of ATL6026 or variants or derivatives thereof (e.g. antibodies with the HCDR1-3 of ATL_0007450, ATL 0007819, ATL_0007820, ATL_0007821 , ATL_0007822, ATL_0007823, ATL_0007824, ATL 0007825, ATL_0007826, ATL_0007827, ATL_0007829, ATL_0007889, ATL_0007890,ATL 0007892, ATL_0007893, ATL_0007896, ATL_0007899, ATL_0007900, ATL_0007901 , ATL 0007902, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_008944, ATL_0008946, ATL_0008945, ATL_0008947), the antibody binds to an epitope that comprises one or more (or all) of residues Leu 39, Glu40, Val43, Gln44, Lys46, Ala47, Leu59, Phe60, Ile61 , Gln62, Cys63, Gln70, Asp73, Thr74, Arg76, Lys77, Asp80, His81 of 15-PGDH, provided as SEQ ID NO: 82, or corresponding residues in a homologous sequence. In some embodiments, e.g. in instances where the antibody comprises the HCDR1-3 of ATL6058, the antibody binds to an epitope that comprises one or more (or all of) residues Asp221 ; Leu224; Asn227; Thr231 ; Asp235; Ala237; Leu238; Thr246; Thr247; Ser248; Lys249; Gly250; Ile251 ; His252; Phe253; Asp255 of 15 PGDH, provided as SEQ ID NO: 82, or corresponding residues in a homologous sequence.

[0128] An “antigen binding domain” describes the part of a molecule that binds to all or part of the target antigen. An antibody generally comprises six complementarity-determining regions (CDRs); three in the VH region: HCDR1 , HCDR2 and HCDR3, and three in the VL region: LCDR1 , LCDR2, and LCDR3. The six CDRs together (or specific residues therein) typically define the paratope of the antigen binding domain, which is the part of the antigen binding domain which binds to the target antigen. The paratope of an antibody as described herein may comprise any one or more or all of the VH residues in Table 10, in IMGT numbering. The paratope of an antibody as described herein selected from ATL6026 or a variant or derivative thereof as described herein (including e.g. ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL 0007450, ATL_0007819, ATL_0007820, ATL_0007821 , ATL_0007822, ATL_0007823, ATL 0007824, ATL_0007825, ATL_0007826, ATL_0007827, ATL_0007829, ATL_0007889, ATL 0007890, ATL_0007892, ATL_0007893, ATL_0007896, ATL_0007899, ATL_0007900, ATL 0007901 , ATL_0007902, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955) may comprise any one or more or all of the VH residues listed in Table 10 for ATL6026, in IMGT numbering. These were predicted by in silica modelling. The paratope of an antibody as described herein selected from ATL6026 or a variant or derivative thereof as described herein (including e.g. ATL_0008944, ATL_0008945, ATL 0008946, ATL_0008947, ATL_0007450, ATL_0007819, ATL_0007820, ATL_0007821 , ATL 0007822, ATL_0007823, ATL_0007824, ATL_0007825, ATL_0007826, ATL_0007827, ATL 0007829, ATL_0007889, ATL_0007890, ATL_0007892, ATL_0007893, ATL_0007896, ATL 0007899, ATL_0007900, ATL_0007901 , ATL_0007902, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955) may comprise any one or more or all of the VH residues listed in Table 21 in IMGT numbering for ATL6026 or corresponding residues in variants and derivatives thereof. These were experimentally demonstrated by X-ray crystallography. The paratope of an antibody as described herein selected from ATL6058 or a variant or derivative thereof as described herein (including e.g. ATL_0007926, ATL 0007927, ATL_0007928, ATL_0007929, ATL_0007930, ATL_0007931 , ATL_0007932, ATL 0007933, ATL_0007956, ATL_0007467, ATL_0007468, ATL_0007469, ATL_0007470, ATL_0007471 , ATL_0007472, ATL_0007473) may comprise any one or more or all of the VH residues listed in Table 10 for ATL6058, in IMGT numbering. The paratope of an antibody as described herein may comprise any one or more or all of the VL residues in Table 10, in IMGT numbering. The paratope of an antibody as described herein selected from ATL6026 or a variant or derivative thereof as described herein (including e.g. ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL_0007450,ATL 0007819, ATL 0007820, ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824 ATL 0007825, ATL 0007826, ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890 ATL 0007892, ATL 0007893, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 ATL 0007902, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955) may comprise any one or more or all of the VL residues listed in Table 10 for ATL6026, in IMGT numbering. These were predicted by in silica modelling. The paratope of an antibody as described herein selected from ATL6026 or a variant or derivative thereof as described herein (including e.g. ATL_0008944, ATL_0008945, ATL_0008946, ATL 0008947, ATL 0007450, ATL 0007819, ATL 0007820, ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826, ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902, ATL 0007925, ATL 0007952, ATL 0007953, ATL 0007955) may comprise any one or more or all of the VL residues listed in Table 21 in IMGT numbering for ATL6026 or corresponding residues in variants and derivatives thereof. These were experimentally demonstrated by X-ray crystallography. The paratope of an antibody as described herein selected from ATL6058 or a variant or derivative thereof as described herein (including e.g. ATL_0007926, ATL 0007927, ATL_0007928, ATL_0007929, ATL_0007930, ATL_0007931 , ATL_0007932, ATL 0007933, ATL_0007956, ATL_0007467, ATL_0007468, ATL_0007469, ATL_0007470, ATL_0007471 , ATL_0007472, ATL_0007473) may comprise any one or more or all of the VL residues listed in Table 10 for ATL6058, in IMGT numbering. The paratope of an antibody as described herein may comprise the following VH residues 29, 35, 36, 37, 38, 55, 57, 59, 62, 64, 66, 107, 108, 109, 110, 111 , 111 A, 111 B, 111 C, 112D, 112C, 112B, 112A, 113, 114 in IMGT numbering. In embodiments, the paratope comprises one or more or all of the following VH residues: at position 29, T or S or A; at position 35, T; at position, 36, S; at position 37, Y, at position 38, G or F; at position 55, W; at position 57, S or Y; at position 59, Y or S; at position 62; N or A or Q; at position 64, N or S or A; at position 66, N or S; at position 107, D; at position 108, L; at position 109: G or F; at position 110: P or F; at position 111 Y or G; at position 111 , Y or G; at position 111 A, Y; at position 111 B, Y; at position 111C, D or E; at position 112D, S or A; at position 112C, S; at position 112B, G; at position 112A, Y or S; at position 113, Y; at position 114, H.

[0129] In some embodiments, the paratope comprises the following VH residues 29, 36, 37, 38, 55, 57, 59, 62, 64, 66, 107, 109, 110, 111 , 111 A, 111 B, 111C, 112D, 112C, 112B, 112A, 113, in IMGT numbering. In some embodiments, the paratope comprises the following VH residues: at position 29, T; at position, 36, S; at position 37, Y, at position 38, G; at position 55, W; at position 57, S; at position 59, Y; at position 62; N or A or Q; at position 64, N or A; at position 66, N; at position 107, D; at position 109: G; at position 110: P; at position 111 , Y; at position 111 A, Y; at position 111 B, Y; at position 111 C, D or E; at position 112D, S or A; at position 112C, S; at position 112B, G; at position 112A, Y; at position 113, Y. This may be particularly the case for antibodies of the disclosure that are selected from ATL6026 and variants and derivatives thereof.

[0130] In some embodiments, the paratope comprises the following VH residues 29, 35, 36, 37, 38, 57, 59, 64, 108, 109, 110, 111 , 112A, 114 in IMGT numbering. In some embodiments, the paratope comprises the following VH residues: at position 29, S or A; at position 35, T ; at position, 36, S; at position 37, Y, at position38, F; at position 57, Y; at position 59, S; at position 64, S; at position 108, L; at position 109: F; at position 110: F; at position 111 , G; at position 112A, S; Y; at position 114, H. This may be particularly the case for antibodies of the disclosure that are selected from ATL6058 and variants and derivatives thereof.

[0131] The paratope described herein may comprise the following VL residues: 35, 36, 37, 38, 52, 55, 109, 113, 114 in IMGT numbering. In embodiments, the paratope comprises the following VL residues: at position 35, A; at position 36, G or S; at position 37: Y or S; at position 38: Y or D; at position 52, R or P or L; at position 55, Y; at position 109, N or S or Q or A; at position 113, S or N or A, at position 114, L or S. In embodiments, the paratope comprises VL residues 35, 36, 37, 109, 113, 114 in IMGT numbering. In embodiments, the paratope comprises the following VL residues: at position 35, A; at position 36, G; at position 37, Y; at position 109, N or Q or A; at position 113, S or N or A or Q, at position 114, L. This may be particularly the case for antibodies of the disclosure that are selected from ATL6026 and variants and derivatives thereof.

[0132] In embodiments, the paratope comprises VL residues 36, 38, 52, 55 in IMGT numbering. In embodiments, the paratope comprises the following VL residues: at position 36, S; at position 38: S; at position 52, R; at position 55, Y. This may be particularly the case for antibodies of the disclosure that are selected from ATL6058 and variants and derivatives thereof.

[0133] In some embodiments, the paratope comprises the following VH residues: 29, 36, 37, 59, 108, 111 , 111 A, 111 B, 111 C, 112C, 112D, in IMGT numbering. In some embodiments, the paratope comprises the following VH residues: at position 29, T; at position, 36, S; at position 37, Y, at position 59, Y; at position 108: L; at position 111 , Y; at position 111 A, Y; at position 111 B, Y; at position 111C, D or E; at position 112D, S or A; at position 112C, S. This may be particularly the case for antibodies of the disclosure that are selected from ATL6026 and variants and derivatives thereof. In embodiments, the paratope comprises VL residues 35, 36, 38 in IMGT numbering. In embodiments, the paratope comprises the following VL residues: at position 35, A; at position 36, G; at position 38, D. This may be particularly the case for antibodies of the disclosure that are selected from ATL6026 and variants and derivatives thereof.

[0134] One or more of (or all of) VH residues Thr29, Ser36, Tyr37; Tyr59, Leu108, Tyr111 , Tyr111 A, Tyr111 B, Asp111C, Seri 12C, Seri 12D, may interact with one or more residues of 15-PGDH; and / or one or more of (or all of) VL residues Ala35, Gly36, Asp38, may interact with one or more residues of 15-PGDH. For example, the antibody may comprise a VH with: (i) at position 29: threonine, at position 36: serine, at position 37: tyrosine; at position 59: tyrosine, at position 108: leucine, at position 111 : tyrosine, at position 111 A: tyrosine, at position 111 B: tyrosine, at position 111C: aspartic acid, at position 112C: serine, at position 112D: serine, or (ii) a sequence with conservative amino acid substitutions at one or more of these positions. The antibody may comprise a VL with: (i) at position 35: alanine, at position 36: glycine, at position 38: aspartic acid, or (ii) a sequence with conservative amino acid substitutions at one or more of these positions. In embodiments, residue Y37 of the VH of the antibody (in IMGT numbering) may interact with residue L39 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. A corresponding sequence may be a corresponding mouse or Macaca Fascicularis or rat sequence. In embodiments, residue Y59 of the VH of the antibody (in IMGT numbering)may interact with residue Q44 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y111 of the VH of the antibody (in IMGT numbering) may interact with residue F60 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y111A of the VH of the antibody (in IMGT numbering) may interact with residue K46 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y111 B of the VH of the antibody (in IMGT numbering) may interact with one or more of residues R76, D80, D73, 161 , Q62, F60, K77 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue D111 C of the VH of the antibody (in IMGT numbering) may interact with residue Q62 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue S112D of the VH of the antibody (in IMGT numbering) may interact with residues Q62, T74 and / or Q70 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue S112C of the VH of the antibody (in IMGT numbering) may interact with residue Q70 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue D38 of the VL of the antibody (in IMGT numbering) may interact with residues K77 and / or R76 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue L108 of the VH of the antibody (in IMGT numbering) may interact with residue L39 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue S36 and / or residue T29 of the VH of the antibody (in IMGT numbering) may interact with residue E40 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue S36 and / or residue Y111 A of the VH of the antibody (in IMGT numbering) may interact with residueV43 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y111 and / or residue Y111 A of the VH of the antibody (in IMGT numbering) may interact with residue K46 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y59 of the VH of the antibody (in IMGT numbering) may interact with residue A47 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y111 of the VH of the antibody (in IMGT numbering) may interact with residue L59 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y111 and / or residue Y111 A and / or residue Y111 B of the VH of the antibody (in IMGT numbering) may interact with residue F60 and / or residue 161 , and / or residue D73, and / or residue R76 and / or residue K77 and / or residue D80 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue Y111 B and / or residue D111 C and / or residue S112D of the VH of the antibody (in IMGT numbering) may interact with residue Q62 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue S112D of the VH of the antibody (in IMGT numbering) may interact with residue S63 and / or residue Q70 and / or residue T74 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue S112C of the VH of the antibody (in IMGT numbering) may interact with residue Q70 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residuein a corresponding sequence. In embodiments, residue Y111 of the VH of the antibody (in IMGT numbering) may interactwith residue H81 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue D38 of the VL of the antibody (in IMGT numbering) may interact with residue R76 and / or residue K77 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue G36 of the VL of the antibody (in IMGT numbering) may interact with residue D80 and / or residue H81 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. In embodiments, residue A35 of the VL of the antibody (in IMGT numbering) may interact with residue H81 of human 15-PGDH as defined in SEQ ID NO: 82, or a corresponding residue in a corresponding sequence. Any of the references to residues of antibodies in the present paragraph may refer to residues of ATL6026 or corresponding residues in any variant or derivative thereof (including e.g. ATL_0008944, ATL_0008945, ATL_0008946, ATL 0008947, ATL 0007450, ATL 0007819, ATL 0007820, ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826, ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902, ATL 0007925, ATL 0007952, ATL 0007953, ATL_0007955). The present disclosure relates primarily to antibody molecules, whether whole antibody (e.g. IgG, such as lgG1) or antibody fragments (e.g. single-chain variable fragment (scFv), antibody fragments (Fab) or bivalent antibody fragments (F(ab’)2), single-domain antibody (sdAb). Antibody antigen binding regions (also referred to as “antigen binding portions”) are provided, as are antibody heavy chain variable (VH) and light chain variable (VL) domains. Within VH and VL domains are provided complementarity determining regions (CDRs), which may be provided within different framework regions (FRs), to form VH or VL domains, as the case may be. An antigen binding site may consist of an antibody VH domain and / or a VL domain. Thus, the term “isolated antibody” and “antibody” encompass whole antibody, and fragments thereof that maintain the binding functionality of the full antibody.

[0135] Antibodies according to the present disclosure may be provided in isolated form. The term “antibody” encompasses a fragment or derivative thereof, or a synthetic antibody or antibody fragment.

[0136] The antibody may be an scFv antibody molecule, a nanobody, or a whole antibody. The antibody may comprise an antibody constant region. The antibody may be a whole antibody. The antibody may be an lgG1 or variant thereof. The antibody may be an IgG 1 variant L234A / L235A (LALA) (such as an antibody comprising a constant region as set out in SEQ ID NO: 87). lgG1 variant may have reduced effector function. The antibody may comprise a human lgG1 lambda or kappa constant region. The antibody may comprise a constant region as set out in SEQ ID NO: 88 or SEQ ID NO: 89.

[0137] An antibody or fragment thereof may be a monoclonal antibody (mAb). mAbs are homogenous populations of antibodies specifically targeting a single epitope on an antigen. Antibodies and methods for their construction and use are well-known in the art and are described in, for example, Holliger & Hudson, Nature Biotechnology 23(9):1126-1136 (2005). In view of today’s techniques in relation to monoclonal antibody technology, antibodies can be prepared to most targets. It is possible to take monoclonal and other antibody molecules and use techniques of recombinant DNA technology to produce other antibody or chimeric molecules which retain the specificity of the original antibody. Such techniques may involve introducingCDRs or variable regions of one antibody into a different antibody molecule (see e.g. GB 2188638A and EP0239400).

[0138] A monoclonal monospecific IgG antibody molecule contains two antigen binding domains, each of which are able to bind the same target (i.e. it is bivalent for a single target). A Fab fragment generally comprises a VH domain, a CH1 domain, a VL domain and a CL domain. A full antibody may comprise a pair of Fab fragments and an Fc fragment comprising a pair of chains each comprising a CH2 domain and a CH3 domain. An Fv fragment comprises a VH domain and a VL domain. The VH region and VL region comprise framework regions (FRs) either side of each CDR, which provide a scaffold for the CDRs. From N-terminus to C-terminus, VH regions comprise the following structure: N term-[HFR1]-[HCDR1]-[HFR2]-[HCDR2]-[HFR3]-[HCDR3]-[HFR4]-C term; and VL regions comprise the following structure: N term-[LFR1]-[LCDR1]-[LFR2]-[LCDR2]-[LFR3]-[LCDR3]-[LFR4]-C term.

[0139] The term “ScFv molecules” refers to molecules wherein the VH and VL partner domains are covalently linked, e.g. by a flexible oligopeptide. Fab, Fv, ScFv and sdAb antibody fragments can all be all be expressed and / or secreted from expression systems, such as E.coli and mammalian cells thus allowing the facile production of large amounts of the said fragments.

[0140] Whole antibodies, and F(ab’)2 fragments are “bivalent”. The term “bivalent” means that the said antibodies and F(ab’)2 fragments have two antigen combining sites. In contrast, Fab, Fv, ScFv and sdAb fragments are monovalent, having only one antigen combining site.

[0141] Antibodies according to the present disclosure may be detectably labelled or, at least, capable of detection. For example, the antibody may be labelled with a radioactive atom or a coloured molecule or a fluorescent molecule or a molecule which can be readily detected in any other way. Suitable detectable molecules include fluorescent proteins, luciferase, enzyme substrates, and radiolabels. The binding moiety (antibody or fragment thereof) may be directly labelled with a detectable label or it may be indirectly labelled. For example, the binding moiety may be an unlabelled antibody which can be detected by another antibody which is itself labelled. Alternatively, the second antibody may have bound to it biotin and binding of labelled streptavidin to the biotin is used to indirectly label the first antibody.

[0142] A “fragment” of an antibody may comprise any number of residues of a “parental” antibody, whilst retaining target binding ability. A fragment may lack effector function, for example may be entirely unable to bind or show diminished binding to the Fc receptor, relative to the parent. A fragment is typically smaller than the parental antibody. A fragment may comprise 50%, 60%, 70%, 80%, 90%, 95% or more of the contiguous or non-contiguous amino acids of the parental antibody. A fragment may comprise 50, 100, 150, 200, 250, 300 or more contiguous or non-contiguous amino acids of the parental antibody. A fragment may comprise deletions in the Fc region, or of the Fc region. A fragment may retain the CDRs and / or the variable domains of the parental antibody, unaltered. In some embodiments, a fragment is a Fab fragment or an F(ab’)2 fragment. CDR sequences are described herein using the IMGT numbering (Lefranc, M.-P., Immunology Today, 18, 509 (1997)).

[0143] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: (i) a CDRH1 comprising the sequence of HCDR1_ATL_0008944;HCDR1_ATL_0008945; HCDR1_ATL_0008946; HCDR1_ATL_0008947; HCDR1_ATL_0006026; HCDR1 ATL 0006027; HCDR1_ATL_0006058; HCDR1_ATL_0006074; HCDR1_ATL_0006075; HCDR1 ATL 0007925; HCDR1_ATL_0007952; HCDR1_ATL_0007953; HCDR1_ATL_0007955; HCDR1 ATL 0007933; HCDR1_ATL_0007956; HCDR1_ATL_0007450; HCDR1_ATL_0007819; HCDR1 ATL 0007820; HCDR1_ATL_0007821 ; HCDR1_ATL_0007822; HCDR1_ATL_0007823; HCDR1 ATL 0007824; HCDR1_ATL_0007825; HCDR1_ATL_0007826; HCDR1_ATL_0007827; HCDR1 ATL 0007829; HCDR1_ATL_0007889; HCDR1_ATL_0007890; HCDR1_ATL_0007892; HCDR1 ATL 0007893; HCDR1_ATL_0007895; HCDR1_ATL_0007896; HCDR1_ATL_0007899; HCDR1 ATL 0007900; HCDR1_ATL_0007901 ; HCDR1_ATL_0007902; HCDR1_ATL_0007917; HCDR1 ATL 0007918; HCDR1_ATL_0007919; HCDR1_ATL_0007920; HCDR1_ATL_0007921 ; HCDR1 ATL 0007922; HCDR1_ATL_0007923; HCDR1_ATL_0007924; HCDR1_ATL_0007926, HCDR1 ATL 0007927, HCDR1_ATL_0007928, HCDR1_ATL_0007929, HCDR1_ATL_0007930, HCDR1 ATL 0007931 , HCDR1_ATL_0007932, HCDR1_ATL_0007933, HCDR1_ATL_0007956, HCDR1 ATL 0007467, HCDR1_ATL_0007468, HCDR1_ATL_0007469, HCDR1_ATL_0007470, HCDR1_ATL_0007471, HCDR1_ATL_0007472; or HCDR1_ATL_0007473; and (ii) a CDRH2 comprising the sequence of HCDR2_ATL_0008944; HCDR2_ATL_0008945; HCDR2_ATL_0008946; HCDR2 ATL 0008947; HCDR2_ATL_0006026; HCDR2_ATL_0006027; HCDR2_ATL_0006058; HCDR2 ATL 0006074; HCDR2_ATL_0006075; HCDR2_ATL_0007925; HCDR2_ATL_0007952; HCDR2 ATL 0007953; HCDR2_ATL_0007955; HCDR2_ATL_0007933; HCDR2_ATL_0007956; HCDR2 ATL 0007450; HCDR2_ATL_0007819; HCDR2_ATL_0007820; HCDR2_ATL_0007821 ; HCDR2 ATL 0007822; HCDR2_ATL_0007823; HCDR2_ATL_0007824; HCDR2_ATL_0007825; HCDR2 ATL 0007826; HCDR2_ATL_0007827; HCDR2_ATL_0007829; HCDR2_ATL_0007889; HCDR2 ATL 0007890; HCDR2_ATL_0007892; HCDR2_ATL_0007893; HCDR2_ATL_0007895; HCDR2 ATL 0007896; HCDR2_ATL_0007899; HCDR2_ATL_0007900; HCDR2_ATL_0007901 ; HCDR2 ATL 0007902; HCDR2_ATL_0007917; HCDR2_ATL_0007918; HCDR2_ATL_0007919; HCDR2 ATL 0007920; HCDR2_ATL_0007921 ; HCDR2_ATL_0007922; HCDR2_ATL_0007923; HCDR2 ATL 0007924; HCDR2_ATL_0007926, HCDR2_ATL_0007927, HCDR2_ATL_0007928, HCDR2 ATL 0007929, HCDR2_ATL_0007930, HCDR2_ATL_0007931 , HCDR2_ATL_0007932, HCDR2 ATL 0007933, HCDR2_ATL_0007956, HCDR2_ATL_0007467, HCDR2_ATL_0007468, HCDR2 ATL 0007469, HCDR2_ATL_0007470, HCDR2_ATL_0007471 , HCDR2_ATL_0007472; or HCDR2_ATL_0007473 and (iii) a CDRH3 comprising the sequence of HCDR3_ATL_0008944; HCDR3_ATL_0008945; HCDR3_ATL_0008946; HCDR3_ATL_0008947; HCDR3_ATL_0006026; HCDR3_ATL_0006027; HCDR3_ATL_0006058; HCDR3_ATL_0006074; HCDR3_ATL_0006075; HCDR3_ATL_0007925; HCDR3_ATL_0007952; HCDR3_ATL_0007953; HCDR3_ATL_0007955; HCDR3_ATL_0007933; HCDR3_ATL_0007956; HCDR3_ATL_0007450; HCDR3_ATL_0007819; HCDR3_ATL_0007820; HCDR3_ATL_0007821 ; HCDR3_ATL_0007822; HCDR3_ATL_0007823; HCDR3_ATL_0007824; HCDR3_ATL_0007825; HCDR3_ATL_0007826; HCDR3_ATL_0007827; HCDR3_ATL_0007829; HCDR3_ATL_0007889; HCDR3_ATL_0007890; HCDR3_ATL_0007892; HCDR3_ATL_0007893; HCDR3_ATL_0007895; HCDR3_ATL_0007896; HCDR3_ATL_0007899; HCDR3_ATL_0007900; HCDR3_ATL_0007901 ; HCDR3_ATL_0007902; HCDR3_ATL_0007917;HCDR3_ATL_0007918; HCDR3_ATL_0007919; HCDR3_ATL_0007920; HCDR3_ATL_0007921 ; HCDR3_ATL_0007922; HCDR3_ATL_0007923; HCDR3_ATL_0007924; HCDR3_ATL_0007926, HCDR3_ATL_0007927, HCDR3_ATL_0007928, HCDR3_ATL_0007929, HCDR3_ATL_0007930, HCDR3_ATL_0007931 , HCDR3_ATL_0007932, HCDR3_ATL_0007933, HCDR3_ATL_0007956, HCDR3_ATL_0007467, HCDR3_ATL_0007468, HCDR3_ATL_0007469, HCDR3_ATL_0007470, HCDR3_ATL_0007471 , HCDR3_ATL_0007472; or HCDR3_ATL_0007473.

[0144] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: (i) a CDRH1 comprising the sequence of HCDR1_ATL_0008944; HCDR1 ATL 0008945; HCDR1_ATL_0008946; HCDR1_ATL_0008947; HCDR1_ATL_0006026; HCDR1 ATL 0006058; HCDR1_ATL_0007925; HCDR1_ATL_0007952; HCDR1_ATL_0007953; HCDR1 ATL 0007955; HCDR1_ATL_0007933; or HCDR1_ATL_0007956; and (ii) a CDRH2 comprising the sequence of HCDR2_ATL_0008944; HCDR2_ATL_0008945; HCDR2_ATL_0008946; HCDR2 ATL 0008947; HCDR2_ATL_0006026; HCDR2_ATL_0006058; HCDR2_ATL_0007925; HCDR2 ATL 0007952; HCDR2_ATL_0007953; HCDR2_ATL_0007955; HCDR2_ATL_0007933; or HCDR2_ATL_0007956; and (iii) a CDRH3 comprising the sequence of HCDR3_ATL_0008944; HCDR3_ATL_0008945; HCDR3_ATL_0008946; HCDR3_ATL_0008947; HCDR3_ATL_0006026; HCDR3_ATL_0006058; HCDR3_ATL_0007925; HCDR3_ATL_0007952; HCDR3_ATL_0007953; HCDR3_ATL_0007955; HCDR3_ATL_0007933; or HCDR3_ATL_0007956.

[0145] An antibody according to the present disclosure may have a CDRH1 that is 8 to 10 amino acids in length. An antibody according to the present disclosure may have a CDRH2 that is 7 or 8 amino acids in length. An antibody according to the present disclosure may have a CDRH3 that is 14 to 20 amino acids in length. An antibody according to the present disclosure may have a CDRH1 comprising the sequence of HCDR1_ATL_0006058, or a sequence comprising 1 to 5 mutations, such as substitutions, compared to said sequence. The mutations, such as substitutions, may be at position 28 and / or position 29 (e.g. D28E and / or S29A).

[0146] An antibody according to the present disclosure may have a CDRH1 comprising the sequence of HCDR1_ATL_0006026, or a sequence comprising 1 to 4, mutations, such as substitutions, compared to said sequence. The mutations, such as substitutions, may be at any position that is not positions 27 and 37 (IMGT numbering). An antibody according to the present disclosure may have a CDRH1 with a G at position 27 and a Y at position 37 (IMGT numbering).

[0147] An antibody according to the present disclosure may have a CDRH2 comprising the sequence of HCDR2_ATL_0006058, or a sequence comprising 1 to 6 substitutions compared to said sequence.

[0148] An antibody according to the present disclosure may have a CDRH2 comprising the sequence of HCDR2_ATL_0006026, or a sequence comprising 1 to 6 substitutions compared to said sequence. The antibody may have an I at position 56, a G at position 63, and / or a T at position 65. The mutations, such as substitutions may be at position 62 (e.g. N62A or N62Q), position 63 (e.g. G63A) position 64 (e.g. N64A) and / or position 65 (e.g. T65A or T65S).An antibody according to the present disclosure may have a CDRH3 comprising the sequence of HCDR3_ATL_0006058, or a sequence comprising 1 to 5 substitutions compared to said sequence.

[0149] An antibody according to the present disclosure may have a CDRH3 comprising the sequence of HCDR3_ATL_0006026, or a sequence comprising 1 to 5 substitutions compared to said sequence. The substitutions may be at any position that is not positions 105, 115 and 166 (IMGT numbering). Position 105 may be a G. Position 106 may be an R. Position 115 may be a F. Position 116 may be a D. The mutations, such as substitutions may be at position 111C (e.g. D111CE) and / or at position 112D (e.g. S112DA). An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0006026, a CDRH2 comprising the sequence of HCDR2_ATL_0006026, and a CDRH3 comprising the sequence of HCDR3_ATL_0006026, or a set of CDRs comprising 1 to 6 mutations (total of 1 to 6 mutations over all CDRs) compared to these sequences.

[0150] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0007925, a CDRH2 comprising the sequence of HCDR2_ATL_0007925, and a CDRH3 comprising the sequence of HCDR3_ATL_0007925, or a set of CDRs comprising 1 to 6 mutations (total of 1 to 6 mutations over all CDRs) compared to these sequences.

[0151] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0007952, a CDRH2 comprising the sequence of HCDR2_ATL_0007952, and a CDRH3 comprising the sequence of HCDR3_ATL_0007952, or a set of CDRs comprising 1 to 6 mutations (total of 1 to 6 mutations over all CDRs) compared to these sequences.

[0152] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0007953, a CDRH2 comprising the sequence of HCDR2_ATL_0007953, and a CDRH3 comprising the sequence of HCDR3_ATL_0007953, or a set of CDRs comprising 1 to 6 mutations (total of 1 to 6 mutations over all CDRs) compared to these sequences.

[0153] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0007955, a CDRH2 comprising the sequence of HCDR2_ATL_0007955, and a CDRH3 comprising the sequence of HCDR3_ATL_0007955, or a set of CDRs comprising 1 to 6 mutations (total of 1 to 6 mutations over all CDRs) compared to these sequences.

[0154] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0006058, a CDRH2 comprising the sequence of HCDR2_ATL_0006058, and a CDRH3 comprising the sequence of HCDR3_ATL_0006058, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0007933, a CDRH2 comprising the sequence of HCDR2_ATL_0007933, and a CDRH3 comprising the sequence of HCDR3_ATL_0007933, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0155] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ATL_0007956, a CDRH2 comprising the sequence of HCDR2_ATL_0007956, and a CDRH3 comprising the sequence of HCDR3_ATL_0007956, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0156] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ ATL 0008944, a CDRH2 comprising the sequence of HCDR2_ ATL_0008944, and a CDRH3 comprising the sequence of HCDR3_ ATL_0008944, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0157] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ ATL 0008945, a CDRH2 comprising the sequence of HCDR2_ ATL_0008945, and a CDRH3 comprising the sequence of HCDR3_ ATL_0008945, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0158] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ ATL 0008946, a CDRH2 comprising the sequence of HCDR2_ ATL_0008946, and a CDRH3 comprising the sequence of HCDR3_ ATL_0008946, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0159] An antibody according to the present disclosure may comprise a heavy chain variable domain (VH) with the following CDRs: a CDRH1 comprising the sequence of HCDR1_ ATL 0008947, a CDRH2 comprising the sequence of HCDR2_ ATL_0008947, and a CDRH3 comprising the sequence of HCDR3_ ATL_0008947, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0160] Mutations as used herein refers to amino acid substitutions, insertions, or deletions. Mutations may be introduced by standard techniques, such as site-directed mutagenesis, PCR-mediated mutagenesis and gene synthesis.

[0161] The antibodies of the disclosure explicitly encompass combinations of any of the VH of antibodies ATL 0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL_0006026, ATL_0006027, ATL 0006058, ATL_0006074, ATL_0006075, ATL_0007925, ATL_0007952, ATL_0007953, ATL 0007955, ATL_0007933, ATL_0007956, ATL_0007450, ATL_0007819, ATL_0007820, ATL_0007821, ATL_0007822, ATL_0007823, ATL_0007824, ATL_0007825, ATL_0007826,ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893 ATL 0007895, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902 ATL 0007917, ATL 0007918, ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922 ATL 0007923, ATL 0007924, ATL 0007926, ATL 0007927, ATL 0007928, ATL 0007929 ATL 0007930, ATL 0007931 , ATL 0007932, ATL 0007933, ATL 0007956, ATL 0007467 ATL 0007468, ATL 0007469, ATL 0007470, ATL 0007471 , ATL 0007472, ATL 0007473 (i.e ATL 0008944 VH, ATL 0008945 VH, ATL 0008946 VH, ATL 0008947 VH, ATL 0006026 VH ATL 0006027 VH, ATL 0006058 VH, ATL 0006074 VH, ATL 0006075 VH, ATL 0007925 VH ATL 0007952 VH, ATL 0007953 VH, ATL 0007955 VH, ATL 0007933 VH, ATL 0007956 VH ATL 0007450 VH, ATL 0007819 VH, ATL 0007820 VH, ATL 0007821 VH, ATL 0007822 VH ATL 0007823 VH, ATL 0007824 VH, ATL 0007825 VH, ATL 0007826 VH, ATL 0007827 VH ATL 0007829 VH, ATL 0007889 VH, ATL 0007890 VH, ATL 0007892 VH, ATL 0007893 VH ATL 0007895 VH, ATL 0007896 VH, ATL 0007899 VH, ATL 0007900 VH, ATL 0007901 VH ATL 0007902 VH, ATL 0007917 VH, ATL 0007918 VH, ATL 0007919 VH, ATL 0007920 VH ATL 0007921 VH, ATL 0007922 VH, ATL 0007923 VH, ATL 0007924 VH, ATL 0007926 VH ATL 0007927 VH, ATL 0007928 VH, ATL 0007929 VH, ATL 0007930 VH, ATL 0007931 VH ATL 0007932 VH, ATL 0007933 VH, ATL 0007956 VH, ATL 0007467 VH, ATL 0007468 VH ATL 0007469 VH, ATL_0007470 VH, ATL_0007471 VH, ATL 0007472 VH, ATL_0007473 VH) with any of the VL of ATL 0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL_0006026, ATL_0006027, ATL 0006058, ATL 0006074, ATL 0006075, ATL 0007925, ATL 0007952, ATL 0007953 ATL 0007955, ATL 0007933, ATL 0007956, ATL 0007450, ATL 0007819, ATL 0007820 ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826 ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893 ATL 0007895, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902 ATL 0007917, ATL 0007918, ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922 ATL 0007923, ATL 0007924, ATL 0007926, ATL 0007927, ATL 0007928, ATL 0007929 ATL 0007930, ATL 0007931 , ATL 0007932, ATL 0007933, ATL 0007956, ATL 0007467 ATL 0007468, ATL_0007469, ATL_0007470, ATL_0007471 , ATL_0007472, ATL_0007473 i.e ATL 0008944 VL, ATL 0008945 VL, ATL 0008946 VL, ATL 0008947 VL, ATL 0006026 VL, ATL 0006027 VL, ATL 0006058 VL, ATL 0006074 VL, ATL 0006075 VL, ATL 0007925 VL, ATL 0007952 VL, ATL 0007953 VL, ATL 0007955 VL, ATL 0007933 VL, ATL 0007956 VL, ATL 0007450 VL, ATL 0007819 VL, ATL 0007820 VL, ATL 0007821 VL, ATL 0007822 VL, ATL 0007823 VL, ATL 0007824 VL, ATL 0007825 VL, ATL 0007826 VL, ATL 0007827 VL, ATL 0007829 VL, ATL 0007889 VL, ATL 0007890 VL, ATL 0007892 VL, ATL 0007893 VL, ATL 0007895 VL, ATL 0007896 VL, ATL 0007899 VL, ATL 0007900 VL, ATL 0007901 VL, ATL 0007902 VL, ATL 0007917 VL, ATL 0007918 VL, ATL 0007919 VL, ATL 0007920 VL, ATL 0007921 VL, ATL 0007922 VL, ATL 0007923 VL, ATL 0007924 VL, ATL 0007926 VL, ATL 0007927 VL, ATL 0007928 VL, ATL 0007929 VL, ATL 0007930 VL, ATL 0007931 VL, ATL 0007932 VL, ATL 0007933 VL, ATL 0007956 VL, ATL 0007467 VL, ATL 0007468 VL, ATL 0007469 VL, ATL_0007470 VL, ATL 0007471 VL, ATL_0007472 VL, ATL_0007473 VL).The antibodies of the disclosure explicitly encompass antibodies comprising a VH with all 3 CDRH of antibodies ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL_0006026, ATL_0006027, ATL 0006058, ATL 0006074, ATL 0006075, ATL 0007925, ATL 0007952, ATL 0007953, ATL 0007955, ATL 0007933, ATL 0007956, ATL 0007450, ATL 0007819, ATL 0007820, ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826, ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893, ATL 0007895, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902, ATL 0007917, ATL 0007918, ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922, ATL 0007923, ATL 0007924, ATL 0007926, ATL 0007927, ATL 0007928, ATL 0007929, ATL 0007930, ATL 0007931 , ATL 0007932, ATL 0007933, ATL 0007956, ATL 0007467, ATL 0007468, ATL 0007469, ATL 0007470, ATL 0007471 , ATL 0007472, ATL 0007473; in combination with a VL comprising all 3 CDRL any of the VL of ATL_0008944, ATL_0008945, ATL 0008946, ATL 0008947, ATL 0006026, ATL 0006027, ATL 0006058, ATL 0006074 ATL 0006075, ATL 0007925, ATL 0007952, ATL 0007953, ATL 0007955, ATL 0007933 ATL 0007956 ATL 0007450, ATL 0007819, ATL 0007820, ATL 0007821 , ATL 0007822 ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826, ATL 0007827, ATL 0007829 ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893, ATL 0007895, ATL 0007896 ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902, ATL 0007917, ATL 0007918 ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922, ATL 0007923, ATL 0007924 ATL 0007926, ATL 0007927, ATL 0007928, ATL 0007929, ATL 0007930, ATL 0007931 ATL 0007932, ATL 0007933, ATL 0007956, ATL 0007467, ATL 0007468, ATL 0007469 ATL 0007470, ATL_0007471 , ATL_0007472, ATL_0007473.

[0162] In an antibody according to the present disclosure, at least one of the VH CDR1 -3 sequences may vary. A variant may have one, two, three, four, five or six (e.g. one, two, or three) amino acid mutations, such as substitutions, compared with the set of VH CDR1 -3 described above. A variant may have one to six (e.g. one to three) amino acid mutations, such as substitutions, compared with the set of VH CDR1 -3 described above. Substitutions may be present at any one or more of the following positions: In HCDR1 : 28 (e.g. D28E), 29 (e.g. S29A); and / or in HCDR2: 62 (e.g. N62A or N62Q), 63 (e.g. G63A), 64 (e.g. N64A), 65 (e.g. T65A or T65S); and / or in HCDR3: 1 1 1 C (e.g. D1 1 1 CE), 1 12D (e.g. S1 12DA). Substitutions in antibodies that have HCDRs based on the HCDRs of ATL_0006058 including one or more substitutions as described herein may include substitutions at the following positions: 28 (e.g. D28E), and / or 29 (e.g. S29A) (both in HCDR1 ). Substitutions in antibodies that have HCDRs based on the HCDRs of ATL_0006026 including one or more substitutions as described herein may include substitutions at the following positions: in HCDR2: 62 (e.g. N62A or N62Q), 63 (e.g. G63A), 64 (e.g. N64A), and / or 65 (e.g. T65A or T65S); and / or in HCDR3: 1 1 1 C (e.g. D1 1 1 CE), 1 12D (e.g. S1 12DA).

[0163] In embodiments, an antibody according to the present disclosure comprises CDRs with sequences that each have zero, one, two or three, mutations, such as substitutions compared with VH CDR sequences of any antibody described herein. For example, an antibody according to the disclosure may comprise VH CDRs with the sequences of any antibody above, except that one, two or each of the CDRHs comprise asubstitution, where the total number of substitutions across CDRHs does not exceed 3. In embodiments, a variant may have one, two or three substitutions, preferably at most one or two substitutions in each of one or more of the VH CDR1-3 described above. CDRH1 regions of any antibodies or fragments described herein may have a length of 7 or 8 amino acids. CDRH2 regions of any antibodies or fragments described herein may have a length of 7 or 8 amino acids. CDRH3 regions of any antibodies or fragments described herein may have a length of 14, 15, 17, or 20 amino acids. In embodiments, a variant may have VH CDRs that have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity sequence identity with any set of VH CDRs described herein.

[0164] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: (i) a CDRL1 comprising the sequence of LCDR1_ATL_0008944;

[0165] LCDR1 ATL 0008945; LCDR1_ATL_0008946; LCDR1_ATL_0008947; LCDR1_ATL_0006026;

[0166] LCDR1 ATL 0006027; LCDR1_ATL_0006058; LCDR1_ATL_0006074; LCDR1_ATL_0006075;

[0167] LCDR1 ATL 0007925; LCDR1_ATL_0007952; LCDR1_ATL_0007953; LCDR1_ATL_0007955;

[0168] LCDR1 ATL 0007933; LCDR1_ATL_0007956; LCDR1_ATL_0007450; LCDR1_ATL_0007819;

[0169] LCDR1 ATL 0007820; LCDR1_ATL_0007821 ; LCDR1_ATL_0007822; LCDR1_ATL_0007823;

[0170] LCDR1 ATL 0007824; LCDR1_ATL_0007825; LCDR1_ATL_0007826; LCDR1_ATL_0007827;

[0171] LCDR1 ATL 0007829; LCDR1_ATL_0007889; LCDR1_ATL_0007890; LCDR1_ATL_0007892;

[0172] LCDR1 ATL 0007893; LCDR1_ATL_0007895; LCDR1_ATL_0007896; LCDR1_ATL_0007899;

[0173] LCDR1 ATL 0007900; LCDR1_ATL_0007901 ; LCDR1_ATL_0007902; LCDR1_ATL_0007917;

[0174] LCDR1 ATL 0007918; LCDR1_ATL_0007919; LCDR1_ATL_0007920; LCDR1_ATL_0007921 ;

[0175] LCDR1 ATL 0007922; LCDR1_ATL_0007923; LCDR1_ATL_0007924; LCDR1_ATL_0007926, LCDR1 ATL 0007927, LCDR1_ATL_0007928, LCDR1_ATL_0007929, LCDR1_ATL_0007930, LCDR1_ATL_0007931 , LCDR1_ATL_0007932, LCDR1_ATL_0007933, LCDR1_ATL_0007956, LCDR1 ATL 0007467, LCDR1_ATL_0007468, LCDR1_ATL_0007469, LCDR1_ATL_0007470, LCDR1 ATL 0007471 , LCDR1_ATL_0007472; or LCDR1_ATL_0007473; and (ii) a CDRL2 comprising the sequence of LCDR2_ATL_0008944; LCDR2_ATL_0008945; LCDR2_ATL_0008946;

[0176] LCDR2 ATL 0008947; LCDR2_ATL_0006026; LCDR2_ATL_0006027; LCDR2_ATL_0006058;

[0177] LCDR2 ATL 0006074; LCDR2_ATL_0006075; LCDR2_ATL_0007925; LCDR2_ATL_0007952;

[0178] LCDR2 ATL 0007953; LCDR2_ATL_0007955; LCDR2_ATL_0007933; LCDR2_ATL_0007956;

[0179] LCDR2 ATL 0007450; LCDR2_ATL_0007819; LCDR2_ATL_0007820; LCDR2_ATL_0007821 ;

[0180] LCDR2 ATL 0007822; LCDR2_ATL_0007823; LCDR2_ATL_0007824; LCDR2_ATL_0007825;

[0181] LCDR2 ATL 0007826; LCDR2_ATL_0007827; LCDR2_ATL_0007829; LCDR2_ATL_0007889;

[0182] LCDR2 ATL 0007890; LCDR2_ATL_0007892; LCDR2_ATL_0007893; LCDR2_ATL_0007895;

[0183] LCDR2 ATL 0007896; LCDR2_ATL_0007899; LCDR2_ATL_0007900; LCDR2_ATL_0007901 ;

[0184] LCDR2 ATL 0007902; LCDR2_ATL_0007917; LCDR2_ATL_0007918; LCDR2_ATL_0007919;

[0185] LCDR2 ATL 0007920; LCDR2_ATL_0007921 ; LCDR2_ATL_0007922; LCDR2_ATL_0007923;

[0186] LCDR2 ATL 0007924; LCDR2_ATL_0007926, LCDR2_ATL_0007927, LCDR2_ATL_0007928, LCDR2 ATL 0007929, LCDR2_ATL_0007930, LCDR2_ATL_0007931 , LCDR2_ATL_0007932, LCDR2 ATL 0007933, LCDR2_ATL_0007956, LCDR2_ATL_0007467, LCDR2_ATL_0007468, LCDR2 ATL 0007469, LCDR2_ATL_0007470, LCDR2_ATL_0007471 , LCDR2_ATL_0007472; orLCDR2_ATL_0007473; and (iii) a CDRL3 comprising the sequence of LCDR3_ATL_0008944;

[0187] LCDR3_ATL_0008945; LCDR3_ATL_0008946; LCDR3_ATL_0008947; LCDR3_ATL_0006026;

[0188] LCDR3_ATL_0006027; LCDR3_ATL_0006058; LCDR3_ATL_0006074; LCDR3_ATL_0006075;

[0189] LCDR3_ATL_0007925; LCDR3_ATL_0007952; LCDR3_ATL_0007953; LCDR3_ATL_0007955;

[0190] LCDR3_ATL_0007933; LCDR3_ATL_0007956; LCDR3_ATL_0007450; LCDR3_ATL_0007819;

[0191] LCDR3_ATL_0007820; LCDR3_ATL_0007821 ; LCDR3_ATL_0007822; LCDR3_ATL_0007823;

[0192] LCDR3_ATL_0007824; LCDR3_ATL_0007825; LCDR3_ATL_0007826; LCDR3_ATL_0007827;

[0193] LCDR3_ATL_0007829; LCDR3_ATL_0007889; LCDR3_ATL_0007890; LCDR3_ATL_0007892;

[0194] LCDR3_ATL_0007893; LCDR3_ATL_0007895; LCDR3_ATL_0007896; LCDR3_ATL_0007899;

[0195] LCDR3_ATL_0007900; LCDR3_ATL_0007901 ; LCDR3_ATL_0007902; LCDR3_ATL_0007917;

[0196] LCDR3_ATL_0007918; LCDR3_ATL_0007919; LCDR3_ATL_0007920; LCDR3_ATL_0007921 ;

[0197] LCDR3_ATL_0007922; LCDR3_ATL_0007923; LCDR3_ATL_0007924; LCDR3_ATL_0007926, LCDR3_ATL_0007927, LCDR3_ATL_0007928, LCDR3_ATL_0007929, LCDR3_ATL_0007930, LCDR3_ATL_0007931 , LCDR3_ATL_0007932, LCDR3_ATL_0007933, LCDR3_ATL_0007956, LCDR3_ATL_0007467, LCDR3_ATL_0007468, LCDR3_ATL_0007469, LCDR3_ATL_0007470, LCDR3_ATL_0007471 , LCDR3_ATL_0007472; or LCDR3_ATL_0007473.

[0198] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: (i) a CDRL1 comprising the sequence of LCDR1_ATL_0008944; LCDR1_ATL_0008945; LCDR1 ATL 0008946; LCDR1_ATL_0008947; LCDR1_ATL_0006026; LCDR1_ATL_0006058; LCDR1 ATL 0007925; LCDR1_ATL_0007952; LCDR1_ATL_0007953; LCDR1_ATL_0007955; LCDR1_ATL_0007933; or LCDR1_ATL_0007956; and (ii) a CDRL2 comprising the sequence of LCDR2 ATL 0008944; LCDR2_ATL_0008945; LCDR2_ATL_0008946; LCDR2_ATL_0008947 LCDR2 ATL 0006026; LCDR2_ATL_0006058; LCDR2_ATL_0007925; LCDR2_ATL_0007952; LCDR2 ATL 0007953; LCDR2_ATL_0007955; LCDR2_ATL_0007933; or LCDR2_ATL_0007956; and (iii) a CDRL3 comprising the sequence of LCDR3_ATL_0008944; LCDR3_ATL_0008945; LCDR3_ATL_0008946; LCDR3_ATL_0008947; LCDR3_ATL_0006026; LCDR3_ATL_0006058; LCDR3_ATL_0007925; LCDR3_ATL_0007952; LCDR3_ATL_0007953; LCDR3_ATL_0007955; LCDR3_ATL_0007933; or LCDR3_ATL_0007956.

[0199] An antibody according to the present disclosure may have a CDRL1 that is 5 to 8 amino acids in length. An antibody according to the present disclosure may have a CDRL2 that is 3 amino acids in length. An antibody according to the present disclosure may have a CDRL3 that is 9 or 10 amino acids in length.

[0200] An antibody according to the present disclosure may have a CDRL1 comprising the sequence of LCDR1_ATL_0006058, or a sequence comprising 1 or 2 mutations, such as substitutions, compared to said sequence.

[0201] An antibody according to the present disclosure may have a CDRL1 comprising the sequence of LCDR1_ATL_0006026, or a sequence comprising 1 or 2, mutations, such as substitutions compared to said sequence. The antibody may have an S at position 28.An antibody according to the present disclosure may have a CDRL2 comprising the sequence of LCDR2_ATL_0006058, or a sequence comprising 1 or 2, mutations, such as substitutions, compared to said sequence.

[0202] An antibody according to the present disclosure may have a CDRL2 comprising the sequence of LCDR2_ATL_0006026, or a sequence comprising 1 or 2 mutations, such as substitutions compared to said sequence. The antibody may have a substitution at position 57, e.g. N57A or N57Q and / or at position 65, e.g. S65N or S65A. The antibody may have a G at position 56 and / or an S at position 65.

[0203] An antibody according to the present disclosure may have a CDRL3 comprising the sequence of LCDR3_ATL_0006058, or a sequence comprising 1 to 5 mutations, such as substitutions compared to said sequence.

[0204] An antibody according to the present disclosure may have a CDRL3 comprising the sequence of LCDR3_ATL_0006026, or a sequence comprising 1 to 5 mutations, such as substitutions, compared to said sequence. The antibody may have a Q at position 105. The antibody may have a substitution at position 109, e.g N109Q or N109A, and / or at position 113, e.g S113N or S113A or S113Q.

[0205] In an antibody according to the present disclosure at least one of the VL CDR1-3 sequences may vary. A variant may have 1 , 2, or 3 amino acid mutations, such as substitutions compared with the set of VL CDR1 -3 described above. In embodiments, the mutations do not include a mutation at position 109 or position 113 in standard IMGT numbering. For example, the mutations may not include a mutation in CDRL3. In embodiments, an antibody according to the disclosure comprises CDRs with sequences that have between 1 and 3 mutations, such as substitutions, compared with the VL CDR sequences of an antibody described herein. For example, an antibody according to the disclosure may comprise a mutation, such as a substitution, where the total number of mutations, such as substitutions, does not exceed 3. In embodiments, a variant may have one, two or three, preferably at most one or two mutations, such as substitutions, in each of one or more of the VL CDR1-3 described above. The antibody may have substitutions at the following positions compared to the sequences described herein: (i) In the LCDR2: position 57 (e.g. N57A or N57Q), position 65 (e.g. S65N or S65A): and / or (ii) In the LCDR3: position 109 (e.g. N109Q or N109A); position 113 (e.g. S113N or S113A or S113Q).

[0206] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0006026, a CDRL2 comprising the sequence of LCDR2_ATL_0006026, and a CDRL3 comprising the sequence of LCDR3_ATL_0006026, or a set of CDRs comprising 1 to 4 mutations (total of 1 to 4 mutations over all CDRs) compared to these sequences.

[0207] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0007925, a CDRL2 comprising the sequence of LCDR2_ATL_0007925, and a CDRL3 comprising the sequence of LCDR3_ATL_0007925, or a set of CDRs comprising 1 to 4 mutations (total of 1 to 4 mutations over all CDRs) compared to these sequences.An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0007952, a CDRL2 comprising the sequence of LCDR2_ATL_0007952, and a CDRL3 comprising the sequence of LCDR3_ATL_0007952, or a set of CDRs comprising 1 to 4 mutations (total of 1 to 4 mutations over all CDRs) compared to these sequences.

[0208] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0007953, a CDRL2 comprising the sequence of LCDR2_ATL_0007953, and a CDRL3 comprising the sequence of LCDR3_ATL_0007953, or a set of CDRs comprising 1 to 4 mutations (total of 1 to 4 mutations over all CDRs) compared to these sequences.

[0209] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0007955, a CDRL2 comprising the sequence of LCDR2_ATL_0007955, and a CDRL3 comprising the sequence of LCDR3_ATL_0007955, or a set of CDRs comprising 1 to 4 mutations (total of 1 to 4 mutations over all CDRs) compared to these sequences.

[0210] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0006058, a CDRL2 comprising the sequence of LCDR2_ATL_0006058, and a CDRL3 comprising the sequence of LCDR3_ATL_0006058, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0211] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0007933, a CDRL2 comprising the sequence of LCDR2_ATL_0007933, and a CDRL3 comprising the sequence of LCDR3_ATL_0007933, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0212] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ATL_0007956, a CDRL2 comprising the sequence of LCDR2_ATL_0007956, and a CDRL3 comprising the sequence of LCDR3_ATL_0007956, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences.

[0213] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ ATL_0008944, a CDRL2 comprising the sequence of LCDR2_ ATL_0008944, and a CDRL3 comprising the sequence of LCDR3_ ATL_0008944, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences. In embodiments, the mutations do not include a mutation at position 109 or position 113 in standard IMGT numbering. For example, the mutations may not include a mutation in CDRL3.An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ ATL_0008945, a CDRL2 comprising the sequence of LCDR2_ ATL_0008945, and a CDRL3 comprising the sequence of LCDR3_ ATL_0008945, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences. In embodiments, the mutations do not include a mutation at position 109 or position 113 in standard IMGT numbering. For example, the mutations may not include a mutation in CDRL3.

[0214] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ ATL_0008946, a CDRL2 comprising the sequence of LCDR2_ ATL_0008946, and a CDRL3 comprising the sequence of LCDR3_ ATL_0008946, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences. In embodiments, the mutations do not include a mutation at position 109 or position 113 in standard IMGT numbering. For example, the mutations may not include a mutation in CDRL3.

[0215] An antibody according to the present disclosure may comprise a light chain variable domain (VL) with the following CDRs: a CDRL1 comprising the sequence of LCDR1_ ATL_0008947, a CDRL2 comprising the sequence of LCDR2_ ATL_0008947, and a CDRL3 comprising the sequence of LCDR3_ ATL_0008947, or a set of CDRs comprising one, two, or three mutations (total of one, two, or three mutations over all CDRs) compared to these sequences. In embodiments, the mutations do not include a mutation at position 109 or position 113 in standard IMGT numbering. For example, the mutations may not include a mutation in CDRL3.

[0216] The VH CDRs 1-3 and optionally VL CDRs 1-3 of any of the antibodies described above may also be particularly useful in conjunction with a number of different framework regions.

[0217] Accordingly, light and / or heavy chains having CDRs 1-3 as described above may possess an alternative framework region. Suitable framework regions are known in the art and are described for example in M. Lefranc & G. Le Franc (2001) “The Immunoglobulin Facts Book”, Academic Press.

[0218] An antibody of the disclosure may have the CDRH1 , CDRH2 and CDRH3 of the VH domain within a germline framework. An antibody of the disclosure may have a light chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibodies ATL_0008944, ATL_0008945, ATL 0008946, ATL 0008947, ATL 0006026, ATL 0006027, ATL 0006074, ATL 0006075, ATL 0006058, ATL 0007925, ATL 0007952, ATL 0007953, ATL 0007955, ATL 0007933, ATL 0007956, ATL 0007450, ATL 0007819, ATL 0007820, ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826, ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893, ATL 0007895, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902, ATL 0007917, ATL 0007918, ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922, ATL 0007923, ATL 0007924, ATL 0007926, ATL 0007927, ATL 0007928, ATL 0007929, ATL 0007930, ATL 0007931 , ATL 0007932, ATL 0007933, ATL 0007956, ATL 0007467, ATL 0007468, ATL 0007469,ATL_0007470, ATL_0007471 , ATL_0007472, or ATL_0007473, for example the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibodies ATL_0008944, ATL_0008945, ATL_0008946, ATL 0008947, ATL_0006026, ATL_0006058, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_0007933, or ATL_0007956, or a set of framework sequences with one to three mutations, such as substitutions, compared with these framework sequences. The antibody of the disclosure may have substitutions at one or more of the following positions compared to the sequences described herein: at position 5 (e.g. Q5V); and / or at position 40 (e.g. A40S); and / or at position 49 (e.g. R49G); and / or at position 53 (e.g. M53A); and / or at position 66 (e.g. S66N); and / or at position 78 (e.g. M78I or M78A); and / or at position 81 (e.g. D81 E); and / or at position 85 (e.g. K85N); and / or at position 89 (e.g. M89A); and / or at position 92 (e.g. T92S); and / or at position 97 (e.g. D97E); and / or at position 98 (e.g. D98E); and / or at position 99 (e.g. T99A); and / or at position 122 (e.g. M122T); and / or at position 123 (e.g. M123T).

[0219] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0006026, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0220] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0007925, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0221] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0007952, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0222] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0007953, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0223] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0007955, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0224] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0006058, or framework sequences with one to eight substitutions compared to these framework sequences (a total of one to eight substitutions across all framework sequences).

[0225] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0007933, or framework sequences with one toeight substitutions compared to these framework sequences (a total of one to eight substitutions across all framework sequences).

[0226] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0008944, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0227] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0008945, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0228] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0008946, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0229] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0008947, or framework sequences with one to nine substitutions compared to these framework sequences (a total of one to nine substitutions across all framework sequences).

[0230] An antibody of the disclosure may have a heavy chain variable domain (VH) with the framework sequences HFWR1 , HFWR2, HFWR3 and HFWR4 of antibody ATL_0007956, or framework sequences with one to eight substitutions compared to these framework sequences (a total of one to eight substitutions across all framework sequences).

[0231] The antibody may have any one or more of (or all of):

[0232] In the HFWR1 : a Q at position 1 , a V at position 2, a Q at position 3, a L at position 4, Q or V at position 5, Q or E at position 6, S or W at position 7, G at position 8, A or P at position 9, E or G at position 11 , V or L at position 12, K at position 14, P at position 15, G or S at position 16, S or T at position 18, V or L at position 21 , S or T at position 22, C at position 23, A or V at position 25, S or Y at position 26;

[0233] In the HCDR1 : G at position 27, T or S at position 29, F or I at position 30, S or G at position 36, Y at position 37;

[0234] In the HFRW2: a I or W at position 39, S or A at position 40, W at position 41 , V or I at position 42, R at position 43, Q at position 44, P or A at position 46, G at position 47, Q or K at position 48, R or G at position 49, L at position 50, E at position 51 , W at position 52, M or I at position 53, G at position 54;

[0235] In the HCDR2: 1 or V at position 56, G at position 63, T or A at position 65;In the HFWR3: Y at position 67, A or N at position 68, Q or P at position 69, K or S at position 70, L or F at position 71 , Q or K at position 72, G or S at position 74, R at position 75, V at position 76, T at position 77, M or I at position 78, T or S at position 79, D at position 81 , T or K at position 82, S at position 83, T or K at position 84, T or Q at position 86, A or F at position 87, M or L at position 89, E or K at position 90, L at position 91 , L or V at position 94, R or T at position 95, S or A at position 96, D at position 98, T at position 99, A at position 100, V at position 101 , Y at position 102, Y at 103, C at position 104;

[0236] In the HCDR3: A at position 105, R or S at position 106, F at position 115, D at position 116; In the HFWR4: W at position 118, G at position 119, A at position 120, G at position 121 , T or M at position 122, V at 124, T at position 125, V at position 126, S at position 127, S at position 128. The antibody may have any one or more of (or all of):

[0237] In the HFWR1 : Q at position 1 , V at position 2, Q at position 3, L at position 4, Q or V at position 5, Q or E at position 6, S at position 7, G at position 8, A or P at position 9, no position 10, E or G at position 11 , V or L at position 12, K or V at position 13, K at position 14, P at position 15, G or S at position 16, A or E at position 17, S or T at position 18, V or L at position 19, K or S at position 20, V or L at position 21 , S or T at position 22, C at position 23, K or T at position 24, A or V at position 25, S at position 26;

[0238] In the HCDR1 : G at position 27, Y or D or E at position 28, T or S or A at position 29, F or I at position 30, no position 31 -34, T at position 35, S at position 36, Y at position 37, G or F at position 38;

[0239] In the HFRW2: I or W at position 39, S or A at position 40, W at position 41 , V or I at position 42, R at position 43, Q at position 44, P or A at position 45, P or A at position 46, G at position 47, Q or K at position 48, R or G at position 49, L at position 50, E at position 51 , W at position 52, M or I or A at position 53, G at position 54, W or R at position 55;

[0240] In the HCDR2: 1 or V at position 56, S or Y at position 57, A at position 58, Y or S at position 59, no position 60-61 , N or A or Q or nothing at position 62, G or A at position 63, N or S or A at position 64, T or A or S at position 65;

[0241] In the HFWR3: N or S at position 66, Y at position 67, A or N at position 68, Q or P at position 69, K or S at position 70, L at position 71 , Q or K at position 72, no position 73, G or S at position 74, R at position 75, V at position 76, T at position 77, M or I or A at position 78, T or S at position 79, T or V at position 80, D or E at position 81 , T at position 82, S at position 83, T or K at position 84, S or K or N at position 85, T or Q at position 86, A or F at position 87, Y or S at position 88, M or L or A at position 89, E or K at position 90, L at position 91 , R or T or S at position 92, S at position 93, L or V at position 94, R or T at position 95, S or A at position 96, D or A or E at position 97, D or E at position 98, T or A at position 99, A at position 100, V at position 101 , Y at position 102, Y at position 103, C at position 104;In the HCDR3: A at position 105, R at position 106, D at position 107, L at position 108, G or F at position 109, P or F at position 110, Y or G at position 111 , Y or nothing at position 111 A, Y or nothing at position 111 B, D or E or nothing at position 111 C, S or A or nothing at position 112D, S or nothing at position 1120, G or nothing at position 112B, Y or S at position 112A, Y or G at position 112, Y or S at position 113, G or H at position 114, F at position 115, D at position 116, 1 or P at position 117;

[0242] In the HFWR4: W at position 118, G at position 119, Q at position 120, G at position 121 , T or M at position 122, M or L or T at position 123, V at position 124, T at position 125, V at position 126, S at position 127, S at position 128.

[0243] The antibody of the disclosure may have a D at position 98 and / or a T at position 99. The presence of these residues may positively affect stability and / or binding. A computational structure prediction (AlphaFold2) of antibody ATL_0006058 indicated that D98 makes a salt bridge with R75 and T99 is involved in beta-sheet structure. Therefore, based on this prediction maintaining these residues (or residues that are able to establish the same interactions, such as e.g. R, H, K, E instead of D at position 98) is likely to be beneficial (although not strictly necessary), particularly in ATL_0006058 and antibodies derived therefrom (including e.g. including e.g. ATL_0007926, ATL_0007927, ATL_0007928, ATL_0007929, ATL_0007930, ATL_0007931 , ATL_0007932, ATL_0007933, ATL_0007956, ATL_0007467, ATL_0007468, ATL 0007469, ATL_0007470, ATL_0007471 , ATL_0007472, ATL_0007473). A computational structure prediction (AlphaFold2) of antibody ATL_0006026 indicated that D98 makes a salt bridge with R75, however T99 was not indicated to involved in beta-sheet structure in ATL_0006026. Therefore, based on this prediction maintaining D98 is likely to be beneficial (although not strictly necessary, and the amino acid can be replaced by other amino acids that are able to form salt bridges, such as R, H, K, E, as evidenced by the binding of e.g. ATL_7925, which has E98), particularly in ATL_0006026 and antibodies derived therefrom (including e.g. e.g. ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL_0007450, ATL 0007819, ATL_0007820, ATL_0007821 , ATL_0007822, ATL_0007823, ATL_0007824, ATL 0007825, ATL_0007826, ATL_0007827, ATL_0007829, ATL_0007889, ATL_0007890, ATL 0007892, ATL_0007893, ATL_0007896, ATL_0007899, ATL_0007900, ATL_0007901 , ATL 0007902, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955).

[0244] An antibody of the disclosure may have the CDRL1 , CDRL2 and CDRL3 of the VL domain within a germline framework. An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibodies ATL_0008944, ATL 0008945, ATL 0008946, ATL 0008947, ATL 0006026, ATL 0006027, ATL 0006074, ATL 0006075, ATL 0006058, ATL 0007925, ATL 0007952, ATL 0007953, ATL 0007955, ATL 0007933, ATL 0007956, ATL 0007450, ATL 0007819, ATL 0007820, ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826, ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893, ATL 0007895, ATL 0007896, ATL 0007899, ATL 0007900, ATL_0007901 , ATL 0007902, ATL 0007917, ATL 0007918, ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922, ATL 0007923, ATL 0007924, ATL 0007926, ATL 0007927, ATL 0007928, ATL 0007929, ATL 0007930, ATL 0007931 ,ATL 0007932, ATL_0007933, ATL_0007956, ATL_0007467, ATL_0007468, ATL_0007469, ATL_0007470, ATL_0007471 , ATL_0007472, or ATL_0007473, for example the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibodies ATL_0008944, ATL_0008945, ATL_0008946, ATL 0008947, ATL_0006026, ATL_0006058, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_0007933, or ATL_0007956 or a set of framework sequences with one to three mutations, such as substitutions, compared with these framework sequences. The antibody of the disclosure may have substitutions at one or more of the following positions compared to the sequences described herein: position 2 (e.g. A2S); and / or at position 8 (e.g. S8P); and / or position 49 (e.g. P49A); and / or at position 52 (e.g. P52L or R52L); and / or at position 74 (e.g. G74D); and / or at position 90 (e.g. V90A or S90T); and / or at position 124 (e.g. V124L).

[0245] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0006026, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0246] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0007925, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0247] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0007952, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0248] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0007953, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0249] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0007955, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0250] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0006058, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0251] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0007933, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0007956, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0252] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0008944, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0253] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0008945, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0254] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0008946, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0255] An antibody of the disclosure may have a light chain variable domain (VL) with the framework sequences LFWR1 , LFWR2, LFWR3 and LFWR4 of antibody ATL_0008947, or framework sequences with one to five substitutions compared to these framework sequences (a total of one to five substitutions across all framework sequences).

[0256] The antibody may have any one or more of (or all of):

[0257] In the LFWR1 : an L at position 4, T at position 5, Q at position 6, S at position 12, G at position 16, S or R at position 22, C at position 23, G or A at position 25;

[0258] In the CDRLI : S at position 28, G or - at position 31 , D or Y at position 36;

[0259] In the LFRW2: W at position 41 , Y at position 42, Q at position 43, Q or H at position 44, P at position 46, a G at position 47, an A or P at position 49, a P at position 50, a K or R at position 51 , a I or F at position 54, a Y or S at position 55;

[0260] In the LCDR2: 3 amino acids;

[0261] In the LFWR3: a R at position 67, a R or A at position 68, a S or T at position 69, a G at position 70, V or I at position 71 , P or S at position 72, R at position 75, F at position 76, S at position 77, G or A at position 78, S at position 79, S at position 83, G at position 84, T or N at position 85, F or A at position 87, S or T at position 88, L at position 89, I at position 91 , T or S at position 92, G or R at position 93, L or A at position 94, E or D at position 97, D at position 98, F or E at position 99, A at position 100, Y at position 102, A at position 103, C at position 104,

[0262] In the LCDR3: Q or S at position 105, Q or S at position 106, Y or R at position 107;In the LFWR4: F at position 118, G at positionl 19, G or Q at position 120, G at position 121 , T at position 122, V or L at position 124, T or E at position 125, V or I at position 126, L or K at position 127.

[0263] The antibody may have any one or more of (or all of):

[0264] In the LFWR1 : Q or E at position 1 , A or I or S at position 2, V at position 3, L at position 4, T at position 5, Q at position 6, P or S at position 7, P or S at position 8, S or G at position 9, T or nothing at position 10, V or L at position 11 , S at position 12, G or L at position 13, A or S at position 14, P at position 15, G at position 16, Q or E at position 17, R at position 18, V or A at position 19, T at position 20, I or L at position 21 , S at position 22, C at position 23, T or R at position 24, G or A at position 25, S at position 26;

[0265] In the CDRL1 : S or Q at position 27, S at position 28, N or V at position 29, I or T at position 30, G or nothing at position 31 , nothing at positions 32-34, A or nothing at position 35, G or S at position 36, Y or S at position 37, D or Y at position 38;

[0266] In the LFRW2: V or L at position 39, H or A at position 40, W at position 41 , Y at position 42, Q at position 43, Q at position 44, L or K at position 45, P at position 46, G at position 47, T or Q at position 48, A or P at position 49, P at position 50, K or R at position 51 , P or R or L at position 52, L at position 53, I at position 54, Y at position 55;

[0267] In the LCDR2: G at position 56, N or T or A or Q at position 57, nothing at positions 58-64, S or N at position 65;

[0268] In the LFWR3: N or S at position 66, R at position 67, a P or A at position 68, a S or T at position 69, a G at position 70, V or I at position 71 , P at position 72, nothing at position 73, D or G at position 74, R at position 75, F at position 76, S at position 77, G at position 78, S at position 79, K or G at position 80, nothing at positions 81-82, S at position 83, G at position 84, T at position 85, S or D at position 86, F or A at position 87, S or T at position 88, L at position 89, V or S or A or T at position 90, I at position 91 , T or S at position 92, G or R at position 93, L at position 94, Q or E at position 95, A or P at position 96, E at position 97, D at position 98, F or E at position 99, A at position 100, D or V at position 101 , Y at position 102, Y at position 103, C at position 104;

[0269] In the LCDR3: Q at position 105, Q or S at position 106, Y at position 107, D or G at position 108, N or S or Q or A at position 109, nothing at positions 110-112, S or N or Q or A or nothing at position 113, L or S at position 114, S or P at position 115, V or P at position 116, A or T at position 117; In the LFWR4: F at position 118, G at position 119, G or Q at position 120, G at position 121 , T at position 122, K or R at position 123, V or L at position 124, T or E at position 125, V or I at position 126, L or K at position 127.

[0270] In embodiments, the antibody of the disclosure does not have an N at position 113. For example, the antibody of the disclosure may have an N or a Q at position 109 and / or an A or Q or S at position 113. The N113 L114 S115 (NLS) motif poses a theoretical liability risk for N-linked glycosylation at the N113 site inLCDR3. Theoretically, N-linked glycosylation in a CDR could lead to perturbation of binding and thus affect function of the antibody and / or impact stability. Accordingly, the presence of an N at position 113 may negatively affect binding and / or stability. In embodiments, the antibody of the disclosure has an A or Q at position 113 and a N at position 109, or a Q at position 109 and a S at position 113. Such embodiments may have even lower risks of chemical modifications which may affect binding and / or stability. A computational structure prediction (AlphaFold2) of antibody ATL_0006026 indicated that positions N109, S113, and L114 are paratope residues. Therefore, based on this prediction maintaining these residues (or residues that are able to establish the same interactions, such as e.g. Q instead of N at position 109 and A or Q instead of S at position 113) is likely to be beneficial (although not strictly necessary), particularly in ATL_0006026 and antibodies derived therefrom (including e.g. including e.g. ATL_0008944, ATL 0008945, ATL_0008946, ATL_0008947, ATL_0007926, ATL_0007927, ATL_0007928, ATL 0007929, ATL_0007930, ATL_0007931 , ATL_0007932, ATL_0007933, ATL_0007956, ATL 0007467, ATL_0007468, ATL_0007469, ATL_0007470, ATL_0007471 , ATL_0007472, ATL_0007473).

[0271] An antibody of the disclosure may have a sequence comprising any or all of the amino acids that are conserved across (i.e. present in all of) ATL_0006026, ATL_0006027; ATL_0006074; ATL_0006075; ATL_0006058, when comparing sequences using IMGT numbering (see Fig. 13).

[0272] An antibody of the disclosure may have a sequence comprising any or all of the amino acids that are conserved across (i.e. present in all of) ATL_0006026, ATL_0006058, ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_0007933, ATL_0007956 when comparing sequences using IMGT numbering (see Fig. 22, Fig. 26). An antibody of the disclosure may have a VH sequence comprising any or all of the amino acids of the VH of ATL_0006026 that are conserved across ATL_0006026, ATL 0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_0008944, ATL_0008945, ATL_0008946, and ATL_0008947. An antibody of the disclosure may have a VL sequence comprising any or all of the amino acids of the VL of ATL_0006026 that are conserved across ATL_0006026, ATL 0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_0008944, ATL_0008945, ATL_0008946, and ATL_0008947. An antibody of the disclosure may have a VH sequence comprising any or all of the amino acids of the VH of ATL_0006058 that are conserved across ATL_0006058, ATL_0007933, and ATL_0007956. An antibody of the disclosure may have a VL sequence comprising any or all of the amino acids of the VL of ATL_0006058 that are conserved across ATL_0006058, ATL_0007933, and ATL_0007956.Thus, an antibody of the disclosure may have a VH sequence based on the VH sequence of ATL_0006026 and including one or more substitutions provided that the sequence maintains the identity of the amino acids at positions 1 -4, 6-9, 11 -30, 35-59, 64, 66-72, 74-80, 82-96, 1 GO-111 C, 112C-122, and 124-128 in IMGT numbering. An antibody of the disclosure may have a VL sequence based on the VL sequence of ATL_0006026 and including one or more substitutions provided that the sequence maintains the identity of the amino acids at positions 1 , 3-7, 9, 11-31 , 35-57, 66-72, 74-80, 83-89, 91 -108, 114-123, and 125-127 in IMGT numbering. In embodiments, an antibody of the disclosure may have a VL sequence based on the VL sequence of ATL_0006026 and including one or more substitutions provided that the sequence maintains the identity of the amino acid at position 52 (proline 52; P52) in IMGTnumbering. Based on the binding data provided herein, P52 appears beneficial (although not strictly necessary, as evidenced by the binding of numerous variants disclosed herein with the P52L mutation) for binding to 15-PGDH for variants of ATL_6026 (but not variants of ATL_6058). An antibody of the disclosure may have a VH sequence based on the VH sequence of ATL_0006058 and including one or more substitutions provided that the sequence maintains the identity of the amino acids at positions 1-9, 11-27, 29-30, 35-39, 41-48, 50-59, 63-65, 67-72, 74-77, 79-80, 82-84, 86-91 , 93-111 , 112A-121 , and 123-128 in IMGT numbering. An antibody of the disclosure may have a VL sequence based on the VL sequence of ATL_0006058 and including one or more substitutions provided that the sequence maintains the identity of the amino acids at positions 1 -30, 36-48, 50-51 , 53-57, 65-72, 74-80, 83-89, 91-109, and 114-127 in IMGT numbering. In embodiments, an antibody of the disclosure has a VH sequence of ATL_0006026 or ATL_0006058 with one or more substitutions, provided that the substitutions are not at positions conserved amongst the variants in Fig. 26. In embodiments, an antibody of the disclosure has a VH sequence of ATL_0006026 with one or more substitutions provided that the substitutions are not at positions 1-4, 7-8, 10, 14-15, 23, 26-27, 31-37, 41 , 43-44, 47, 50-51 , 54, 60-61 , 63, 67, 71 , 73, 75-77, 82-83, 91 , 100, 101 -104, 105-108, 115-116, 118-121 , 124-128 in IMGT numbering. In embodiments, an antibody of the disclosure has a VH sequence of ATL_0006058 with one or more substitutions provided that the substitutions are not at positions 1 -4, 7-8, 10, 14-15, 23, 26-27, 31 -37, 41 , 43-44, 47, 50-51 , 54, 60-61 , 63, 67, 71 , 73, 75-77, 82-83, 91 , 100, 101-104, 105-108, 115-116, 118-121 , 124-128 in IMGT numbering. In embodiments, an antibody of the disclosure has a VL sequence of ATL_0006026 or ATL_0006058 with one or more substitutions, provided that the substitutions are not at positions conserved amongst the variants in Fig. 26. In embodiments, an antibody of the disclosure has a VL sequence of ATL_0006026 with one or more substitutions provided that the substitutions are not at positions 3-6, 12, 15-16, 18, 22-23, 26, 28, 41-44, 46-47, 50, 53-56, 58-64, 67, 70, 72-73, 75-79, 81-85, 89, 91 , 94, 97-100, 102-105, 107, 11Q-112, 118-122 in IMGT numbering. In embodiments, an antibody of the disclosure has a VL sequence of ATL_0006058 with one or more substitutions provided that the substitutions are not at positions 3-6, 12, 15-16, 18, 22-23, 26, 28, 41-44, 46-47, 50, 53-56, 58-64, 67, 70, 72-73, 75-79, 81-85, 89, 91 , 94, 97-100, 102-105, 107, 110-112, 118-122 in IMGT numbering.

[0273] In this specification, antibodies may have VH (and optionally VL) regions comprising an amino acid sequence that are identical or have a high percentage sequence identity to the VH and / or VL amino acid sequences of ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL_0006026, ATL_0006027; ATL 0006074; ATL 0006075; ATL 0006058, ATL 0007925, ATL 0007952, ATL 0007953 ATL 0007955, ATL 0007933, ATL 0007956, ATL 0007450, ATL 0007819, ATL 0007820 ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826 ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893 ATL 0007895, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902 ATL 0007917, ATL 0007918, ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922 ATL 0007923, ATL_0007924, for example ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL 0006026, ATL_0006058 ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL 0007933, ATL_0007956, for example ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947. For example, antibodies according to the present invention include antibodies that bind PGDH and have aVH region that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the VH region amino acid sequence of ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL_0006026, ATL_0006058, ATL 0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL_0007933, or ATL_0007956.

[0274] An antibody according to the disclosure may have a heavy chain variable domain (VH) comprising a sequence that has a least 95% sequence identity with the sequence of one or more of SEQ ID NO:1-5, SEQ ID NO:90-93, SEQ ID N0:109-110, SEQ ID NO: 118-134.

[0275] Antibodies according to the present invention include antibodies that bind PGDH and have a VL region that comprises an amino acid sequence having at least 70%, more preferably one of at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the VL region amino acid sequence of ATL 0008944, ATL 0008945, ATL 0008946, ATL 0008947, ATL 0006026, ATL 0006027 ATL 0006074; ATL 0006075; ATL 0006058, ATL 0007925, ATL 0007952, ATL 0007953 ATL 0007955, ATL 0007933, ATL 0007956, ATL 0007450, ATL 0007819, ATL 0007820 ATL 0007821 , ATL 0007822, ATL 0007823, ATL 0007824, ATL 0007825, ATL 0007826 ATL 0007827, ATL 0007829, ATL 0007889, ATL 0007890, ATL 0007892, ATL 0007893 ATL 0007895, ATL 0007896, ATL 0007899, ATL 0007900, ATL 0007901 , ATL 0007902 ATL 0007917, ATL 0007918, ATL 0007919, ATL 0007920, ATL 0007921 , ATL 0007922 ATL 0007923, ATL_0007924, for example ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947, ATL 0006026, ATL_0006058 ATL_0007925, ATL_0007952, ATL_0007953, ATL_0007955, ATL 0007933, ATL_0007956, for example ATL_0008944, ATL_0008945, ATL_0008946, ATL_0008947. An antibody according to the disclosure may have a light chain variable domain (VL) comprising a sequence that has at least 95% sequence identity with the sequence of one or more of SEQ ID NO: 6-10, SEQ ID NO: 94, SEQ ID NO:111 , SEQ ID NO: 135-152, SEQ ID NO: 202-205.

[0276] An antibody according to the disclosure may have a light chain variable domain (VL) comprising the sequence of one of SEQ ID NOs: 202-205.

[0277] An antibody according to the present disclosure may comprise:

[0278] (a) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 1 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 6; or

[0279] (b) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 2 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 7; or

[0280] (c) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 3 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 8; or(d) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 4 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 9; or

[0281] (e) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 5 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 10;

[0282] (f) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 90 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or

[0283] (g) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 91 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or

[0284] (h) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 92 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or

[0285] (i) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or

[0286] (j) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 109 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 111 ; or

[0287] (k) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 110 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 111.

[0288] (l) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 202; or

[0289] (m) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 203; or(n) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 204; or

[0290] (o) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 205.

[0291] The antibodies of the disclosure are derived from human antibodies and may therefore be referred to as human antibodies. Antibodies of the disclosure were obtained by pairing the VH and VL of a human VH domain with a human VL domain library, or through serum proteomics followed by native VH-VL pairing Thus, antibodies of the disclosure may differ from naturally occurring antibodies at least by their VH-VL pairing. Antibodies of the disclosure may comprise human VH and / or VL sequences. Antibodies of the disclosure may be formulated as human lgG1 antibodies or variants thereof, such as e.g. LALA lgG1. Antibodies of the disclosure may have a human framework sequence and / or a human Fc domain.

[0292] Antibodies of the disclosure may have a lambda (A) (e.g. that of SEQ ID NO: 88) or kappa (K) (e.g. that of SEQ ID NO: 89) light chain.

[0293] Overall percentage identity of a variable region or full-length heavy light / chain sequence may be combined with specific CDR sequences from the same antibody. Percentage (%) sequence identity is defined as the percentage of amino acid residues in a candidate sequence that are identical with residues in a comparative sequence after aligning the sequences and introducing gaps if necessary, to achieve the maximum sequence identity, and not considering any conservative substitutions as part of the sequence identity. Sequence identity is preferably calculated over the entire length of the respective sequences. Where the aligned sequences are of different length, sequence identity of the shorter comparison sequence may be determined over the entire length of the longer given sequence or, where the comparison sequence is longer than the given sequence, sequence identity of the comparison sequence may be determined over the entire length of the shorter given sequence. Sequence identity may be defined with reference to the algorithm GAP (Wisconsin GCG package, Accelerys Inc, San Diego USA).

[0294] Also described herein are single domain antibodies (sdAbs), otherwise known as nanobodies, comprising the heavy chain CDRs and / or the VH sequence of any antibody described herein. Isolated nucleic acids encoding an antibody, antigen binding fragment, or polypeptide as described herein are provided. Also provided is a vector comprising a nucleic acid described herein, and a host cell comprising the vector. For example, the host cell may be a eukaryotic, or mammalian, e.g. Chinese Hamster Ovary (CHO), cell or may be a prokaryotic cell, e.g. E. coli. In some embodiments, the vector is a viral vector, for example a bacteriophage. Further provided are methods for making an antibody, or antibody fragment as described herein, the method comprising culturing a host cell as described herein under conditions suitable for the expression of a vector encoding the antibody, or antibody fragment, and isolating and / or purifying theantibody, or antibody fragment. The method further comprises formulating the antibody or antibody fragment into a composition including at least an additional component.

[0295] Therapeutic uses and in vitro and in vivo effects

[0296] Antibodies described herein may inhibit 15-PGDH thereby altering, such as restoring and / or increasing, circulating PGE2 levels. Antibodies described herein may alter PGE2 levels in an in vitro cell culture. Antibodies described herein may increase levels of circulating PGE2. Antibodies described herein may increase the half-life of circulating PGE2 in vivo. In turn, this increases PGE2-induced signaling pathways implicated in PD, including neuroinflammation, mitochondrial function, oxidative stress, striatal projection neuron activity and / or apoptosis through both EP-receptor and / or non-receptor mediated mechanisms, e.g. via organic anion transporting polypeptides as described in Roth et al., 2012. Accordingly, antibodies described herein may be useful in the treatment of Parkinson’s disease.

[0297] The antibodies described herein are expected to act on the central nervous system indirectly through modulation of extracellular (also referred to as “circulating”) PGE2, which, due to its low molecular weight is able to cross the blood-brain barrier (Delvi et al., 2015). For example, inhibition of 15-PGDH may increase the availability and / or half-life of PGE2, thus resulting in more PGE2 crossing the blood-brain barrier. The half-life of PGE2 in human circulation has been reported to be extremely short, less than 30 seconds. Any increase in half-life of PGE2 in circulation may therefore have a significant effect. Further, as PGE2 and its precursors have been shown to be increased in the brain after peripheral delivery (Dalvi et al. 2015), increasing the availability and / or half-life of PGE2 in the periphery is expected to have an effect on brain levels.

[0298] Antibodies described herein may reduce inflammation, such as neuroinflammation. This may be tested in an in vitro cell culture, for example using iPSC-derived neuronal cells, e.g. IPSC-derived dopaminergic neurons; and / or astrocytes, and / or microglia as described herein. Inflammation may be measured, for example, by measuring the levels of pro-inflammatory cytokines, such as IL-6, present in the cell culture IL-6. The levels of IL-6 (and other pro-inflammatory cytokines) may be measured by ELISA, wherein a decrease in IL-6 is indicative of reduced inflammation.

[0299] Antibodies described herein may reduce the abundance of phospho-aSyn129 in cells pre-treated with aSynuclein fibrils, compared to a control condition. This may be tested in an in vitro cell culture, for example using iPSC-derived neuronal cells, e.g. IPSC-derived dopaminergic neurons; and / or astrocytes, and / or microglia as described herein. Antibodies described herein may restore or at least partially restore mitochondrial function after mitochondrial dysfunction induced by exposure of cells to aSynuclein fibrils. This may be tested in an in vitro cell culture, for example using iPSC-derived neuronal cells, e.g. IPSC-derived dopaminergic neurons; and / or astrocytes, and / or microglia as described herein. Mitochondrial function may be tested using a decrease of mitochondrial membrane potential as an indicator of mitochondrial dysfunction. Thus, an antibody described herein may at least partially rescue mitochondrial membrane depolarization induced by exposure to aSynuclein fibrils.

[0300] Antibodies described herein may alter microglial inflammatory state. For example, the antibody may alter, for example reduce, the inflammatory state of microglia in vitro. This may be tested by determiningexpression of the activation marker CD68 on the surface of microglia, for example by flow cytometry. Suitable models include a dopaminergic neurons, astrocytes and microglia triculture as described herein. Antibodies described herein may reduce neuroinflammation in vivo. Antibodies described herein may reduce the levels of one or more inflammatory markers in mouse model (e.g. a C57BL / 6 mouse) of neuroinflammation induced by lipopolysaccharide (LPS) (e.g. LPS exposure via intraperitoneal (i.p.) injection). This may be measured by treating an animal with an antibody and measuring levels of one or more inflammatory markers in the brain and / or plasma of the animal after exposure to LPS. The one or more inflammatory markers may be selected from: nterleukin-1 p (IL-1 p), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a).

[0301] Antibodies described herein may improve or preserve one or more metrics of motor function and / or balance and / or gait and / or postural stability in a model animal, compared to a control. Antibodies of the present disclosure may improve or preserve motor function and / or balance and / or movement and / or postural stability in a model animal. Motor function and / or movement and / or postural stability may be determined using one or more metrics selected from: speed, hind stance time, diagonal interlimb coordination, double support, maximum knee angle, and peak hind leg swing speed, stride time and speed, step width, stance and swing time during a stride, interlimb coordination, toe clearance, iliac crest and hip height, hind limb protraction and retraction, tail position and movement, swing speed during a stride, jerk metric during swing phase, angle ranges and deviations of different joints, vertical and horizontal head movement. Motor function and / or balance and / or postural stability may be determined by measuring the time to fall in a Rotarod test, for example using the method described in the examples of the present disclosure.

[0302] The animal model may be an aged animal, such as e.g. a 22-month old mouse. The animal model may be a mouse model of Parkinson’s disease. The animal model may be an animal (e.g. a 93-95 week old mouse) administered an expression cassette of A53T-mutated alpha synuclein, e.g. in an adeno-associated virus (AAV) vector, for example as described herein. Effects on motor function and / or gait and / or movement and / or posture can be determined using the methods described in examples of the present disclosure. Antibodies described herein may improve one or more metrics of muscle strength and / or muscle function in a subject, optionally a model animal, compared to a control. Antibodies of the present disclosure may increase muscle strength and / or muscle function in a subject, optionally a model animal, compared to a control. For example, the model animal may be a mouse hind limb immobilisation model of disuse atrophy, for example as described in Wu et al., 2023. Antibodies described herein may improve one or more metrics of muscle strength and / or muscle function of a disused muscle or muscle group in a subject, optionally a model animal, compared to a control. Antibodies of the present disclosure may increase muscle strength and / or muscle function of a disused muscle or muscle group in a subject, optionally a model animal, compared to a control. Muscle strength and / or muscle function may be determined by measuring muscle contraction of a muscle or muscle group (e.g. the plantarflexor muscle group) induced by electrical stimulation (e.g. a range of frequencies of electrical stimulation) to determine one or more metrics selected from: isometric force (e.g. maximal peak isometric force), twitch-to-tetanic ratio (a measure of the force of a single muscle twitch compared to the force of a maximal tetanic contraction), the force-frequency relationship (isometric force measured over a range of stimulation frequencies), and the cumulative muscleforce generated across the tested range of frequencies (area under the curve). The maximal peak isometric force (normalised to body weight) may be increased by at least 10%, at least 15%, or at least 18%, compared to a control. The cumulative muscle force generated across the tested range of frequencies (the area under the curve) may be increased by at least 10%, at least 15%, or at least 18%, compared to a control. The isometric force (e.g. maximal peak isometric force) may be normalised against one of body size, body weight, and limb length. The animal model may be an aged animal, such as e.g. an 86-week old mouse. Antibodies of the present disclosure may increase muscle strength and / or muscle function without increasing muscle mass in a model animal, compared to a control. Antibodies of the present disclosure may increase muscle strength and / or muscle function compared to a control, after immobilisation for a predetermined period of time (e.g. at least one week, at least 2 weeks, at least 3 weeks, or about 2 weeks), optionally without increasing muscle mass. Antibodies of the present disclosure may increase muscle strength and / or muscle function compared to a control, after immobilisation for a predetermined period of time (e.g. at least one week, at least 2 weeks, at least 3 weeks, or about 2 weeks) followed by a recovery period of at least 1 week or about 1 week, optionally without increasing muscle mass. Effects on muscle strength and / or muscle function and / or muscle mass can be determined using the methods described in examples of the present disclosure.

[0303] Without wishing to be bound by theory, the effects of the antibodies described herein on muscle strength, muscle function, exercise performance, and / or muscle mass are expected to be mediated indirectly through modulation of PGE2. For example, inhibition of 15-PGDH is expected to increase the availability and / or half-life of PGE2, thus resulting in increased PGE2 signaling, and reducing the effects of muscle atrophy. The antibodies and fragments thereof may find use in therapy.

[0304] A subject to be treated or diagnosed may be any animal or human. The subject is preferably mammalian, more preferably human. The subject may be male or female. The subject may be a patient (i.e. the terms “subject” and “patient” are used interchangeably). Therapeutic uses may be in human or animals (veterinary use). Unless, specified otherwise, the subject is a human.

[0305] Medicaments and pharmaceutical compositions according to aspects of the present invention may be formulated for administration by a number of routes, including but not limited to, parenteral, intravenous, intra-arterial, intramuscular, oral and nasal. The medicaments and compositions may be formulated for injection.

[0306] Pharmaceutical compositions may be prepared using a pharmaceutically acceptable “carrier” composed of materials that are considered safe and effective. “Pharmaceutically acceptable” refers to molecular entities and compositions that are “generally regarded as safe”, e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human. In some embodiments, this term refers to molecular entities and compositions approved by a regulatory agency of the US federal or a state government, as the GRAS list under section 5204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to diluents, binders, lubricantsand disintegrants. Those with skill in the art are familiar with such pharmaceutical carriers and methods of compounding pharmaceutical compositions using such carriers.

[0307] The pharmaceutical compositions provided herein may include one or more excipients, e.g., solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, antioxidants or antimicrobial preservatives. When used, the excipients of the compositions will not adversely affect the stability, bioavailability, safety, and / or efficacy of the active ingredients, i.e. the anti-PGDH antibodies used in the composition. Thus, the skilled person will appreciate that compositions are provided wherein there is no incompatibility between any of the components of the dosage form. Excipients may be selected from the group consisting of buffering agents, solubilizing agents, tonicity agents, chelating agents, antioxidants, antimicrobial agents, and preservatives.

[0308] Administration is preferably in a “therapeutically effective amount”, this being sufficient to show benefit to the individual. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the disease being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington’s Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins.

[0309] Antibodies according to the present disclosure may find uses in a variety of medical contexts. Thus, antibodies according to the present disclosure may be used as a medicament, and may be used in the fabrication of a medicament comprising an antibody of the disclosure. Antibodies of the present disclosure may be used in a method of treatment of a disease or disorder, the method comprising administering to a subject an effective amount of an antibody according to the disclosure. Thus, also described herein are antibodies according to the disclosure, for use in a method of treating a subject.

[0310] Pathological aggregation of a-Syn in the form of Lewy bodies and Lewy neurites is a common feature of Parkinson’s Disease (PD) and other synucleinopathies, or synuclein-mediated neurodegenerative diseases, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) (Goedert et al., 2017), as well Alzheimer’s disease (AD), and chronic traumatic encephalopathy (CTE).

[0311] Accordingly, the subject may be a subject who has been diagnosed as having or being at risk of a synuclein-mediated neurodegenerative disease. The synuclein-mediated neurodegenerative disease may be PD. Subjects deemed at risk of developing PD may be subjects having REM Sleep Behaviour Disorder (RBD). Antibodies of the disclosure have been shown to be able to reduce effects of aging on neurodegeneration, and specifically gait and postural stability. Thus, the subject may be an older subject, such as e.g. a subject over the age of 60, 70, or 80 years old. The subject may be a subject who has been diagnosed as having one or more symptoms of neurodegeneration and / or neuromuscular degeneration. The symptoms of neurodegeneration and / or neuromuscular degeneration may be associated with normal ageing or with a neurodegenerative condition. The subject may be a subject who has been diagnosed as having a neuroinflammation, or a neurodegenerative condition associated with neuroinflammation, for exampleParkinson’s Disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Alzheimer’s Disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). Thus, also described herein is the use of antibodies of the disclosure in the treatment of neurological symptoms associated with aging and / or neurodegeneration and / or neuroinflammation.

[0312] PGDH-15 has been reported to play a role in the development of inflammation (Sun et al., 2021). Accordingly, the subject may a be a subject who has been diagnosed as having or being at risk of an inflammatory disease such as rheumatoid arthritis, skin inflammation such as spontaneous atopic dermatitis and hidradentitis supperativa, and lung inflammation, such as chronic obstructive pulmonary disease, acute lung injury and acute respiratory distress syndrome (ALI / ARDS), and bronchiolitis obliterans.

[0313] 15-PGDH has been reported to be a major contributor to age related muscular atrophy, for example sarcopenia (Palla et al., 2021). The present inventors have demonstrated that treatment of aged mice with an antibody of the disclosure (referred to herein as ATL6026, although multiple related antibodies are also described herein and expected to have similar effects based on the evidence provided herein) had a profound positive effect in gait and stability. The inventors also demonstrated that this elevation in 15-PGDH levels is not just seen in aged tissues as reported previously, identifying that the levels of 15-PGDH are also significantly upregulated in young mice with an immobilised limb (a limb immobilisation model of disuse atrophy reported in Wu et al., 2023), suggesting that 15-PGDH is also a contributor to disuse atrophy, for example disuse atrophy caused by immobilisation. Furthermore, using the same limb immobilisation model of disuse atrophy the inventors demonstrated that treatment with an antibody of the disclosure (referred to herein as ATL7955, although multiple related antibodies are also described herein and expected to have similar effects based on the evidence provided herein) significantly increased muscle strength and function. Accordingly, the subject may be a subject who has been diagnosed as having or being at risk of a disease or disorder associated with muscle atrophy and / or dystrophy. For example, the disease or disorder may be a myopathy. The disease or disorder may be aging-related muscle atrophy. As used herein, the term "myopathy" refers to a muscular disease in which the muscle fibers do not function properly, typically resulting in muscular weakness. Myopathies include muscular diseases that are neuromuscular or musculoskeletal in nature. In some embodiments, the myopathy is an inherited myopathy. Inherited myopathies include, without limitation, dystrophies (e.g. Duchenne’s muscular dystrophy), myotonias, congenital myopathies (e.g. nemaline myopathy, multi / minicore myopathy, and centronuclear myopathy), mitochondrial myopathies, familial periodic myopathies, inflammatory myopathies (e.g. muscle atrophy as a result of acute or chronic inflammatory conditions) and metabolic myopathies (e.g., glycogen storage diseases and lipid storage disorder). In some embodiments, the myopathy is an acquired myopathy. Acquired myopathies include, without limitation, external substance induced myopathy (e.g., drug-induced myopathy e.g. muscle atrophy induced by treatment with incretin therapies e.g. GIP and / or GLP (e.g. GLP-1) agonists, and glucocorticoid myopathy, alcoholic myopathy, and myopathy due to other toxic agents), myositis (e.g. dermatomyositis, polymositis and inclusion body myositis), myositis ossificans, rhabdomyolysis, and myoglobinurias, and disuse atrophy. In some embodiments, the myopathy is disuse atrophy, which may be caused by a bone fracture (e.g. a hip fracture), by a nerve injury (e.g., spinal cord injury (SCI)), by immobilisation, by bed rest, and / or by obesity (obesity may decrease physical activity bymaking it more challenging to be physically active). The immobilisation may be immobilisation of a bone fracture, for example a immobilisation of a bone fracture by splinting and / or casting. In some embodiments the myopathy is related to a disease or disorder such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), cachexia, e.g. cachexia syndromes due to renal failure, AIDS, cardiac conditions, obesity (e.g. muscle atrophy induced by treatment of obese patients with incretin therapies e.g. GIP and / or GLP (e.g. GLP-1) agonists), and / or cancer. In some embodiments the myopathy is related to ageing (e.g. sarcopenia and / or sarcopenic obesity). Thus, in embodiments, the subject is a subject who has been treated with an incretin therapy.

[0314] The antibodies of the disclosure may be used in therapy with further therapeutic agents. As used herein, a “further therapeutic agent” is an additional compound, protein, vector, antibody, cell or entity with a therapeutic effect. The antibodies may be co-administered with a further therapeutic agent. The antibodies may be co-formulated with a further therapeutic agent. The antibodies may be sequentially administered before or after a further therapeutic agent.

[0315] The present disclosure also provides methods of treatment of a subject who has been diagnosed as having or being at risk of a synuclein-mediated neurodegenerative disease, the methods comprising administering to the subject a therapeutically effective amount of an antibody that binds to and inhibits PGDH. The antibody may be for example an antibody as described herein.

[0316] The present disclosure also provides methods of treatment of a subject who has been diagnosed as having or being at risk of having or developing muscle atrophy and / or dystrophy, the methods comprising administering to the subject a therapeutically effective amount of an antibody as described herein. Also described herein is a method of treating, preventing or alleviating muscle strength and / or function loss, optionally muscle strength and / or function loss associated with immobilization, the method comprising administering to the subject a therapeutically effective amount of an antibody as described herein. Also described herein are antibodies according to the present disclosure, for use in treating, preventing or alleviating muscle strength and / or function loss in a subject in need thereof, such as e.g. a subject who has been diagnosed as having or being at risk of having or developing muscle atrophy and / or dystrophy, or a subject who has been diagnosed as being at risk of having muscle function and / or strength loss associated with immobilization.

[0317] Some methods of the present disclosure involve a sample containing cells. The sample may be a culture of cells grown in vitro. For example, the culture may comprise a suspension of cells or cells cultured in a culture plate or dish.

[0318] Methods according to the present disclosure may be performed, or products may be present, in vitro, ex vivo, or in vivo. The term “in vitro" is intended to encompass experiments with materials, biological substances, cells and / or tissues in laboratory conditions or in culture whereas the term “in vivo" is intended to encompass experiments and procedures with intact multi-cellular organisms. “Ex vivo" refers to something present or taking place outside an organism, e.g. outside the human or animal body, which may be on tissue (e.g. whole organs) or cells taken from the organism.The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately, or in any combination of such features, be utilised for realising the invention in diverse forms thereof.

[0319] While the invention has been described in conjunction with the exemplary embodiments described above, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth above are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

[0320] For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

[0321] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0322] Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0323] It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value is optional and means for example + / - 10%.

[0324] Sequences

[0325] SEQ ID NO Description Sequence

[0326] 1 ATL 0006026 VH QVQLQQSGAEVKKPGASVKVSOKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTMVTVSS

[0327] 2 ATL 0006027 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVR QAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTST AYMELSSLRSEDTAVYYCARGVSSGWSPDAFDIWGQGT MVTVSS

[0328]

[0329] ATL 0006058 VH QVQLQESGPGLVKPSETLSLTCTVSGDSITSYFWAWIRQ ATL 0007469 VH PAGKRLEWIGRVYASGSTSYNPSLKSRVTMSVDTSKKQF SLKLTSVTAADTAVYYCARDLFFGSGSHFDPWGQGMLVT VSS ATL 0006074 VH QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIR QPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQF SLKLSSVTAADTAVYYCARRRLLLWFGGETGFDYWGQG TLVTVSS ATL 0006075 VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWI RQHPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQ FSLKLSSVTAADTAVYYCASGTLGYCSSTSCYSDAFDIW GQGTTVTVSS ATL 0006026 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ ATL 0007450 VL QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLVITG ATL 0007819 VL LQAEDEADYYCQSYDNSLSVAFGGGTKVTVL ATL 0007820 VL

[0330] ATL 0007821 VL

[0331] ATL 0007822 VL

[0332] ATL 0007823 VL

[0333] ATL 0007824 VL

[0334] ATL 0007825 VL

[0335] ATL 0007826 VL

[0336] ATL 0007827 VL

[0337] ATL 0007829 VL

[0338] ATL 0006027 VL SSELTQDPAVSVALGQTVGIRCQGDSLRSSYANWYQQK PGQAPKLVIYGKNKRPSGIPDRFSGSTSGNTASLSITGAL ADDEADYYCQSRDTSGAQILFGGGTKVTVL ATL 0006058 VL EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQQ ATL 0007468 VL KPGQPPRRLIYGTSSRATGIPGRFSGSGSGTDFTLSISRL EPEDFAVYYCQQYGSSPPTFGQGTRLEIK ATL 0006074 VL QSALTQPASVSGSPGQSITISCTGTSSDVGGYNYVSWYQ HHPGKAPKLMIYDVSNRPSGVSNRFSGSKSGNTASLTIS GLQAEDEADYYCSSYTSSSLRVFGGGTKLTVL ATL 0006075 VL QS ALTQ PAS VSGS PGQS ITLSCTGTSS D IG VQTYVS WYQ HHPGKAPRLIFSEVGNRPSGVSTRFSASKSGNTASLTISG LQTEDEALYYCSSYINTNTPVLFGGGTKLTVL HCDR1_ ATL 0008944 GYTFTSYG

[0339] HCDR1 ATL 0008945

[0340] HCDR1 ATL 0008946

[0341] HCDR1 ATL 0008947

[0342] HCDR1 ATL 0006026

[0343]

[0344] HCDR1 ATL 0007925

[0345] HCDR1 ATL 0007952

[0346] HCDR1 ATL 0007953

[0347] HCDR1 ATL 0007955

[0348] HCDR1 ATL 0007450

[0349] HCDR1 ATL 0007819

[0350] HCDR1 ATL 0007820

[0351] HCDR1 ATL 0007821

[0352] HCDR1 ATL 0007822

[0353] HCDR1 ATL 0007823

[0354] HCDR1 ATL 0007824

[0355] HCDR1 ATL 0007825

[0356] HCDR1 ATL 0007826

[0357] HCDR1 ATL 0007827

[0358] HCDR1 ATL 0007829

[0359] HCDR1 ATL 0007889

[0360] HCDR1 ATL 0007890

[0361] HCDR1 ATL 0007892

[0362] HCDR1 ATL 0007893

[0363] HCDR1 ATL 0007895

[0364] HCDR1 ATL 0007896

[0365] HCDR1 ATL 0007899

[0366] HCDR1 ATL 0007900

[0367] HCDR1 ATL 0007901

[0368] HCDR1 ATL 0007902

[0369] HCDR1 ATL 0007917

[0370] HCDR1 ATL 0007918

[0371] HCDR1 ATL 0007919

[0372] HCDR1 ATL 0007920

[0373] HCDR1 ATL 0007921

[0374] HCDR1 ATL 0007922

[0375] HCDR1 ATL 0007923

[0376] HCDR1 ATL 0007924

[0377] HCDR1 ATL 0006027 GGTFSSYA HCDR1 ATL 0006058 GDSITSYF HCDR1 ATL 0007467

[0378] HCDR1 ATL 0007468

[0379] HCDR1 ATL 0007469

[0380] HCDR1 ATL 0007472

[0381] HCDR1 ATL 0007473

[0382] HCDR1 ATL 0006074 GGSFSGYY

[0383]

[0384] HCDR1 ATL 0006075 GGSISSGGYY HCDR2 ATL 0006026; ISAYNGNT HCDR2 ATL 0007925

[0385] HCDR2 ATL 0007450

[0386] HCDR2 ATL 0007819

[0387] HCDR2 ATL 0007824

[0388] HCDR2 ATL 0007825

[0389] HCDR2 ATL 0007826

[0390] HCDR2 ATL 0007827

[0391] HCDR2 ATL 0007829

[0392] HCDR2 ATL 0007889

[0393] HCDR2 ATL 0007890

[0394] HCDR2 ATL 0007892

[0395] HCDR2 ATL 0007893

[0396] HCDR2 ATL 0007895

[0397] HCDR2 ATL 0007896

[0398] HCDR2 ATL 0007899

[0399] HCDR2 ATL 0007900

[0400] HCDR2 ATL 0007901

[0401] HCDR2 ATL 0007902

[0402] HCDR2 ATL 0007919

[0403] HCDR2 ATL 0007920

[0404] HCDR2 ATL 0007923

[0405] HCDR2 ATL 0006027 IIPIFGTA HCDR2 ATL 0006058 VYASGST HCDR2 ATL 0007933

[0406] HCDR2 ATL 0007956

[0407] HCDR2 ATL 0007467

[0408] HCDR2 ATL 0007468

[0409] HCDR2 ATL 0007469

[0410] HCDR2 ATL 0007470

[0411] HCDR2 ATL 0007471

[0412] HCDR2 ATL 0007472

[0413] HCDR2 ATL 0007473

[0414] HCDR2 ATL 0007926

[0415] HCDR2 ATL 0007927

[0416] HCDR2 ATL 0007928

[0417] HCDR2 ATL 0007929

[0418] HCDR2 ATL 0007930

[0419] HCDR2 ATL 0007931

[0420] HCDR2 ATL 0007932

[0421]

[0422] HCDR2_ATL_0006074 INHSGST HCDR2_ATL_0006075 IYYSGST HCDR3_ATL_0006026; ARDLGPYYYDSSGYYYGFDI HCDR3_ATL_0007925

[0423] HCDR3_ATL_0007450

[0424] HCDR3_ATL_0007819

[0425] HCDR3_ATL_0007820

[0426] HCDR3_ATL_0007821

[0427] HCDR3_ATL_0007822

[0428] HCDR3_ATL_0007823

[0429] HCDR3_ATL_0007824

[0430] HCDR3_ATL_0007825

[0431] HCDR3_ATL_0007826

[0432] HCDR3_ATL_0007827

[0433] HCDR3_ATL_0007889

[0434] HCDR3_ATL_0007890

[0435] HCDR3_ATL_0007892

[0436] HCDR3_ATL_0007893

[0437] HCDR3_ATL_0007895

[0438] HCDR3_ATL_0007896

[0439] HCDR3_ATL_0007899

[0440] HCDR3_ATL_0007900

[0441] HCDR3_ATL_0007901

[0442] HCDR3_ATL_0007902

[0443] HCDR3_ATL_0007918

[0444] HCDR3_ATL_0007919

[0445] HCDR3_ATL_0007921

[0446] HCDR3_ATL_0007924

[0447] HCDR3_ATL_0006027 ARGVSSGWSPDAFDI HCDR3_ATL_0006058 ARDLFFGSGSHFDP HCDR3_ATL_0007933

[0448] HCDR3_ATL_0007956

[0449] HCDR3_ATL_0007467

[0450] HCDR3_ATL_0007468

[0451] HCDR3_ATL_0007469

[0452] HCDR3_ATL_0007470

[0453] HCDR3_ATL_0007471

[0454] HCDR3_ATL_0007472

[0455] HCDR3_ATL_0007473

[0456] HCDR3_ATL_0007926

[0457] HCDR3_ATL_0007927

[0458]

[0459] HCDR3_ATL_0007928

[0460] HCDR3_ATL_0007929

[0461] HCDR3_ATL_0007930

[0462] HCDR3_ATL_0007931

[0463] HCDR3_ATL_0007932

[0464] HCDR3_ATL_0006074 ARRRLLLWFGGETGFDY HCDR3_ATL_0006075 ASGTLGYCSSTSCYSDAFDI LCDR1_ ATL 0008944 SSNIGAGYD LCDR1 ATL 0008945

[0465] LCDR1 ATL 0008946

[0466] LCDR1 ATL 0008947

[0467] LCDR1 ATL 0006026

[0468] LCDR1 ATL 0007925

[0469] LCDR1 ATL 0007952

[0470] LCDR1 ATL 0007953

[0471] LCDR1 ATL 0007955

[0472] LCDR1 ATL 0007450

[0473] LCDR1 ATL 0007819

[0474] LCDR1 ATL 0007820

[0475] LCDR1 ATL 0007821

[0476] LCDR1 ATL 0007822

[0477] LCDR1 ATL 0007823

[0478] LCDR1 ATL 0007824

[0479] LCDR1 ATL 0007825

[0480] LCDR1 ATL 0007826

[0481] LCDR1 ATL 0007827

[0482] LCDR1 ATL 0007829

[0483] LCDR1 ATL 0007889

[0484] LCDR1 ATL 0007890

[0485] LCDR1 ATL 0007892

[0486] LCDR1 ATL 0007893

[0487] LCDR1 ATL 0007895

[0488] LCDR1 ATL 0007896

[0489] LCDR1 ATL 0007899

[0490] LCDR1 ATL 0007900

[0491] LCDR1 ATL 0007901

[0492] LCDR1 ATL 0007902

[0493] LCDR1 ATL 0007917

[0494] LCDR1 ATL 0007918

[0495] LCDR1 ATL 0007919

[0496] LCDR1 ATL 0007920

[0497]

[0498] LCDR1_ATL_0007921 LCDR1_ATL_0007922

[0499] LCDR1 ATL 0007923

[0500] LCDR1 ATL 0007924

[0501] LCDR1 ATL 0006027 SLRSSY LCDR1 ATL 0006058 QSVTSSY LCDR1 ATL 0007933

[0502] LCDR1 ATL 0007956

[0503] LCDR1 ATL 0007467

[0504] LCDR1 ATL 0007468

[0505] LCDR1 ATL 0007469

[0506] LCDR1 ATL 0007470

[0507] LCDR1 ATL 0007471

[0508] LCDR1 ATL 0007472

[0509] LCDR1 ATL 0007473

[0510] LCDR1 ATL 0007926

[0511] LCDR1 ATL 0007927

[0512] LCDR1 ATL 0007928

[0513] LCDR1 ATL 0007929

[0514] LCDR1 ATL 0007930

[0515] LCDR1 ATL 0007931

[0516] LCDR1 ATL 0007932

[0517] LCDR1 ATL 0006074 SSDVGGYNY LCDR1 ATL 0006075 SSDIGVQTY LCDR2 ATL 0006026 GNS LCDR2 ATL 0007450

[0518] LCDR2 ATL 0007819

[0519] LCDR2 ATL 0007820

[0520] LCDR2 ATL 0007821

[0521] LCDR2 ATL 0007822

[0522] LCDR2 ATL 0007823

[0523] LCDR2 ATL 0007824

[0524] LCDR2 ATL 0007825

[0525] LCDR2 ATL 0007826

[0526] LCDR2 ATL 0007827

[0527] LCDR2 ATL 0007829

[0528] LCDR2 ATL 0007889

[0529] LCDR2 ATL 0007890

[0530] LCDR2 ATL 0007892

[0531] LCDR2 ATL 0007893

[0532] LCDR2 ATL 0007895

[0533]

[0534] LCDR2_ATL_0007896 LCDR2_ATL_0007901

[0535] LCDR2 ATL 0007902

[0536] LCDR2 ATL 0007920

[0537] LCDR2 ATL 0006027 GKN LCDR2 ATL 0006058 GTS LCDR2_ ATL 0007933

[0538] LCDR2_ ATL 0007956

[0539] LCDR2_ ATL 0007467

[0540] LCDR2_ ATL 0007468

[0541] LCDR2_ ATL 0007469

[0542] LCDR2_ ATL 0007470

[0543] LCDR2_ ATL 0007471

[0544] LCDR2_ ATL 0007472

[0545] LCDR2_ ATL 0007473

[0546] LCDR2_ ATL 0007926

[0547] LCDR2_ ATL 0007927

[0548] LCDR2_ ATL 0007928

[0549] LCDR2_ ATL 0007929

[0550] LCDR2_ ATL 0007930

[0551] LCDR2_ ATL 0007931

[0552] LCDR2_ ATL 0007932

[0553] LCDR2 ATL 0006074 DVS LCDR2 ATL 0006075 EVG LCDR3_ ATL 0008947 QSYDNSLSVA LCDR3_ATL_0006026 LCDR3_ATL_0007450 LCDR3_ATL_0007819 LCDR3_ATL_0007820 LCDR3_ATL_0007821 LCDR3_ATL_0007822 LCDR3_ATL_0007823 LCDR3_ATL_0007824 LCDR3_ATL_0007825 LCDR3_ATL_0007826 LCDR3_ATL_0007827 LCDR3_ATL_0007829 LCDR3_ATL_0007889 LCDR3_ATL_0007890 LCDR3_ATL_0007892

[0554] LCDR3_ATL_0007893

[0555]

[0556] LCDR3_ATL_0007895

[0557] LCDR3_ATL_0007896

[0558] LCDR3_ATL_0007899

[0559] LCDR3_ATL_0007900

[0560] LCDR3_ATL_0007918

[0561] LCDR3_ATL_0006027 QSRDTSGAQIL LCDR3_ATL_0006058 QQYGSSPPT

[0562] LCDR3_ ATL 0007933

[0563] LCDR3_ ATL 0007956

[0564] LCDR3_ATL_0007467

[0565] LCDR3_ATL_0007468

[0566] LCDR3_ATL_0007469

[0567] LCDR3_ATL_0007470

[0568] LCDR3_ATL_0007471

[0569] LCDR3_ATL_0007472

[0570] LCDR3_ATL_0007473

[0571] LCDR3_ATL_0007926

[0572] LCDR3_ATL_0007927

[0573] LCDR3_ATL_0007928

[0574] LCDR3_ATL_0007929

[0575] LCDR3_ATL_0007930

[0576] LCDR3_ATL_0007931

[0577] LCDR3_ATL_0007932

[0578] LCDR3_ATL_0006074 SSYTSSSLRV LCDR3_ATL_0006075 SSYINTNTPVL

[0579] HFWR1 ATL 0006026 QVQLQQSGAEVKKPGASVKVSCKAS HFWR2 ATL 0008944 ISWVRQAPGQGLEWMGW HFWR2 ATL 0008945

[0580] HFWR2 ATL 0008946

[0581] HFWR2 ATL 0008947

[0582] HFWR2 ATL 0006026

[0583] HFWR2 ATL 0007925

[0584] HFWR2 ATL 0007952

[0585] HFWR2 ATL 0007953

[0586] HFWR2 ATL 0007955

[0587] HFWR2 ATL 0007450

[0588] HFWR2 ATL 0007820

[0589] HFWR2 ATL 0007821

[0590] HFWR2 ATL 0007822

[0591] HFWR2 ATL 0007823

[0592] HFWR2 ATL 0007824

[0593]

[0594] HFWR2 ATL 0007825

[0595] HFWR2 ATL 0007826

[0596] HFWR2 ATL 0007827

[0597] HFWR2 ATL 0007829

[0598] HFWR2 ATL 0007889

[0599] HFWR2 ATL 0007890

[0600] HFWR2 ATL 0007892

[0601] HFWR2 ATL 0007893

[0602] HFWR2 ATL 0007895

[0603] HFWR2 ATL 0007896

[0604] HFWR2 ATL 0007899

[0605] HFWR2 ATL 0007900

[0606] HFWR2 ATL 0007901

[0607] HFWR2 ATL 0007902

[0608] HFWR2 ATL 0007917

[0609] HFWR2 ATL 0007918

[0610] HFWR2 ATL 0007919

[0611] HFWR2 ATL 0007920

[0612] HFWR2 ATL 0007921

[0613] HFWR2 ATL 0007922

[0614] HFWR2 ATL 0007923

[0615] HFWR2 ATL 0007924

[0616] HFWR3_ATL_0006026 NYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYC HFWR3_ATL_0007450

[0617] HFWR3_ATL_0007819

[0618] HFWR3_ATL_0007820

[0619] HFWR3_ATL_0007821

[0620] HFWR3_ATL_0007822

[0621] HFWR3_ATL_0007823

[0622] HFWR3_ATL_0007829

[0623] HFWR3_ATL_0007889

[0624] HFWR3_ATL_0007890

[0625] HFWR3_ATL_0007892

[0626] HFWR3_ATL_0007893

[0627] HFWR3_ATL_0007895

[0628] HFWR3_ATL_0007896

[0629] HFWR3_ATL_0007899

[0630] HFWR3_ATL_0007900

[0631] HFWR3_ATL_0007901

[0632] HFWR3_ATL_0007902

[0633] HFWR3_ATL_0007922

[0634] HFWR4 ATL 0006026 WGQGTMVTVSS

[0635]

[0636] LFWR1 ATL 0006026 QAVLTQPSSVSGAPGQRVTISCTGS LFWR1 ATL 0007450

[0637] LFWR1 ATL 0007819

[0638] LFWR1 ATL 0007820

[0639] LFWR1 ATL 0007821

[0640] LFWR1 ATL 0007822

[0641] LFWR1 ATL 0007823

[0642] LFWR1 ATL 0007824

[0643] LFWR1 ATL 0007825

[0644] LFWR1 ATL 0007826

[0645] LFWR1 ATL 0007827

[0646] LFWR1 ATL 0007829

[0647] LFWR1 ATL 0007892

[0648] LFWR1 ATL 0007893

[0649] LFWR1 ATL 0007899

[0650] LFWR1 ATL 0007900

[0651] LFWR1 ATL 0007901

[0652] LFWR1 ATL 0007902

[0653] LFWR1 ATL 0007917

[0654] LFWR2 ATL 0008944 VHWYQQLPGTAPKPLIY LFWR2 ATL 0008945

[0655] LFWR2 ATL 0008946

[0656] LFWR2 ATL 0008947

[0657] LFWR2 ATL 0006026

[0658] LFWR2_ ATL 0007925

[0659] LFWR2_ ATL 0007952

[0660] LFWR2_ ATL 0007953

[0661] LFWR2_ ATL 0007955

[0662] LFWR2 ATL 0007450

[0663] LFWR2 ATL 0007819

[0664] LFWR2 ATL 0007820

[0665] LFWR2 ATL 0007821

[0666] LFWR2 ATL 0007822

[0667] LFWR2 ATL 0007823

[0668] LFWR2 ATL 0007824

[0669] LFWR2 ATL 0007825

[0670] LFWR2 ATL 0007826

[0671] LFWR2 ATL 0007827

[0672] LFWR2 ATL 0007829

[0673] LFWR2 ATL 0007889

[0674] LFWR2 ATL 0007890

[0675] LFWR2 ATL 0007892

[0676]

[0677] LFWR2 ATL 0007893

[0678] LFWR2 ATL 0007896

[0679] LFWR2 ATL 0007899

[0680] LFWR2 ATL 0007900

[0681] LFWR2 ATL 0007901

[0682] LFWR2 ATL 0007902

[0683] LFWR2 ATL 0007920

[0684] LFWR3_ATL_0006026 NRPSGVPDRFSGSKSGTSASLVITGLQAEDEADYYC LFWR3_ATL_0007450

[0685] LFWR3_ATL_0007819

[0686] LFWR3_ATL_0007820

[0687] LFWR3_ATL_0007821

[0688] LFWR3_ATL_0007822

[0689] LFWR3_ATL_0007823

[0690] LFWR3_ATL_0007824

[0691] LFWR3_ATL_0007825

[0692] LFWR3_ATL_0007826

[0693] LFWR3_ATL_0007827

[0694] LFWR3_ATL_0007829

[0695] LFWR3_ATL_0007889

[0696] LFWR3_ATL_0007890

[0697] LFWR3_ATL_0007893

[0698] LFWR3_ATL_0007899

[0699] LFWR3_ATL_0007900

[0700] LFWR3_ATL_0007901

[0701] LFWR3_ATL_0007902

[0702] LFWR3_ATL_0007921

[0703] LFWR4 ATL 0006026 FGGGTKVTVL

[0704] LFWR4 ATL 0007450

[0705] LFWR4 ATL 0007819

[0706] LFWR4 ATL 0007820

[0707] LFWR4 ATL 0007821

[0708] LFWR4 ATL 0007822

[0709] LFWR4 ATL 0007823

[0710] LFWR4 ATL 0007824

[0711] LFWR4 ATL 0007825

[0712] LFWR4 ATL 0007826

[0713] LFWR4 ATL 0007827

[0714] LFWR4 ATL 0007829

[0715] LFWR4 ATL 0007889

[0716] LFWR4 ATL 0007890

[0717] LFWR4 ATL 0007892

[0718]

[0719] LFWR4_ATL_0007899

[0720] LFWR4_ATL_0007900

[0721] LFWR4 ATL 0007901

[0722] LFWR4 ATL 0007902

[0723] LFWR4 ATL 0007922

[0724] HFWR1 ATL 0006027 QVQLVQSGAEVKKPGSSVKVSCKAS HFWR2 ATL 0006027 ISWVRQAPGQGLEWMGG HFWR3_ATL_0006027 NYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC HFWR4 ATL 0006027 WGQGTMVTVSS

[0725] LFWR1 ATL 0006027 SS ELTQ D P AVS VALGQTVG I RCQG D LFWR2 ATL 0006027 ANWYQQKPGQAPKLVIY

[0726] LFWR3_ATL_0006027 KRPSGIPDRFSGSTSGNTASLSITGALADDEADYYC LFWR4 ATL 0006027 FGGGTKVTVL

[0727] HFWR1 ATL 0006058 QVQLQESGPGLVKPSETLSLTCTVS HFWR1 ATL 0007933

[0728] HFWR1 ATL 0007956

[0729] HFWR1 ATL 0007467

[0730] HFWR1 ATL 0007468

[0731] HFWR1 ATL 0007469

[0732] HFWR1 ATL 0007470

[0733] HFWR1 ATL 0007471

[0734] HFWR1 ATL 0007472

[0735] HFWR1 ATL 0007473

[0736] HFWR1 ATL 0007926

[0737] HFWR1 ATL 0007927

[0738] HFWR1 ATL 0007928

[0739] HFWR1 ATL 0007929

[0740] HFWR1 ATL 0007930

[0741] HFWR1 ATL 0007931

[0742] HFWR1 ATL 0007932

[0743] HFWR2 ATL 0006058 WAWIRQPAGKRLEWIGR

[0744] HFWR2_ ATL 0007469

[0745] HFWR2_ ATL 0007927

[0746] HFWR3_ATL_0006058 SYNPSLKSRVTMSVDTSKKQFSLKLTSVTAADTAVYYC HFWR3_ATL_0007469

[0747] HFWR4 ATL 0006058 WGQGMLVTVSS

[0748] HFWR4 ATL 0007933

[0749] HFWR4 ATL 0007469

[0750] HFWR4 ATL 0007927

[0751] LFWR1 ATL 0006058 EIVLTQSPGTLSLSPGERATLSCRAS

[0752]

[0753] LFWR1 ATL 0007933

[0754] LFWR1 ATL 0007956

[0755] LFWR1 ATL 0007467

[0756] LFWR1 ATL 0007468

[0757] LFWR1 ATL 0007469

[0758] LFWR1 ATL 0007470

[0759] LFWR1 ATL 0007471

[0760] LFWR1 ATL 0007472

[0761] LFWR1 ATL 0007473

[0762] LFWR1 ATL 0007926

[0763] LFWR1 ATL 0007927

[0764] LFWR1 ATL 0007928

[0765] LFWR1 ATL 0007929

[0766] LFWR1 ATL 0007930

[0767] LFWR1 ATL 0007931

[0768] LFWR1 ATL 0007932

[0769] LFWR2 ATL 0006058 LAWYQQKPGQPPRRLIY

[0770] LFWR2 ATL 0007468

[0771] LFWR3_ATL_0006058 SRATGIPGRFSGSGSGTDFTLSISRLEPEDFAVYYC LFWR3_ATL_0007468

[0772] LFWR4 ATL 0006058 FGQGTRLEIK

[0773] LFWR4 ATL 0007933

[0774] LFWR4 ATL 0007956

[0775] LFWR4 ATL 0007467

[0776] LFWR4 ATL 0007468

[0777] LFWR4 ATL 0007469

[0778] LFWR4 ATL 0007470

[0779] LFWR4 ATL 0007471

[0780] LFWR4 ATL 0007472

[0781] LFWR4 ATL 0007473

[0782] LFWR4 ATL 0007926

[0783] LFWR4 ATL 0007927

[0784] LFWR4 ATL 0007928

[0785] LFWR4 ATL 0007929

[0786] LFWR4 ATL 0007930

[0787] LFWR4 ATL 0007931

[0788] LFWR4 ATL 0007932

[0789] HFWR1 ATL 0006074 QVQLQQWGAGLLKPSETLSLTCAVY HFWR2 ATL 0006074 WSWIRQPPGKGLEWIGE HFWR3_ATL_0006074 NYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC HFWR3_ATL_0007472

[0790]

[0791] HFWR4_ATL_0006074 WGQGTLVTVSS

[0792] LFWR1_ATL_0006074 QSALTQPASVSGSPGQSITISCTGT

[0793] LFWR2 ATL 0006074 VSWYQHHPGKAPKLMIY

[0794] LFWR3_ATL_0006074 NRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYC LFWR4 ATL 0006074 FGGGTKLTVL

[0795] LFWR4 ATL 0007893

[0796] LFWR4 ATL 0007895

[0797] LFWR4 ATL 0007896

[0798] LFWR4 ATL 0007917

[0799] LFWR4 ATL 0007918

[0800] LFWR4 ATL 0007919

[0801] LFWR4 ATL 0007920

[0802] LFWR4 ATL 0007921

[0803] LFWR4 ATL 0007923

[0804] LFWR4 ATL 0007924

[0805] HFWR1 ATL 0006075 QVQLQESGPGLVKPSQTLSLTCTVS

[0806] HFWR2 ATL 0006075 WSWI RQH PGKGLEWIGY

[0807] HFWR3_ATL_0006075 YYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC HFWR4 ATL 0006075 WGQGTTVTVSS

[0808] LFWR1 ATL 0006075 QSALTQPASVSGSPGQSITLSCTGT

[0809] LFWR2 ATL 0006075 VSWYQHHPGKAPRLIFS

[0810] LFWR3_ATL_0006075 NRPSGVSTRFSASKSGNTASLTISGLQTEDEALYYC LFWR4 ATL 0006075 FGGGTKLTVL

[0811] Recombinant Human 15- MAHMVNGKVALVTGAAQGIGRAFAEALLLKGAKVALVDW PGDH (C-term Avi-His6)

[0812] NLEAGVQCKAALDEQFEPQKTLFIQCDVADQQQLRDTFR KVVDHFGRLDILVNNAGVNNEKNWEKTLQINLVSVISGTY LGLDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASK HGIVGFTRSAALAANLMNSGVRLNAICPGFVNTAILESIEK EENMGQYIEYKDHIKDMIKYYGILDPPLIANGLITLIEDDAL NGAIMKITTSKGIHFQDYDTTPFQAKTQSLSGGGGSTPPT PSTPPTGLNDIFEAQKIEWHEHHHHHH

[0813] Uniprot ID P15428 MHVNGKVALVTGAAQGIGRAFAEALLLKGAKVALVDWNL PGDH HUMAN 15- EAGVQCKAALDEQFEPQKTLFIQCDVADQQQLRDTFRKV

[0814] hydroxyprostaglandin

[0815] dehydrogenase [NAD(+)] VDHFGRLDILVNNAGVNNEKNWEKTLQINLVSVISGTYLG OS=Homo sapiens

[0816] LDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASKHG IVGFTRSAALAANLMNSGVRLNAICPGFVNTAILESIEKEE NMGQYIEYKDHIKDMIKYYGILDPPLIANGLITLIEDDALNG AIMKITTSKGIHFQDYDTTPFQAKTQ

[0817]

[0818] rhPGDH - Recombinant MHVNGKVALVTGAAQGIGRAFAEALLLKGAKVALVDWNL Human 15-PGDH (C-term EAGVQCKAALDEQFEPQKTLFIQCDVADQQQLRDTFRKV

[0819] His6)

[0820] VDHFGRLDILVNNAGVNNEKNWEKTLQINLVSVISGTYLG LDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASKHG IVGFTRSAALAANLMNSGVRLNAICPGFVNTAILESIEKEE NMGQYIEYKDHIKDMIKYYGILDPPLIANGLITLIEDDALNG AIMKITTSKGIHFQDYDTTPFQAKTQHHHHHH

[0821] Uniprot ID Q8MJY8 MHVNGKVALVTGAAQGIGRAFAEALLLKGAKVALVDWNL PGDH_MACFA 15- EAGVQCKAALDEKFEPQKTLFIQCDVADQQQLRDTFRKV

[0822] hydroxyprostaglandin

[0823] dehydrogenase [NAD(+)] VDHFGRLDILVNNAGVNNEKNWEKTLQINLVSVISGTYLG OS= Macaca fascicularis LDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASKHG IVGFTRSAALAANLMNSGVRLNAICPGFVNTAILESIEKEE NMGQYIEYKDHIKDMIKYYGILDPPLIANGLITLIEDDALNG AIMKITTSKGIHFQDYDATPFQAKSQ

[0824] Recombinant Mouse 15- MHVNGKVALVTGAAQGIGKAFAEALLLHGAKVALVDWNL PGDH (C-term His6)

[0825] EAGVKCKAALDEQFEPQKTLFVQCDVADQKQLRDTFRKV

[0826] (Sino Biological, 50531- M08E) VDHFGRLDILVNNAGVNNEKNWEQTLQINLVSVISGTYLG LDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASKHG IIGFTRSAAMAANLMKSGVRLNVICPGFVDTPILESIEKEE NMGQYIEYKDQIKAMMKFYGVLHPSTIANGLINLIEDDALN GAIMKITASKGIHFQDYDISPLLVKAPLTSHHHHHHHHHH

[0827] Uniprot ID Q8VCC1 MHVNGKVALVTGAAQGIGKAFAEALLLHGAKVALVDWNL PGDH MOUSE 15- EAGVKCKAALDEQFEPQKTLFVQCDVADQKQLRDTFRKV

[0828] hydroxyprostaglandin

[0829] dehydrogenase [NAD(+)] VDHFGRLDILVNNAGVNNEKNWEQTLQINLVSVISGTYLG OS=Mus musculus

[0830] LDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASKHG IIGFTRSAAMAANLMKSGVRLNVICPGFVDTPILESIEKEE NMGQYIEYKDQIKAMMKFYGVLHPSTIANGLINLIEDDALN GAIMKITASKGIHFQDYDISPLLVKAPLTS

[0831] Human heavy chain ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV constant sequence for SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT lgG1 LALA QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP PSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK

[0832] Human lambda light chain GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTV constant sequence AWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQ

[0833] WKSHRSYSCQVTHEGSTVEKTVAPTECS

[0834]

[0835] Human kappa light chain RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ constant sequence WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADY EKHKVYACEVTHQGLSSPVTKSFNRGEC ATL 0007925 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR ATL 0007919 VH QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTETST STAYMELRSLRSDETAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007952 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYQGNTNYAQKLQGRVTMTTDTS TSTAYMELRSLRSDETAVYYCARDLGPYYYDASGYYYGF DIWGQGTTVTVSS ATL 0007953 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYQGNANYAQKLQGRVTMTTETS TSTAYMELRSLRSDETAVYYCARDLGPYYYDASGYYYGF DIWGQGTTVTVSS ATL 0008944 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR ATL 0008945 VH QAPGQGLEWMGWISAYNANSNYAQKLQGRVTMTTDTST ATL 0008946 VH STAYMELRSLRSEDAAVYYCARDLGPYYYDASGYYYGFD ATL 0008947 VH IWGQGTTVTVSS

[0836] ATL 0007955 VH

[0837] ATL 0007925 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ ATL 0007952 VL QLPGTAPKPLIYGNNNRPSGVPDRFSGSKSGTSASLAITG ATL 0007953 VL LQAEDEADYYCQSYDNNLSVAFGGGTKLTVL ATL 0007955 VL

[0838] HFWR1 ATL 0008944 QVQLVQSGAEVKKPGASVKVSCKAS

[0839] HFWR1 ATL 0008945

[0840] HFWR1 ATL 0008946

[0841] HFWR1 ATL 0008947

[0842] HFWR1 ATL 0007925

[0843] HFWR1 ATL 0007952

[0844] HFWR1 ATL 0007953

[0845] HFWR1 ATL 0007955

[0846] HFWR1_ ATL 0007450

[0847] HFWR1_ ATL 0007819

[0848] HFWR1_ ATL 0007820

[0849] HFWR1_ ATL 0007821

[0850] HFWR1_ ATL 0007822

[0851] HFWR1_ ATL 0007823

[0852] HFWR1_ ATL 0007824

[0853] HFWR1_ ATL 0007825

[0854]

[0855] HFWR1_ ATL 0007826

[0856] HFWR1_ ATL 0007827

[0857] HFWR1_ ATL 0007829

[0858] HFWR1_ ATL 0007889

[0859] HFWR1_ ATL 0007890

[0860] HFWR1_ ATL 0007892

[0861] HFWR1_ ATL 0007893

[0862] HFWR1_ ATL 0007895

[0863] HFWR1_ ATL 0007896

[0864] HFWR1_ ATL 0007899

[0865] HFWR1_ ATL 0007900

[0866] HFWR1_ ATL 0007901

[0867] HFWR1_ ATL 0007902

[0868] HFWR1_ ATL 0007917

[0869] HFWR1_ ATL 0007918

[0870] HFWR1_ ATL 0007919

[0871] HFWR1_ ATL 0007920

[0872] HFWR1_ ATL 0007921

[0873] HFWR1_ ATL 0007922

[0874] HFWR1_ ATL 0007923

[0875] HFWR1_ ATL 0007924

[0876] HCDR2 ATL 0007952 ISAYQGNT

[0877] HCDR2 ATL 0007917

[0878] HCDR2 ATL 0007918

[0879] HCDR2 ATL 0007921

[0880] HCDR2 ATL 0007922

[0881] HCDR2 ATL 0007924

[0882] HCDR2 ATL 0007953 ISAYQGNA

[0883] HCDR2 ATL 0008944 ISAYNANS

[0884] HCDR2 ATL 0008945

[0885] HCDR2 ATL 0008946

[0886] HCDR2 ATL 0008947

[0887] HCDR2 ATL 0007955

[0888] HFWR3_ATL_0007925 NYAQKLQGRVTMTTETSTSTAYMELRSLRSDETAVYYC HFWR3 _ATL_0007953

[0889] HFWR3_ ATL 0007919

[0890] HFWR3_ATL_0007952 NYAQKLQGRVTMTTDTSTSTAYMELRSLRSDETAVYYC HFWR3_ATL_0007917

[0891] HFWR3_ATL_0007920

[0892] HFWR3_ATL_0007921

[0893] HFWR3_ATL_0008944 NYAQKLQGRVTMTTDTSTSTAYMELRSLRSEDAAVYYC HFWR3_ATL_0008945

[0894]

[0895] HFWR3_ATL_0008946

[0896] HFWR3_ATL_0008947

[0897] HFWR3_ATL_0007955

[0898] HCDR3_ATL_0008944 ARDLGPYYYDASGYYYGFDI HCDR3_ATL_0008945

[0899] HCDR3_ATL_0008946

[0900] HCDR3_ATL_0008947

[0901] HCDR3_ATL_0007952

[0902] HCDR3_ATL_0007953

[0903] HCDR3_ATL_0007955

[0904] HCDR3_ATL_0007829

[0905] HFWR4 ATL 0008944 WGQGTTVTVSS HFWR4 ATL 0008945

[0906] HFWR4 ATL 0008946

[0907] HFWR4 ATL 0008947

[0908] HFWR4 ATL 0007925

[0909] HFWR4 ATL 0007952

[0910] HFWR4 ATL 0007953

[0911] HFWR4 ATL 0007955

[0912] HFWR4 ATL 0007450

[0913] HFWR4 ATL 0007819

[0914] HFWR4 ATL 0007820

[0915] HFWR4 ATL 0007821

[0916] HFWR4 ATL 0007822

[0917] HFWR4 ATL 0007823

[0918] HFWR4 ATL 0007824

[0919] HFWR4 ATL 0007825

[0920] HFWR4 ATL 0007826

[0921] HFWR4 ATL 0007827

[0922] HFWR4 ATL 0007829

[0923] HFWR4 ATL 0007889

[0924] HFWR4 ATL 0007890

[0925] HFWR4 ATL 0007892

[0926] HFWR4 ATL 0007893

[0927] HFWR4 ATL 0007895

[0928] HFWR4 ATL 0007896

[0929] HFWR4 ATL 0007899

[0930] HFWR4 ATL 0007900

[0931] HFWR4 ATL 0007901

[0932] HFWR4 ATL 0007902

[0933] HFWR4 ATL 0007917

[0934]

[0935] HFWR4_ATL_0007918

[0936] HFWR4_ATL_0007919

[0937] HFWR4 ATL 0007920

[0938] HFWR4 ATL 0007921

[0939] HFWR4 ATL 0007922

[0940] HFWR4 ATL 0007923

[0941] HFWR4 ATL 0007924

[0942] LFWR1 ATL 0008944 QSVLTQPPSVSGAPGQRVTISCTGS LFWR1 ATL 0008945

[0943] LFWR1 ATL 0008946

[0944] LFWR1 ATL 0008947

[0945] LFWR1 ATL 0007925

[0946] LFWR1 ATL 0007952

[0947] LFWR1 ATL 0007953

[0948] LFWR1 ATL 0007955

[0949] LFWR1 ATL 0007896

[0950] LFWR1 ATL 0007920

[0951] LFWR1 ATL 0007921

[0952] LFWR1 ATL 0007922

[0953] LCDR2 ATL 0008944 GNN

[0954] LCDR2 ATL 0008945

[0955] LCDR2 ATL 0008946

[0956] LCDR2 ATL 0008947

[0957] LCDR2 ATL 0007925

[0958] LCDR2 ATL 0007952

[0959] LCDR2 ATL 0007953

[0960] LCDR2 ATL 0007955

[0961] LCDR2 ATL 0007900

[0962] LCDR2 ATL 0007919

[0963] LCDR2 ATL 0007923

[0964] LFWR3_ATL_0008944 NRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYC LFWR3_ATL_0008945

[0965] LFWR3_ATL_0008946

[0966] LFWR3_ATL_0008947

[0967] LFWR3_ATL_0007925

[0968] LFWR3_ATL_0007952

[0969] LFWR3_ATL_0007953

[0970] LFWR3_ATL_0007955

[0971] LFWR3_ATL_0007892

[0972] LFWR3_ATL_0007895

[0973] LFWR3_ATL_0007896

[0974]

[0975] LFWR3_ATL_0007917

[0976] LFWR3_ATL_0007918

[0977] LFWR3_ATL_0007919

[0978] LFWR3_ATL_0007920

[0979] LFWR3_ATL_0007922

[0980] LFWR3_ATL_0007923

[0981] LFWR3_ATL_0007924

[0982] LCDR3_ATL_0007925 QSYDNNLSVA

[0983] LCDR3_ATL_0007952

[0984] LCDR3_ATL_0007953

[0985] LCDR3_ATL_0007955

[0986] LCDR3_ATL_0007902

[0987] LCDR3_ATL_0007917

[0988] LCDR3_ATL_0007922

[0989] LCDR3_ATL_0007923

[0990] LCDR3_ATL_0007924

[0991] LFWR4 ATL 0008944 FGGGTKLTVL

[0992] LFWR4 ATL 0008945

[0993] LFWR4 ATL 0008946

[0994] LFWR4 ATL 0008947

[0995] LFWR4 ATL 0007925

[0996] LFWR4 ATL 0007952

[0997] LFWR4 ATL 0007953

[0998] LFWR4 ATL 0007955

[0999] ATL 0007933 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTISVETSKNQF SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGMLV TVSS ATL 0007956 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWSWIRQ ATL 0007926 VH PAGKGLEWIGRVYASGSTNYNPSLKSRVTISVETSKNQF SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007933 VL EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQQ ATL 0007956 VL KPGQAPRLLIYGTSSRATGIPDRFSGSGSGTDFTLTISRLE ATL 0007467 VL PEDFAVYYCQQYGSSPPTFGQGTRLEIK ATL 0007469 VL

[1000] ATL 0007470 VL

[1001] ATL 0007471 VL

[1002] ATL 0007472 VL

[1003] ATL 0007473 VL

[1004] ATL 0007928 VL

[1005]

[1006] ATL 0007929 VL

[1007] ATL 0007930 VL

[1008] ATL 0007931 VL

[1009] ATL 0007932 VL

[1010] HCDR1 ATL 0007933 GESITSYF

[1011] HCDR1 ATL 0007956

[1012] HCDR1 ATL 0007470

[1013] HCDR1 ATL 0007926

[1014] HCDR1 ATL 0007927

[1015] HCDR1 ATL 0007928

[1016] HCDR1 ATL 0007929

[1017] HCDR1 ATL 0007930

[1018] HCDR1 ATL 0007931

[1019] HCDR1 ATL 0007932

[1020] HFWR2 ATL 0007933 WSWIRQPAGKGLEWIGR

[1021] HFWR2 ATL 0007956

[1022] HFWR2 ATL 0007467

[1023] HFWR2 ATL 0007468

[1024] HFWR2 ATL 0007470

[1025] HFWR2 ATL 0007471

[1026] HFWR2 ATL 0007472

[1027] HFWR2 ATL 0007473

[1028] HFWR2 ATL 0007926

[1029] HFWR2 ATL 0007930

[1030] HFWR2 ATL 0007931

[1031] HFWR2 ATL 0007932

[1032] HFWR3_ATL_0007933 NYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYC HFWR3_ATL_0007956

[1033] HFWR3_ATL_0007926

[1034] HFWR3_ATL_0007928

[1035] HFWR3_ATL_0007929

[1036] HFWR4 ATL 0007956 WGQGTLVTVSS

[1037] HFWR4 ATL 0007467

[1038] HFWR4 ATL 0007468

[1039] HFWR4 ATL 0007470

[1040] HFWR4 ATL 0007471

[1041] HFWR4 ATL 0007472

[1042] HFWR4 ATL 0007473

[1043] HFWR4 ATL 0007926

[1044] HFWR4 ATL 0007928

[1045] HFWR4 ATL 0007929

[1046]

[1047] HFWR4 ATL 0007930

[1048] HFWR4 ATL 0007931

[1049] HFWR4 ATL 0007932

[1050] LFWR2 ATL 0007933 LAWYQQKPGQAPRLLIY

[1051] LFWR2 ATL 0007956

[1052] LFWR2 ATL 0007467

[1053] LFWR2 ATL 0007469

[1054] LFWR2 ATL 0007470

[1055] LFWR2 ATL 0007471

[1056] LFWR2 ATL 0007472

[1057] LFWR2 ATL 0007473

[1058] LFWR2 ATL 0007928

[1059] LFWR2 ATL 0007929

[1060] LFWR2 ATL 0007930

[1061] LFWR2 ATL 0007931

[1062] LFWR2 ATL 0007932

[1063] LFWR3_ATL_0007933 SRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC LFWR3_ATL_0007956

[1064] LFWR3_ATL_0007467

[1065] LFWR3_ATL_0007469

[1066] LFWR3_ATL_0007470

[1067] LFWR3_ATL_0007471

[1068] LFWR3_ATL_0007472

[1069] LFWR3_ATL_0007473

[1070] LFWR3_ATL_0007926

[1071] LFWR3_ATL_0007927

[1072] LFWR3_ATL_0007928

[1073] LFWR3_ATL_0007929

[1074] LFWR3_ATL_0007930

[1075] LFWR3_ATL_0007931

[1076] LFWR3_ATL_0007932

[1077] ATL 0007450 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR ATL 0007889 VH QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTST ATL 0007902 VH STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD ATL 0007901 VH IWGQGTTVTVSS

[1078] ATL 0007900 VH

[1079] ATL 0007899 VH

[1080] ATL 0007896 VH

[1081] ATL 0007895 VH

[1082] ATL 0007893 VH

[1083]

[1084] ATL 0007892 VH

[1085] ATL 0007890 VH

[1086] ATL 0007819 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWAGWISAYNGNTNYAQKLQGRVTMTTDTST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007820 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYAGNTNYAQKLQGRVTMTTDTST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007821 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNANTNYAQKLQGRVTMTTDTST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007822 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGATNYAQKLQGRVTMTTDTST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007823 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNANYAQKLQGRVTMTTDTS TSTAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGF

[1087] □IWGQGTTVTVSS

[1088] ATL 0007824 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTITTDTST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007825 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTETST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007826 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTST STAYAELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007827 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTST STAYMELRSLRSEDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007829 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR

[1089] QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTST

[1090]

[1091] STAYMELRSLRSDDTAVYYCARDLGPYYYDASGYYYGFD IWGQGTTVTVSS ATL 0007917 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYQGNTNYAQKLQGRVTMTTDTS TSTAYMELRSLRSDETAVYYCARDLGPYYYESSGYYYGF DIWGQGTTVTVSS ATL 0007918 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR ATL 0007924 VH QAPGQGLEWMGWISAYQGNTNYAQKLQGRVTMTTETST STAYMELRSLRSDDTAVYYCARDLGPYYYDSSGYYYGFD IWGQGTTVTVSS ATL 0007920 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTST STAYMELRSLRSDETAVYYCARDLGPYYYESSGYYYGFD IWGQGTTVTVSS ATL 0007921 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYQGNTNYAQKLQGRVTMTTDTS TSTAYMELRSLRSDETAVYYCARDLGPYYYDSSGYYYGF DIWGQGTTVTVSS ATL 0007922 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYQGNTNYAQKLQGRVTMTTDTS TSTAYMELRSLRSDDTAVYYCARDLGPYYYESSGYYYGF DIWGQGTTVTVSS ATL 0007923 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTETST STAYMELRSLRSDDTAVYYCARDLGPYYYESSGYYYGFD IWGQGTTVTVSS ATL 0007889 VL QSVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDNSLSVAFGGGTKVTVL ATL 0007890 VL QAVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDNSLSVAFGGGTKVTVL ATL 0007892 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNSLSVAFGGGTKVTVL ATL 0007893 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDNSLSVAFGGGTKLTVL ATL 0007895 VL QSVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNSLSVAFGGGTKLTVL

[1092]

[1093] ATL 0007896 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNSLSVAFGGGTKLTVL ATL 0007899 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGQSNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDNSLSVAFGGGTKVTVL ATL 0007900 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNNNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDNSLSVAFGGGTKVTVL ATL 0007901 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDQSLSVAFGGGTKVTVL ATL 0007902 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDNNLSVAFGGGTKVTVL ATL 0007917 VL QAVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGQNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNNLSVAFGGGTKLTVL ATL 0007918 VL QAVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGQNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNSLSVAFGGGTKLTVL ATL 0007919 VL QSVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDQSLSVAFGGGTKLTVL ATL 0007920 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDQNLSVAFGGGTKLTVL ATL 0007921 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGQSNRPSGVPDRFSGSKSGTSASLVITG LQAEDEADYYCQSYDQSLSVAFGGGTKLTVL ATL 0007922 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGQSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNNLSVAFGGGTKVTVL ATL 0007923 VL QAVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNNLSVAFGGGTKLTVL ATL 0007924 VL QSVLTQPSSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGQSNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNNLSVAFGGGTKLTVL HFWR2 ATL 0007819 ISWVRQAPGQGLEWAGW

[1094] HCDR2 ATL 0007820 ISAYAGNT

[1095]

[1096] HCDR2_ATL_0007821 ISAYNANT

[1097] HCDR2_ATL_0007822 ISAYNGAT

[1098] HCDR2 ATL 0007823 ISAYNGNA

[1099] HFWR3_ATL_0007824 NYAQKLQGRVTITTDTSTSTAYMELRSLRSDDTAVYYC HFWR3_ATL_0007825 NYAQKLQGRVTMTTETSTSTAYMELRSLRSDDTAVYYC HFWR3_ATL_0007918

[1100] HFWR3_ATL_0007923

[1101] HFWR3_ATL_0007924

[1102] HFWR3_ATL_0007826 NYAQKLQGRVTMTTDTSTSTAYAELRSLRSDDTAVYYC HFWR3_ATL_0007827 NYAQKLQGRVTMTTDTSTSTAYMELRSLRSEDTAVYYC HCDR3_ ATL 0007917 ARDLGPYYYESSGYYYGFDI

[1103] HCDR3_ ATL 0007920

[1104] HCDR3_ ATL 0007922

[1105] HCDR3_ ATL 0007923

[1106] LFWR1 ATL 0007889 QSVLTQPSSVSGAPGQRVTISCTGS

[1107] LFWR1 ATL 0007895

[1108] LFWR1 ATL 0007919

[1109] LFWR1 ATL 0007924

[1110] LFWR1 ATL 0007890 QAVLTQPPSVSGAPGQRVTISCTGS

[1111] LFWR1 ATL 0007918

[1112] LFWR1 ATL 0007923

[1113] LFWR2 ATL 0007895 VHWYQQLPGTAPKLLIY

[1114] LFWR2 ATL 0007917

[1115] LFWR2 ATL 0007918

[1116] LFWR2 ATL 0007919

[1117] LFWR2 ATL 0007921

[1118] LFWR2 ATL 0007922

[1119] LFWR2 ATL 0007923

[1120] LFWR2 ATL 0007924

[1121] LCDR2 ATL 0007917 GQN

[1122] LCDR2 ATL 0007918

[1123] LCDR2 ATL 0007899 GQS

[1124] LCDR2 ATL 0007921

[1125] LCDR2 ATL 0007922

[1126] LCDR2 ATL 0007924

[1127] LCDR3_ ATL 0008945 QSYDQSLSVA

[1128] LCDR3_ATL_0007901

[1129] LCDR3_ATL_0007919

[1130] LCDR3_ATL_0007921

[1131] LCDR3_ATL_0007920 QSYDQNLSVA

[1132]

[1133] Recombinant Macaca MHVNGKVALVTGAAQGIGRAFAEALLLKGAKVALVDWNL EAGVQCKAALDEKFEPQKTLFIQCDVADQQQLRDTFRKV

[1134] fascicularis 15-PGDH (C- VDHFGRLDILVNNAGVNNEKNWEKTLQINLVSVISGTYLG

[1135] term His 6) LDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASKHG IVGFTRSAALAANLMNSGVRLNAICPGFVNTAILESIEKEE NMGQYIEYKDHIKDMIKYYGILDPPLIANGLITLIEDDALNG AIMKITTSKGIHFQDYDATPFQAKSQLEHHHHHH

[1136] Rattus norvegicus 15- MHVNGKVALVTGAAQGIGKAFTEALLLHGAKVALVDWNL ETGVKCKAALDEQFEPQKTLFIQCDVADQKQLRDTFRKV PGDH 15-PGDH (UniProt VDHFGRLDILVNNAGVNNEKNWEQTLQINLVSVISGTYLG

[1137] 008699) LDYMSKQNGGEGGIIINISSIAGLMPVAQQPVYCASKHGII GFTRSAAMAANLMKSGVRLNVICPGFVKTPILESIEKEEN MGQYIEYTDQIKAMMKFYGILDPSAIANGLINLIEDDALNG AIMKITASKGIHFQDYDLFPSFSKAP

[1138] Recombinant Rattus MHVNGKVALVTGAAQGIGKAFTEALLLHGAKVALVDWNL ETGVKCKAALDEQFEPQKTLFIQCDVADQKQLRDTFRKV

[1139] norvegicus 15-PGDH (C- VDHFGRLDILVNNAGVNNEKNWEQTLQINLVSVISGTYLG

[1140] term His6) LDYMSKQNGGEGGIIINISSIAGLMPVAQQPVYCASKHGII GFTRSAAMAANLMKSGVRLNVICPGFVKTPILESIEKEEN MGQYIEYTDQIKAMMKFYGILDPSAIANGLINLIEDDALNG AIMKITASKGIHFQDYDLFPSFSKAPLEHHHHHH

[1141] Recombinant Human 15- MAHMVNGKVALVTGAAQGIGRAFAEALLLKGAKVALVDW NLEAGVQCKAALDEQFEPQKTLFIQCDVADQQQLRDTFR PGDH (C-term His6)

[1142] KVVDHFGRLDILVNNAGVNNEKNWEKTLQINLVSVISGTY LGLDYMSKQNGGEGGIIINMSSLAGLMPVAQQPVYCASK HGIVGFTRSAALAANLMNSGVRLNAICPGFVNTAILESIEK EENMGQYIEYKDHIKDMIKYYGILDPPLIANGLITLIEDDAL NGAIMKITTSKGIHFQDYGSKENLYFQGAGHHHHHH IGHV1 -18*01 Homo QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWVR QAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTTDTST

[1143] Sapiens

[1144] STAYMELRSLRSDDTAVYYCAR IGLV1 -40*01 Homo QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQ PAGKGLEWIGRIYTSGSTNYNPSLKSRVTMSVDTSKNQF

[1145] Sapiens

[1146] SLKLSSVTAADTAVYYCAR IGHV4-4*07 Homo QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKLLIYGNSNRPSGVPDRFSGSKSGTSASLAITG

[1147] Sapiens

[1148] LQAEDEADYYCQSYDSSLSG IGKV3-20*01 Homo EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQ KPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLE

[1149] Sapiens

[1150] PEDFAVYYCQQYGSSP ATL 0007471 VH QVQLQESGPGLVKPSETLSLTCTVSGDAITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTMSVDTSKNQF SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007472 VH QVQLQESGPGLVKPSETLSLTCTVSGDSITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTISVDTSKNQF SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007467 VH QVQLQESGPGLVKPSETLSLTCTVSGDSITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTMSVDTSKNQF ATL 0007468 VH

[1151] SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007473 VH QVQLQESGPGLVKPSETLSLTCTVSGDSITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTMSVETSKNQF SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007928 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWAWIRQ

[1152] PAGKGLEWIGRVYASGSTNYNPSLKSRVTISVETSKNQF

[1153]

[1154] SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007927 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWAWIRQ PAGKRLEWIGRVYASGSTSYNPSLKSRVTISVETSKKQFS LKLTSVTAADTAVYYCARDLFFGSGSHFDPWGQGMLVTV SS ATL 0007931 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTISVETSKKQFS LKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVTV SS ATL 0007932 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTISVETSKNQF SLKLTSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007470 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWSWIRQ PAGKGLEWIGRVYASGSTNYNPSLKSRVTMSVDTSKNQF SLKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVT VSS ATL 0007930 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWSWIRQ PAGKGLEWIGRVYASGSTSYNPSLKSRVTISVETSKNQFS LKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVTV SS ATL 0007929 VH QVQLQESGPGLVKPSETLSLTCTVSGESITSYFWSWIRQ PAGKRLEWIGRVYASGSTNYNPSLKSRVTISVETSKNQFS LKLSSVTAADTAVYYCARDLFFGSGSHFDPWGQGTLVTV SS ATL 0007927 VL EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQQ KPGQAPRRLIYGTSSRATGIPDRFSGSGSGTDFTLTISRL EPEDFAVYYCQQYGSSPPTFGQGTRLEIK ATL 0007926 VL EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQQ KPGQPPRLLIYGTSSRATGIPDRFSGSGSGTDFTLTISRLE PEDFAVYYCQQYGSSPPTFGQGTRLEIK HCDR1 ATL 0007471 GDAITSYF

[1155] HFWR2 ATL 0007928 WAWIRQPAGKGLEWIGR

[1156] HFWR2 ATL 0007929 WSWIRQPAGKRLEWIGR

[1157] HFWR3_ATL_0007931 NYNPSLKSRVTISVETSKKQFSLKLSSVTAADTAVYYC HFWR3_ATL_0007932 NYNPSLKSRVTISVETSKNQFSLKLTSVTAADTAVYYC HFWR3_ATL_0007467 NYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYC HFWR3_ATL_0007468

[1158] HFWR3_ATL_0007470

[1159] HFWR3_ATL_0007471

[1160] HFWR3_ATL_0007473 NYNPSLKSRVTMSVETSKNQFSLKLSSVTAADTAVYYC

[1161]

[1162] 198 HFWR3_ATL_0007927 SYNPSLKSRVTISVETSKKQFSLKLTSVTAADTAVYYC 199 HFWR3_ATL_0007930 SYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYC 200 LFWR2 ATL 0007927 LAWYQQKPGQAPRRLIY

[1163] 201 LFWR2 ATL 0007926 LAWYQQKPGQPPRLLIY

[1164] 202 ATL 0008944 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNALSVAFGGGTKLTVL

[1165] 203 ATL 0008945 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDQSLSVAFGGGTKLTVL

[1166] 204 ATL 0008946 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNQLSVAFGGGTKLTVL

[1167] 205 ATL 0008947 VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQ QLPGTAPKPLIYGNNNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCQSYDNSLSVAFGGGTKLTVL

[1168] 206 LCDR3_ ATL 0008944 QSYDNALSVA

[1169] 207 LCDR3_ ATL 0008946 QSYDNQLSVA

[1170]

[1171] Table 1. Sequences disclosed in this specification.

[1172] Examples

[1173] The present examples demonstrate the identification of new antibodies with therapeutic potential derived from PD patients that are considered resilient and / or cognitively healthy (Examples 1 and 2), that show excellent kinetic properties (Example 3) and stability (Example 4). In silico investigation of the antibody structure and binding to target was performed (Example 5), showing at least two different binding modes for antibodies that inhibit PGDH. In vitro functional studies are described in Example 6, showing the ability of antibodies of the disclosure to suppress the pro-inflammatory cytokine IL6, the abundance of phospho-aSyn129 (a post-translational modification characteristic for the pathogenic aSynuclein species), and restore mitochondrial function in a model of alpha synucleinopathies (“PD in a dish”, a model of inflammation indicted by alpha synuclein in a dopaminergic neurons, astrocytes and microglia triculture). In vivo functional studies are described in Examples 7 and 8, showing the ability of antibodies of the disclosure to reduce levels of neuroinflammation in vivo in mice exposed to LPS (Example 7), and to improve gait and postural stability in aged mice (Example 8). Variants of the antibodies used in Examples 1-8 are described and characterised in Example 9.

[1174] Materials and methods

[1175] Patient Cohorts

[1176] Two cohorts of patients were used in these examples. The PREDICT-PD cohort (predictpd.com) comprises patients with RBD, classified as resilient if they had a formal diagnosis of RBD but were cognitively healthy (MoCA score >25; Nasreddine et al., 2005), and had a UPDRS (Unified Parkinson's Disease Rating Scale, a rating tool used to gauge the severity and progression of Parkinson’s disease in patients; Poewe 2009)part III minus tremor score < 7. The East London Project (ELPD) cohort is a PD cohort comprising patients classified as progressors if they had a formal diagnosis of PD, a MoCA score <26 and UPDRS part III minus tremor score >6 (Zirra et al., 2022). Age matched controls from the PREDICT-PD cohort were also used. Molecular Indexing of Proteins by Self-Assembly (MIPSA)

[1177] Detailed methods for performing MIPSA are provided in Credle et al., 2021 . Briefly, barcodes are introduced near the 5’ end of transcribed mRNA sequences, upstream of the ribosome binding site (RBS). Reverse transcription (RT) of the 5’ end of in vitro transcribed RNA (IVT-RNA) creates a cDNA barcode, which is linked to a haloalkane-labeled RT primer. An N-terminal HaloTag fusion protein is encoded downstream of the RBS, such that in vitro translation results in the intra-complex (“cis”), covalent coupling of the cDNA barcode to the HaloTag and its downstream open reading frame (ORF) encoded protein product. Immunoprecipitation experiments were performed to identify antigen reactivities in the patient serum samples. Briefly, serum samples diluted 1 OO were incubated with the MIPSA library of in vitro translated proteins. The mixture was then added to protein A and protein G beads (ratio 1 :1). After washing the beads, they were used as input for PCR to amplify barcode sequences. A second PCR step added Illumina adapters and indexes. Sequencing was performed on an Illumina NextSeq 500 with a single end read of up to 75 cycles. Reads were assigned to ORFs using an 'ORF dictionary' generated from sequencing the unselected MIPSA library. Hits were identified by comparing read counts to the beads only control. Multiple barcodes per antigen help to increase hit confidence.

[1178] Recombinant 15-PGDH production

[1179] Recombinant human 15-PGDH encoding residues 3-266 and additional C-terminal Avi- and hexahistidine tag (rhPGDH-Avi-His), a commonly used peptide sequence to allow for site specific biotinylation of proteins with that tag via the use of BirA enzyme, was expressed in E. coli and purified using immobilized Nibaffinity chromatography. Purified rhPGDH-Avi-His protein was frozen in 20 mM Tris-HCI pH 7.0, 150 mM NaCI, 0.5 mM DTT and 10% v / v glycerol. Purified rhPGDH-Avi-His was biotinylated using either BirA biotinprotein ligase standard reaction kit (Avidity, LLC) or EZ-Link™ NHS-PEG4 Biotinylation Kit (Thermo Scientific™, 21455) following the manufacturer’s instructions. The biotinylated products (Avi-linked biotinylated-rhPGDH-Avi-Hi; ALB-rhPGDH and NHz-linked biotinylated- rhPGDH-Avi-His; NLB-rhPGDH-Avi-His respectively) were buffer exchanged into 20 mM Tris-HCI pH 7.0, 150 mM NaCI, 0.5 mM DTT and 10% v / v glycerol. Commercial sources of 15-PGDH were reconstituted in phosphate buffered saline, recombinant human 15-PGDH: rhPGDH-His R&D Systems (5660-DH-010) and rhPGDH-His Sino Biological (11205-H08E) and recombinant mouse 15-PGDH: rmPGDH-His Sino Biological (50531-M08E). Biotinylated rmPGDH-His Sino Biological was produced using EZ-Link™ NHS-PEG4 Biotinylation Kit (Thermo Scientific™, 21455) following the manufacturer’s instructions. The biotinylated rmPGDH-His Sino Biological was buffer exchanged into 20 mM Tris-HCI pH 7.0, 150 mM NaCI, 0.5 mM DTT and 10% v / v glycerol.

[1180] Table 2A lists the recombinant antigens used in the examples.

[1181] UniProt

[1182] Acession Catalogue

[1183]

[1184] Antigen name Short name number Supplier numberRecombinant Human 15-PGDH (C-term rhPGDH- Avi-His6) (SEQ ID NO: 81) Avi-His P 15428 In-house N / A Recombinant Human 15-PGDH (C-term R&D

[1185] His6) (SEQ ID NO: 83) rhPGDH-His P15428 Systems 5660-DH-010 Recombinant Human 15-PGDH (C-term Sino

[1186] His6) (SEQ ID NO: 83) rhPGDH-His P15428 Biological 11205-H08E Recombinant Mouse 15-PGDH (C-term rmPGDH- Sino

[1187] His6) (SEQ ID NO: 85) His Q8VCC1 Biological 50531 -M08E Recombinant Human 15-PGDH (C-term

[1188] His6) (SEQ ID NO: 173) rhPGDH-His P15428 In house N / A Recombinant Cyno 15-PGDH (C-term

[1189] His-6) (SEQ ID NO: 170) rcPGDH-His Q8MJY8 In house N / A Recombinant Rat 15-PGDH (C-term His-

[1190]

[1191] 6) (SEQ ID NO: 172) rrPGDH-His 008699 In house N / A

[1192] Table 2A. Summary of antigen constructs used in the examples.

[1193] Screening patient (subjects from Parkinson’s cohorts) serum and plasma for 15-PGDH reactivity by ELISA Recombinant human 15-PGDH (rhPGDH-Avi-His)R&D Systems, 5660-DH-010) as well as negative control antigen Lysozyme (MP Biomedicals, 195303) were directly absorbed to ELISA plates at 1 pg / ml (50 pl per well) and incubated overnight at 4°C. The plates were washed with phosphate-buffered saline (PBS). Antihuman-15-PGDH (Goat IgG) (BioTechne cat# AF5660) was added as a positive control. Plates were blocked with 200 pl / well of blocking solution (1% Bovine Serum Albumin (BSA) w / v in PBS) for 1 hour at room temperature. Following this, the blocking solution was removed and the serum and plasma samples to be assessed were diluted 1 / 100 in blocking solution (1% BSA w / v in PBS) and applied to the plates. Plates were incubated at room temperature for 1 hour. The plates were washed with PBS+0.1% Tween. Goat anti-human F(ab’)2-horseradish peroxidase (HRP) antibody (Jackson Immunoresearch, 109-035-097; Lot: 148466; 1 :10,000 dilution) was then added to each well at 50 pl / well and incubated for 1 hour at room temperature. The plates were washed with PBS+0.1% Tween and 3,3', 5,5;-tetramethylbenzidine (TMB) solution (Life Technology, 002023) was added to each well to detect antibody binding. Plates were incubated for 5 minutes at room temperature prior to the addition of stopping solution (0.5 M sulphuric acid). Absorbance read on Molecular Devices FilterMaxF5 plate reader at 450 nm.

[1194] Serum inhibition of 15-PGDH activity screening

[1195] To screen 15-PGDH-reactive serum samples for 15-PGDH inhibition, a modified commercial enzyme activity assay (Abeam ab273327) was used. The assay is illustrated on Fig. 3A. In the assay, 15-PGDH oxidizes a substrate forming intermediates and NADH. The oxidation of NADH reduces a probe generating fluorescence at Ex / Em=535 / 587 nm. The activity of 15-PGDH is proportional to the fluorescent signal. Serum samples were thawed on ice and centrifuged at 4°C to remove debris and aggregates. Supernatant was drawn off for screening. A reaction mix was prepared from activity kit components (buffer, probe, substrate, and developer) according to the manufacturer’s instructions. Serum was diluted in kit assay buffer to a range of concentrations was pre-incubated with recombinant rhPGDH-Avi-His on ice. Immediately prior to fluorescence reading, reaction mix was added to each serum sample. Final concentrations of kit components were according to the manufacturer’s instructions. Final top concentration of serum was 1 / 30 neat serum, with seven three-fold serial dilution points prepared. Final concentration of recombinant enzyme was 8 nM. The change in fluorescence at 587 nm was monitored for 40 minutes in awhite 96-well plate at 37°C (BMG Clariostar). An age-matched non-reactive serum sample (SU477) was used as control or the known 15-PGDH small molecule inhibitor SW033291 were used as controls.

[1196] Monoclonal antibody inhibition of 15-PGDH activity screening

[1197] To screen monoclonal antibodies for enzyme inhibition, a modification of the above protocol was used. Purified antibody rather than serum was pre-incubated with recombinant PGDH. In most assays the final top concentration of antibody was 7.8e-7 M, with six five-fold serial dilutions prepared.

[1198] In some versions of the assay the reaction mix (except fluorescent reporter) using commercial components was substituted with TBS pH 7.5, 0.01% Tween-20, 150 pM NAD+ (Thermofisher #124530050), 25 pM PGE2 (Tocris / Biotechne #2296).

[1199] Data were analysed by plotting the change in fluorescence / time against the concentration of antibody. Owing to variability in activity observed between runs, likely due to enzyme instability, and because nonspecific inhibition by any antibody at high concentrations was sometimes apparent, data were normalised to the activity in the presence of an equal quantity of control (non-PGDH-reactive) monoclonal isotype-matched antibody (anti-fluorescein ATL_5338). Where sufficient data were available a 4-parameter [inhibitor] vs response model was fitted to compute IC50 values (Graphpad Prism).

[1200] Multiple independent assays (different days, different sites) were conducted with at least two observations of concentration-dependent reduction in enzyme activity, and at least 15% reduction at one or more concentrations, relative to isotype control required to be assessed as an inhibitor of 15-PGDH. All of antibodies ATL_0006026, ATL_0006058, ATL_0006074, ATL_0006075 and ATL_0006027 were found to inhibit PGDH.

[1201] Discovery of 15-PGDH reactive antibodies from patient plasma by mass spectrometry

[1202] Mass spectrometry-based identification of antibodies from plasma was performed according to methods known in the art (REmAb® from Rapid Novor, Inc). Briefly, purification of IgG was performed using 5 mL of serum. Plasma was incubated with 6 mL protein G resin and washed with phosphate buffered saline (PBS). IgG was eluted with a 0.1 M glycine buffer pH 2.7 and neutralized with 1 M Tris-HCI pH 8.0. Nanodrop was used to determine the concentration of total IgG. Streptavidin Sepharose High Performance (Sigma, GE17-5113-01) was used for depleting the non-specific binding IgG fraction. The collected flowthrough was subjected to a first purification with biotinylated 15-PGDH (ALB-rhPGDH) coupled to the streptavidin beads and incubated at 4°C for 1 hour. The flowthrough from this first enrichment was then used as a substrate for a second purification using the same biotinylated antigen captured on streptavidin beads. The two antigen bound samples were washed with PBS and eluted with glycine buffer. The samples were subjected to various enzymatic digestions prepared using different enzymes (Pepsin, Trypsin, Chymotrypsin, Asp-N, Lyc-C, and non-specific). The digestions for each sample were processed with disulfide reduction, alkylation, and then enzyme digestion. Different antibody chains were separated by chromatography and electrophoresis prior to digestion, mass spectrometry analysis, and data analysis. Digestions were analysed by LC-MS / MS using a mass spectrometer following both bottom-up and middledown strategies. Peptides were characterized from LC-MS / MS data using de novo peptide sequencing and then assembled into chains followed by heavy and light candidate sequences pairing into antibodysequences. A bulk BCR sequencing database search was performed, when available, and sequences were scored based on overall coverage and other metrics.

[1203] Phage library generation

[1204] Phage libraries of scFv molecules displayed on M13 phage were generated by cloning the VH repertoires from five of the subjects identified in the serum ELISA analysis as reactive to 15-PGDH (SU_0001238, SU_0001264, SU_0001242, SU_0001271 & SU_0001286) into a sub-library of phagemid vectors containing a library of VL sequences from healthy donors. Phage display libraries, ranging from size 1.9x 107to 8.2 x 108clones, were generated and phages were produced for phage display selections.

[1205] Phage selections

[1206] Phages were prepared by culturing a volume equivalent to optical density OD600=0.1 of phagemid-carrying TG1 stocks into 50mL of 2TYAG (2TY media supplemented with 100 pg / ml ampicillin and 2% glucose) at 37°C with aeration to optical density GD600=0.6. Rescue was performed by addition of M13K07 helper phage (Invitrogen, cat. 18311-019) for 1 hour, followed by harvesting bacteria by centrifugation (3500xg, 10 mins) and changing media to 2TYAK (TY media supplemented with 100 pg / ml ampicillin and 50 pg / ml kanamycin). The cultures were then incubated overnight at 18°C with aeration to rescue phage particles and then separated from bacteria the next day by (4500xg, 15 mins, 4°C). Finally, phages were PEG-precipitated and 0.22 pm filtered.

[1207] In order to isolate scFv binding to 15-PGDH antigen, three rounds of panning selections were performed on 15-PGDH antigen (rhPGDH-Avi-His). 192 clones were analysed by Sanger sequencing and unique sequences shortlisted for phage ELISA.

[1208] To ensure 15-PGDH epitopes were maximally accessible to the phage-displayed scFv an alternative selection strategy was applied using selections against 15-PGDH in solution to find more binding scFv. Three rounds of soluble selections were performed on the phages against biotinylated 15-PGDH (NLB-rhPGDH-Avi-His), using 200 nM NLB-rhPGDH-Avi-His for round 1 , 50 nM NLB-rhPGDH-Avi-His for round 2 and 10 nM NLB-rhPGDH-Avi-His for round 3 respectively. Blocked phage in 6% milk PBS was added to NLB-rhPGDH-Avi-His and then used to resuspend either Streptavidin (M-270, Invitrogen cat. 65305) or Neutravidin Dynabeads pre-blocked in 3% milk PBS. After incubation and washing, the phages were eluted from the beads with trypsin (100 mg, Sigma, cat. T 1426). Selected phages were rescued as above.

[1209] Phage ELISA

[1210] Binding ELISAs were performed on phage clones identified after 3 rounds of selections to identify clones that were specific to 15-PGDH binding. ELISA detection of binders was determined to either nonbiotinylated antigen (rhPGDH-Avi-His) directly immobilised on the plate or to neutravidin captured biotinylated antigen (ALB-rhPGDH-Avi-His or NLB-rhPGDH-Avi-His). Lysozyme (MP Biomedicals, 195303) or NeutrAvidin (Life Technologies, 31000) alone were used as negative controls for each respective ELISA method. For both methods, antigen coated plates and rescued phage were blocked with 3% milk with PBS for 1 hour (room temperature) and then phages were added to the plates and incubated for 1 hour (room temperature). The plates were washed with PBS+0.1% Tween-20 and then incubated with Anti-M13 HRP (SinoBiologocal, 11973-MM05T-H) for 1 hour at room temperature to detect phage binding. The plateswere washed with PBS+0.1% Tween-20 and TMB solution (Life Technology; 002023) added. Plates were incubated for 5 minutes at room temperature prior to the addition of stopping solution (0.5 M sulphuric acid). Absorbance was read on Molecular Devices FilterMaxF5 plate reader at 450 nm. Hits were sequenced by Sanger sequencing to identify the binding single chain, representing the heavy and light chain.

[1211] Monoclonal antibody binding to 15-PGDH: Single point and multi-point ELIS As

[1212] Selected scFv from the phage that bound specifically to 15-PGDH were reformatted and produced as human IgG. IgG binding to 15-PGDH was tested by single point ELISA against either directly immobilized non-biotinylated rhPGDH-Avi-His (plated 15-PGDH) or to Neutravidin captured biotinylated ALB-rhPGDH-Avi-His (NA captured 15-PGDH), as the antibodies were selected against one or both of the forms of PGDH. This tests whether antibodies bind in an ELISA to the form of PGDH they were selected against. Lysozyme (MP Biomedicals #195303) or NeutrAvidin (Life Technologies, 31000) alone were used as negative controls for each respective ELISA. None of the candidate antibodies bound neutravidin only (control). Antigen coated plates were washed with PBS and blocked with 200 pl / well of 3% milk in 1x PBS for 1 hour at room temperature. IgG being tested as well as an isotype control antibody were added and incubated for 1 hour at room temperature. For single point ELISAs a single concentration of 0.1 mg / mL IgG was tested in triplicate and for multi-point ELISAs Ig were added at top concentration of 0.1 mg / ml with a 10-point 5-fold titration series. Plates were washed with PBS+0.1% Tween-20 and Anti-human F(ab’)2- HRP (Jackson Immunoresearch, 109-035-097) was added and incubated for 1 hour at room temperature to detect antibody binding. Anti-His HRP (Invitrogen, MA1-21315-HRP) was used as an antigen coating positive control. The plate was washed with PBS+0.1% Tween-20 and TMB solution (Life Technology, 002023) added. Plates were incubated for 10 minutes at room temperature prior to the addition of stopping solution (0.5 M sulphuric acid). Absorbance was read on Molecular Devices FilterMaxF5 plate reader at 450 nm. Kinetics characterisation of antibodies binding to 15-PGDH by BL I

[1213] Antibodies identified to bind to 15-PGDH by ELISA had their kinetics measured by biolayer interferometry (BLI) on an Octet Red96e (Sartorius). Streptavidin biosensors (Sartorius 18-5019) were used to capture biotinylated human or mouse 15-PGDH (NLB-rhPGDH-Avi-His and rmPGDH-His (Sino Biological, 50531-M08E) respectively). Kinetics was measured by monitoring the change in signal in real time using the Octet Red96e data acquisition software 12.0 (Sartorius) with the system set to 25°C with biosensors shaking at 1000 rpm. The 15-PGDH loaded biosensors were dipped into 1x Kinetics buffer (Sartorius, 18-1105) to achieve a stable baseline (60 seconds), before being dipped into a concentration series of antibody (7-point 2-fold dilution series from 100 nM top concentration) for 600 seconds to measure association, and then returning to 1x Kinetics buffer for 600 seconds to measure dissociation. A reference biosensor loaded with 15-PGDH dipped into 1 x Kinetics buffer without antibody was used. Data analysis was performed using the Octet Data Analysis HT 12.0 software (Sartorius). Raw data for each biosensor had the reference biosensors subtracted before aligning the data on the y-axis to the average of the last 5 s of the baseline, inter-step correction to the end of the dissociation step, and applying Savitzky-Golay filtering. Processed data was then fit with a 1 :1 binding model using a global fit linked to the antibody in the sample.

[1214] Kinetics characterisation of antibodies binding to 15-PGDH by SPRAntibodies identified to bind to 15-PGDH by ELISA had their kinetics measured by surface plasmon resonance (SPR) on a Carterra LSA instrument. A capture surface was prepared by coating a polycarboxylate sensor chip (HC200M, Carterra) with goat polyclonal anti-human IgG Fc antibody. Four concentrations of the test antibodies were then captured on the surface at two separate locations, with binding confirmed by SPR measurement. The chip was equilibrated to PBS + 0.1% Tween. Human 15-PGDH (NLB-rhPGDH-Avi-His) was injected at a range of concentrations up to 590 nM in PBS + 0.1% Tween. Binding kinetics was measured by monitoring the change in signal in real time using the Carterra control software with the system set to 25°C. Analyte was injected for 300 seconds to measure association, followed by buffer only injection for 1200 s to measure dissociation. Data were referenced and aligned to the capture surface and the buffer-only analyte signal. Processed data was then fit with a 1 :1 Langmuir binding model.

[1215] Thermal shift assay

[1216] Protein thermal shift measurements were performed on an Uncle (Unchained labs). Antibodies were diluted to 1mg / ml or 5mg / ml in 20 mM Histidine Acetate, 150 mM NaCI, pH 5.5 buffer and run through a temperature ramp of 25-95°C increasing at a rate of 0.5°C / minute. Samples were run in triplicate, loading 8.8pl in 3 different wells of a uni (Unchained Labs). Laser settings were set to achieve an initial fluorescence in the 300-350 nm range of 10000 - 50000 counts. Melting temperature (Tm1 / Tm2) and aggregation temperature (Tagg / Tonset) were analysed using Uncle Analysis software v6 (Unchained Labs). Tm measurement was calculated using the 350 / 330nm ratio, while Tonset and Tagg were obtained from SLS read at 266nm and 473nm.

[1217] Size exclusion chromatography (SEC-HPLC)

[1218] Antibody samples were loaded onto an Agilent ZORBAX GF-250 (9.4 mm x 250 mm 4-micron, with Agilent ZORBAX DIOL preparative guard column 9.4 mm x 15 mm 6-micron) column, at 25 pg injection load. Sample solution components were separated by size, in 20 mM Sodium phosphate, 300 mM Sodium sulfate, 100 mM Arginine, pH 6.6 ± 0.2. The column compartment temperature was set at 25°C, the injection flow rate was 0.75 mL / minute, run time was 25 minutes, and the absorbance wavelength was 280 nm. A Thermo Fisher Vanquish Flex LC system was used, with Thermo Fisher Chromeleon 7 chromatography data system for chromatogram processing and peak integration.

[1219] SDS-PAGE

[1220] 2pg of antibody sample was prepared by diluting in water and 2x Laemmli Sample Buffer (Bio-Rad). Sample was analysed at both reduced and non-reduced conditions; reduced samples had the addition of 50mM DTT (dithiothreitol, Sigma-Aldrich). All samples were heated to 95°C for 5 mins and loaded into wells of Bolt 4-12% Bis-Tris Plus Protein gels (Thermo Scientific) alongside 5pl of a molecular weight marker was loaded on each gel, Precision Plus Protein Dual Colour Standards (Bio-Rad, 1610737) and run in Bolt MES SDS Running Buffer (Thermo Scientific). Samples were run at a constant 200 Volts for 23 minutes followed by staining with InstantBlue Coomassie Stain for a minimum of 1 hour, gels were destained with water washes and an Image taken by scanning using the GelDoc Go Imaging system (Bio-Rad).

[1221] Recombinant mAb expressionRecombinant antibodies were expressed transiently from ExpiCHO-S cells using manufacturers protocols for Expifectamine transfections (Thermo). Transfections were cultured for 7 or 12 days with feeds, followed by harvesting by mixed with diatomaceous earth (Sartorius) followed by filtration through a 0.22 pm PES membrane. Harvested supernatant was purified using protein A capture resin and elution in low pH buffer. Elution fractions were buffer exchanged into 20mM Histidine acetate, 150mM sodium chloride pH5.5 buffer and stored at -80C.

[1222] Alpha-synuclein fibrils-induced PD model

[1223] Induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (Fujifilm; Catalog #: R1148), astrocytes (Fujifilm; Catalog #: R1092), and microglia (Fujifilm; Catalog #: R1131) were utilized to establish a triculture system to recapitulate physiological conditions of the central nervous system. These cells were cultured under standard conditions until they reached the appropriate confluence for experimentation. On day 4 post-establishment of the triculture system, cells were treated with either a-synuclein (aSyn) fibrils at a concentration of 6 pg / ml or phosphate-buffered saline (PBS) as a control. These conditions were maintained for 5 days to allow for the uptake and potential effects of the aSyn fibrils on the cells. Following the incubation period with aSyn fibrils or PBS, cells within the tri-culture system were exposed to 15-PGDH antibody, (ATL-6026 or ATL-6058), or isotype control antibody (ATL-5338). Each antibody was used at a concentration of 70 nM. The cultures were incubated with these antibodies for an additional 48 hours. On day 11 of the culture, supernatant and whole protein extracts were collected. For protein extraction from the cells, a RIPA cell lysis buffer was used. The buffer composition included 50 mM Tris (pH 8.0), 150 mM NaOl, 5 mM EDTA, 1% NP-40, 0.5% sodium deoxycholate, and 1% SDS. Quantification of lnterleukin-6 (IL6) and 15-PGDH in the collected samples was performed using an enzyme-linked immunosorbent assay (ELISA) service provided by RayBiotech, Inc. (Peachtree Corners, GA, USA). All ELISA assays were conducted according to the manufacturer's protocols. On day 11 of the culture, cells were fixed with 4% paraformaldehyde in PBS for 10 min and then washed with PBS. Immunostaining was performed after permeabilization in PBS with 0.1% Saponin and blocking for 30 min in 10% donkey serum in PBS with 0.1% Saponin. Immunostaining was performed with specific primary antibodies: rabbit alpha-synuclein Antibody, pS129 (1 :100; LSbio, LS-C380861-50), chicken MAP2 antibody (1 :400; Thermofisher, PA1 -10005). Primary antibodies were diluted in 10% donkey serum in PBS with 0.1 % Saponin and incubated overnight at 4 °C. After three PBS washes, cells were incubated with secondary antibodies in 10% donkey serum in PBS with 0.1% Saponin (Alexa Fluor-488 (1 :300; Thermofisher, A78948), Alexa Fluor-647 (1 :300; abeam, ab150075) for 1 h at room temperature, and cells were counterstained with DAPI nuclear stain. Cells were then washed with PBS three times and were visualized. Images were acquired with the ECHO Revolve microscope.

[1224] The experimental design for this study is shown in Figure 15.

[1225] Mitochondrial Membrane Potential Assay

[1226] JC-1 probe (Invitrogen, T3168) was used to measure changes in mitochondrial membrane potential of ceils after exposure to 8ug / mL aSyn fibrils PFFs and treatment with PGDH antibodies. Cells were incubated with 2.0 pg / mL of JC-1 probe at 37 °C for 30 minutes, subsequently washed twice with PBS, and then replaced in fresh media solution. Cells were imaged on the ECHO revolve microscope at 10x magnification usingthe 488nm excitation filter and 530 nm emission filter to capture JC-1 monomers and 543nm excitation filter and 590nm emission filter for capturing JC-1 aggregates. Fluorescence intensity was measured using Image J software and the red / green ratio was plotted for each image in GraphPad Prism.

[1227] In vivo LPS challenge mouse model of inflammation

[1228] The mice used in this experiment were male C57BL / 6 ordered from Charles River Laboratories (St. Constant, Quebec, Canada). Two groups of 8 mice were treated at -6 days, -3 days and -4 hours with either ATL6026 or Isotype control mAb (ATL5338) at 60 mg / kg. A further group of 8 mice were treated at -7 days until -4 hours twice daily with 10mg / kg SW033291 (MedChem Express, Cat. No.: HY-16968). LPS (Sigma Aldrich, Cat. No.: L2630) was administered at 0 hours, 0.25 mg / kg via i.p. to all mice. Serial blood was sampled at 4 hours for all mice in life via saphenous collection. Blood was collected at 24 hours terminal via cardiac puncture. Mice were transcardially perfused with 50mL ice-cold PBS (20mM pH 7.4) and brain samples were then collected. Levels of cytokines (IL-6, TNF-a and IL-1 p) in samples were measured using a Meso Scale Discovery System (MSD) customized V-plex panel.

[1229] In vivo assessment of gait and postural stability in aged mice

[1230] Mice were 22-month-old C57BL / 6J (Jackson Laboratories, USA). Altogether 56 mice were enrolled in the study and divided into 4 groups with 14 animals in each group. Two groups of mice were dosed with ATL6026 or Isotype control (ATL5338) at 60 mg / kg via intraperitoneal (i.p.) injection 1x / week for the duration of the study. Two further groups were dosed with small molecule SW033291 (MedChem Express, Cat. No.: HY-16968) at 10 mg / kg or Vehicle 1x / day for the duration of the study. At the end of week 4 predefined points, including limb joints and tail, were marked on the animal’s body to aid the data capture by a high-speed camera (300 fps) and data analysis was performed by converting the movements into data points. Different gait patterns and movements that were analysed were: a) General gait pattern parameters; b) Body posture and balance; c) Fine motor skills. As gait parameters have several (and complex) intercorrelations different gait features, which are manifested in sets of highly correlating parameters, these features were also analysed and identified using Principal Component Analysis (PCA). An overall gait score combines the above kinematic parameters into one single score.

[1231] Variant Antibody Production

[1232] Recombinant antibodies were expressed transiently from CHO-S cells. Following harvest and clarification, supernatant was purified using protein A capture and elution in low pH buffer. Elution fractions were buffer exchanged into 20mM Histidine acetate, 150mM sodium chloride pH5.5 formulation buffer and stored at -80C.

[1233] CE-SDS

[1234] Non reducing Capillary Electrophoresis-SDS was performed on some of the variants to determine monomeric purity. Samples were mixed with SDS-containing buffer and electrokinetically injected into a cartridge capillary. Peaks were measured at 220 nm.

[1235] SEC-HPLC of variant antibodies

[1236] Size exclusion chromatography (SEC-HPLC) was performed to assess purity of antibody batches on a Thermo Fisher Vanquish Flex UHPLC system. Samples were loaded onto a TOSOH Bioscience TSKgelG3000SWxl 7.8 mm ID x 30 cm L column, at 25 pg injection load of pre filtered samples. The autosampler temperature was set at 4°C, the column compartment temperature was set at 25°C. Sample solution components were separated by size in mobile phase 20 mM Sodium phosphate 100 mM Arginine 300 mM Sodium sulfate pH 6.6 with a flow rate of 0.5 mL / min for 40 minutes. Chromeleon 7.3.1 software was used for analyzing the chromatograms at measurement wavelength of 280 nm (4 nm bandwidth), using drop perpendicular peak integration unless specified. Monomer purity was recorded as the relative of total area under the largest peak.

[1237] Biolayer interferometry (BLl) characterisation of variant antibodies

[1238] For the initial binding screen, anti-human Fc biosensors were equilibrated to assay buffer and immersed in a 5 pg / mL solution of test antibody. Sensors loaded with antibody were immersed in concentration series of up to 400 nM purified recombinant human 15-PGDH, and kinetic association data were acquired. The sensors were returned to assay buffer and kinetic dissociation data were acquired. Data were referenced against buffer-only analyte and isotype-control-loaded (ATL_5338) sensor data.

[1239] For the final binding screen, the assay was modified to support kinetic characterisation. Test antibody loaded anti-human-Fc biosensors were immersed in a dilution series of recombinant human 15-PGDH (SEQ ID NO: 173 or SEQ ID NO: 83), cynomologous monkey 15-PGDH (SEQ ID NO: 170), recombinant mouse 15-PGDH (SEQ ID NO: 85) and recombinant rat 15-PGDH (SEQ ID NO: 172) orthologue analytes at a top concentration of 40 nM (ATL_6026 variants) or 20 nM (ATL_6058 variants). Data were referenced as before and fitted to 1 :1 kinetic binding model, which was used to calculate a KD value for each variant. All BLl measurements were carried out using a Sartorius Octet Red 96e instrument at 25°C. The assay buffer was 10 mM HEPES, 150 mM NaCI, 3 mM EDTA, 0.05% v / v P20.

[1240] Inhibition screening of variant antibodies by fluorescence based enzymatic activity assay

[1241] A BMGLabtech CLARIOstar was used to measure fluorescence intensity with emission set to 460 nm (10 nm bandwidth), and excitation set to 355 nm (10 nm bandwidth) from low volume opaque white plates. The samples were mixed with 15-PGDH in the plate wells, with NAD+ and PGE2 injected during the program run. The assay buffer was 0.1 M Tris-HCI, pH 8.0, 0.01% Tween-20 with NAD+ and PGE2 stock solutions prepared in 0.5 M Tris-HCI, pH 8.0. 15-PGDH enzyme stock solution was prepared in 5 mM Tris-HCI, pH 8.0, 150 mM NaCI, 0.01% Tween-20.

[1242] The assay was based on the principle of conversion of non-fluorescent NAD+ to fluorescent NADH catalyzed by 15-PGDH in the presence of substrate PGE2. Inhibition of 15-PGDH was monitored by measuring the reduction in fluorescence signal.

[1243] For screening, a four-point 10-fold dilution series was used to compare inhibition to the parent by comparing the slope of the increasing fluorescence signal. The isotype control or a non-binding antibody was used as a negative control, while a no-PGDH mix or small molecule inhibitor SW033291 (MedChem Express, Cat. No.: HY-16968) was used as the positive control (data not shown). Maximum inhibition was calculated from the linear model of taking ARFU of the 0 nM concentration of the sample as 100% activity (0% inhibition), and ARFU of zero as 0% activity (100% inhibition).

[1244] Thermostability assessment of variant antibodies using SYPRO thermal shift assayThe Unchained Labs UNcle platform was used to generate the thermal melting profile of mAbs in the presence of SYPRO Orange (Thermo Fisher #S6651). The mAbs were prepared at < 5 mg / mL in 20 mM Histidine acetate, pH 5.5, 150 mM sodium chloride, then mixed in a one-to-one ratio with SYPRO Orange diluted 40-fold with the mAb formulation buffer. 8.8 pL of this mix was loaded into a UNi cuvette chamber in triplicate for each mAb. The Tm using SYPRO program was used with the thermal ramp set from 25°C to 95°C at 0.5°C / minute. The results were analyzed with Uncle Analysis V 6.0.

[1245] Retrogenix Analysis

[1246] This was performed by Charles River (UK) using their proprietary Retrogenix Cell Microarray Technology (see www.criver.com / products-services / discovery-services / screening-and-profiling-assays / retrogenix-cell-microarray-technology).

[1247] Hindlimb Casting for in vivo limb immobilisation model of disuse atrophy

[1248] Mice were anaesthetised via inhalation (~5% isoflurane, adjusted or maintained to effect), placed on a thermostatically controlled table where anaesthesia was maintained via nose-cone (~3% isofluorane, adjusted or maintained to effect). For each mouse the right hindlimb was wiped with povidone-iodine, then ethanol, and loosely wrapped in surgical gauze. A custom-made plastic immobilization device based on Moore et al 2022 were printed using an SLA printer (Form3) using clear resin, and then placed on the limb. The device was fixed to the hindlimb using Vetbond™ tissue adhesive and the mouse was returned to its cage.

[1249] In vivo assessment of plantarflexor muscle strength and function

[1250] Muscle performance was measured in vivo with a 305C muscle lever system (Aurora Scientific Inc., Aurora, CAN). Anaesthesia was accomplished via inhalation (~5% isoflurane, adjusted or maintained to effect), and the animal placed on a thermostatically controlled table where anesthesia maintained via nose-cone (~3% isofluorane, adjusted or maintained to effect). The knee was isolated using a pin pressed against the tibial head and the foot firmly fixed to a footplate on the motor shaft. For the plantarflexor muscle group, contractions were elicited by percutaneous electrical stimulation of the tibial nerve. Optimal isometric twitch torque was determined by increasing the current with a minimum of 30 s between each contraction to avoid fatigue. Force Frequency: A series of stimulations was then performed at increasing frequency of stimulation (0.2ms pulse, 500ms train duration): 1 , 20, 40, 50, 60, 80, 100, 150Hz. Maximal peak isometric force, and force-frequency relationship were plotted. Body weight was measured and served as a normalization.

[1251] X-ray crystallography

[1252] Recombinant human PGDH was produced in E. coll (BL21-CodonPlus (DE3)-RIPL Competent Cells) using a construct containing PGDH with a C-terminal his tag which was used for purification (SEQ ID NO: 173). The Fab fragment of ATL_6026 was produced by transient transfection of ExpiCHO and purified via the CH1 domain. Both components were purified by size exclusion chromatography (SEC) before being mixed together and the complex further purified by another SEC step. The complex was then screened for crystallisation using commercial crystallisation screens. X-ray diffraction data was collected from crystalsgrown in 0.1 M Tris pH 7.1-8.9, 20-40% PEG Smear Low, with protein :reservoir ratio 1 :1 , and cryo protected with 50% PEG 320-430 (among many other formulations that had a similar composition and pH). The best crystal diffracted to 3.35A in space group P63. Some of these crystals were used in seeding experiments where 20 nl of seed stock was added to each drop in another set of commercial screens. Harvested crystals were screened, and the best data was obtained from crystals grown in 0.1 M TRIS pH 8.5 pH, 40% PEG 400, 0.2 M LiSO4 (among many other formulations that had a similar composition and pH). This dataset was processed with Xia2-Dials in P212121 space group to resolution 2.99 A. Multiple Molecular Replacement trials were done using various combinations of protein data bank (PDB) models, using both MolRep and Phaser software. The best solution was found using 2GDZ (PGDH monomer complexed with NAD+; PDB ref : pdb_00002gdz) in combination with a predicted Fab structure subdivided into variable domains and constant domains. The solution with 2 copies of each of these three components yielded R / Rtree of 0.24 / 0.33 after single round of restrained refinement in the program Refmac. Alternating model building in the program Coot and refinement in Refmac produced a final model with R I Rtree of 0.226 I 0.283. Data collection and refinement statistics are set out in Table 2B. The model contains two molecules of PGDH and two molecules of the Fab in the asymmetric unit. The asymmetric unit is the area within the crystal lattice that contains the molecules that are repeated throughout the crystal.

[1253] Wavelength (A) 0.9537

[1254] Resolution range (A) 2.99 - 80.13 (2.99 - 3.04)

[1255] Space group P212121

[1256] Unit cell 71.18 178.83 179.299090 90

[1257] Total reflections 645740 (30574)

[1258] Unique reflections 47232 (2244)

[1259] Multiplicity 13.7 (13.6)

[1260] Completeness (%) 100.0 (97.8)

[1261] Mean l / sigma(l) 4.4 (0.2)

[1262] Wilson B-factor 76.480

[1263] R-merge 0.344 (7.625)

[1264] R-meas 0.358 (7.930)

[1265] R-pim 0.098 (2.165)

[1266] CC1 / 2 1 1.0 (0.4)

[1267] CC* 1 0.8 (0.0)

[1268] Reflections used in refinement 41981 (2256)

[1269] Reflections used for R-free 2203 (102)

[1270] R-work 0.22631 (0.430)

[1271] R-free 0.28254 (0.385)

[1272] CC(work) 0.947

[1273] CC(free) 0.920

[1274] Number of non-hydrogen atoms 9970

[1275] (Macromolecules)

[1276]

[1277] Number of non-hydrogen atoms (Ligands) 88

[1278] Number of non-hydrogen atoms (Solvent) 48

[1279] RMS(bonds) 0.006

[1280] RMS(angles) 1.622

[1281] Ramachandran favored (%) 84.9

[1282] Ramachandran allowed (%) 12.4

[1283] Ramachandran outliers (%) 2.7

[1284] Rotamer outliers (%) 1.64

[1285] Clashscore 18.3

[1286] Average B-factor (Macromolecules) 64.1

[1287] Average B-factor (Solvent) 179.7

[1288]

[1289] Table 2B. Data collection and refinement statistics. Statistics for the highest-resolution shell are shown in parentheses.

[1290] In vivo assessment of motor function in mouse model of Parkinson’s disease

[1291] Mice (Male C57BL / 6, 93-95-weeks old, from Jackson Laboratories) were acclimated at least 3 weeks following arrival. Following acclimation, baseline weights were measured and then assigned to groups in such a manner that there are no significant differences in body weights at baseline.

[1292] Group Age AAV T reatment

[1293] 1 93-95 wk old Null Isotype Control

[1294] 2 93-95 wk old aSyn A53T Isotype Control

[1295] 3 93-95 wk old aSyn A53T Y249060 MPK

[1296]

[1297] Table 2C. Summary of treatment groups for in vivo assessment of motor function in mouse model of Parkinson’s disease.

[1298] On the day of the study start, mice were treated with test article (TA) Y2490 (a murine lgG2a LALA version of ATL_7955) or isotype control (I.P. QW) and were then dosed once a week until study end. Three days later, mice underwent delivery of the AAV (an expression cassette of A53T-mutated alpha synuclein in an adeno-associated virus vector) to the substantia nigra by stereotactic injection (Figure 32B). Animals received a unilateral infusion of an AAV1 / 2 vector expressing human a-synuclein (aSyn) carrying an A53T missense mutation. The expression is driven by the chicken beta actin (OBA) promoter hybridized with the cytomegalovirus (CMV) immediate early enhancer (IEE) sequence. The vector additionally comprises the enhanced woodchuck post-transcriptional regulatory element (wPRE), plus a polyadenylation (PolyA) sequence from bovine growth hormone (BGH).

[1299] An AAV1 / 2- null vector without the above-described expression cassette served as a control for an AAV infusion. Stereotactic infusions along with all handling of the viral material were carried out in a biosafety level 2 (BSL-2) laminar hood (BioWizard Golden line 130, Kojair). Surgical procedures and housing of theanimals until up to 1 week after the AAV1 / 2- infusion was conducted according to BSL-2 level safety regulations (Council Directive 90 / 679 / EEC). After the surgical preparations were completed, a midline skin incision was made on the scalp, and the skin reflected to expose the skull. Using a dental drill, a small craniectomy was made at the selected coordinates relative to bregma (see below) without damaging dura mater.

[1300] Stereotaxic infusion of AAV1 / 2-null or AAV1 / 2-A53T (5.1 x 1012 vg / mL) was performed as follows: A 30-G beveled gastight injection needle (Hamilton Neuros) was connected to a 10-pL Hamilton 1701 RN micro syringe (10 pl) mounted on a digitally guided infusion unit (Digital Lab Standard™, Harvard Apparatus) and pump (Pump 11 , Elite Nanomite, Harvard Apparatus). The needle was lowered to the desired D / V level. Using rate of 0.2 pL / min, altogether 2 pL of the AAV solution was delivered unilaterally to the right (ipsilateral) substantia nigra (SN). After completed infusion, the needle was left in place for an additional 5 minutes prior to slowly withdrawing it. Finally, the incision was sutured and disinfected.

[1301] The following coordinates relative to bregma were used for infusion of the viral material into the mouse SN: AP: -3.0 mm (posterior from bregma) ML: +1 .3 mm DV: -4.2 mm (from the brain surface)

[1302] Fine Motor Kinematic Gait Analysis

[1303] The test was performed on D28 during light phase and befo...

Claims

Claims:

1. An isolated antibody that specifically binds and inhibits 15-PGDH, wherein the antibody comprises:a heavy chain variable domain with the following CDRs:CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL 7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL 7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL 7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL 7921 ; ATL_7922; ATL_7923; ATL_7924);ODRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); SEQ ID NO: 16 (ATL_6026; ATL_7925; ATL_7450;ATL 7819; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL 7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7919; ATL_7920; ATL_7923); SEQ ID NO: 96 (ATL_7952; ATL_7917; ATL_7918;ATL 7921 ; ATL_7922; ATL_7924); SEQ ID NO: 97 (ATL_7953); SEQ ID NO: 154 (ATL_7820); SEQ ID NO: 155 (ATL_7821); SEQ ID NO: 156 (ATL_7822); or SEQ ID NO: 157 (ATL_7823); andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953; ATL_7829); SEQ ID NO: 21(ATL 6026; ATL_7925; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL 7824; ATL_7825; ATL_7826; ATL_7827; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL 7895 ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7918; ATL_7919; ATL 7921 ; ATL_7924); or SEQ ID NO: 162 (ATL_7917; ATL_7920; ATL_7922; ATL_7923); or a set of CDRs containing one to six amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs; anda light chain variable domain (VL), with the following CDRs:CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL 7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL 7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL 7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL 7921 ; ATL_7922; ATL_7923; ATL_7924);CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7925; ATL_7952; ATL_7953; ATL_7900; ATL_7919; ATL_7923); SEQ ID NO: 31 (ATL_6026; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ;ATL 7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL 7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7901 ; ATL_7902; ATL_7920); SEQ ID NO: 166 (ATL_7917; ATL_7918); or SEQ ID NO: 167 (ATL_7899; ATL_7921 ; ATL_7922; ATL_7924); andCDRL3 comprising an amino acid sequence of SEQ ID NO: 207 (ATL_8946); SEQ ID NO: 206 (ATL_8944); SEQ ID NO: 107 (ATL_7955; ATL_7925; ATL_7952; ATL_7953;ATL 7902; ATL_7917; ATL_7922; ATL_7923; ATL_7924); SEQ ID NO: 36 (ATL_8947;ATL 6026; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL 7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL 7895; ATL_7896; ATL_7899; ATL_7900; ATL_7918); or SEQ ID NO: 168 (ATL_8945; ATL 7901 ; ATL_7919; ATL_7921);or a set of CDRs containing one to four amino acid mutations, such as substitutions, compared with the above set of light chain CDRs, optionally wherein the mutations in the light chain CDRs do not include a mutation at position 109 or position 113 in standard IMGT numbering, and / or wherein the mutations do not include a mutation in CDRL3.

2. An antibody that specifically binds and inhibits 15-PGDH, for use in the treatment or prevention of muscle atrophy and / or dystrophy, or a disease or disorder associated with muscle atrophy and / or dystrophy, or in the treatment or prevention of muscle function and / or muscle strength loss in a subject in need thereof, wherein the antibody comprises a heavy chain variable domain with the following CDRs:CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL 7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL 7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL 7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL 7921 ; ATL_7922; ATL_7923; ATL_7924);CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); SEQ ID NO: 16 (ATL_6026; ATL_7925; ATL_7450;ATL 7819; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL 7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7919; ATL_7920; ATL_7923); SEQ ID NO: 96 (ATL_7952; ATL_7917; ATL_7918;ATL 7921 ; ATL_7922; ATL_7924); SEQ ID NO: 97 (ATL_7953); SEQ ID NO: 154 (ATL_7820); SEQ ID NO: 155 (ATL_7821); SEQ ID NO: 156 (ATL_7822); or SEQ ID NO: 157 (ATL_7823); andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953; ATL_7829); SEQ ID NO: 21(ATL 6026; ATL_7925; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL 7824; ATL_7825; ATL_7826; ATL_7827; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL 7895 ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7918; ATL_7919; ATL 7921 ; ATL_7924); or SEQ ID NO: 162 (ATL_7917; ATL_7920; ATL_7922; ATL_7923); or a set of CDRs containing one to six amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs.

3. A method of treating or preventing muscle atrophy and / or dystrophy and / or muscle function and / or muscle strength loss, or a disease or disorder associated with muscle atrophy and / ordystrophy, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an antibody that specifically binds and inhibits 15-PGDH, wherein the antibody comprises a heavy chain variable domain with the following CDRs:CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL 7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL 7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL 7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL 7921 ; ATL_7922; ATL_7923; ATL_7924);ODRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); SEQ ID NO: 16 (ATL_6026; ATL_7925; ATL_7450;ATL 7819; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL 7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7919; ATL_7920; ATL_7923); SEQ ID NO: 96 (ATL_7952; ATL_7917; ATL_7918;ATL 7921 ; ATL_7922; ATL_7924); SEQ ID NO: 97 (ATL_7953); SEQ ID NO: 154 (ATL_7820); SEQ ID NO: 155 (ATL_7821); SEQ ID NO: 156 (ATL_7822); or SEQ ID NO: 157 (ATL_7823); andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953; ATL_7829); SEQ ID NO: 21(ATL 6026; ATL_7925; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL 7824; ATL_7825; ATL_7826; ATL_7827; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL 7895 ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7918; ATL_7919; ATL 7921 ; ATL_7924); or SEQ ID NO: 162 (ATL_7917; ATL_7920; ATL_7922; ATL_7923); or a set of CDRs containing one to six amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs.

4. Use of an antibody that specifically binds and inhibits 15-PGDH in the manufacture of a medicament for the treatment or prevention of muscle atrophy and / or dystrophy or muscle function and / or muscle strength loss, or a disease or disorder associated with muscle atrophy and / or dystrophy, wherein the antibody comprises a heavy chain variable domain with the following CDRs:CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7450; ATL 7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL 7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL 7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL 7921 ; ATL_7922; ATL_7923; ATL_7924);CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); SEQ ID NO: 16 (ATL_6026; ATL_7925; ATL_7450;ATL 7819; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL 7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7919; ATL_7920; ATL_7923); SEQ ID NO: 96 (ATL_7952; ATL_7917; ATL_7918;ATL_7921 ; ATL_7922; ATL_7924); SEQ ID NO: 97 (ATL_7953); SEQ ID NO: 154 (ATL_7820); SEQ ID NO: 155 (ATL_7821); SEQ ID NO: 156 (ATL_7822); or SEQ ID NO: 157 (ATL_7823); andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953; ATL_7829); SEQ ID NO: 21(ATL 6026; ATL_7925; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL 7824; ATL_7825; ATL_7826; ATL_7827; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL 7895 ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7918; ATL_7919; ATL 7921 ; ATL_7924); or SEQ ID NO: 162 (ATL_7917; ATL_7920; ATL_7922; ATL_7923); or a set of CDRs containing one to six amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs.

5. The antibody for use, method, or use according to any of claims 2 to 4, wherein the disease is a myopathy.

6. The antibody for use, method, or use according to any of claims 2-5, wherein the disease or disorder is selected from aging related muscle atrophy, spinal muscular atrophy (SMA), sarcopenia, sarcopenic obesity, Duchenne’s muscular dystrophy, cachexia, inflammatory myopathy, drug-induced myopathy, or disuse atrophy, optionally wherein:(i) the inflammatory myopathy is muscle atrophy associated with an acute or chronic inflammatory disease or disorder; or(ii) the drug-induced myopathy is associated with treatment with an incretin therapy, optionally wherein the incretin therapy is a GIP and / or GLP agonist, optionally a GIP and / or GLP-1 agonist.

7. The antibody for use, method, or use according to any of claims 2-6, wherein the disease or disorder is disuse atrophy.

8. The antibody for use, method, or use according to claim 7, wherein the disuse atrophy is caused by:(i) a bone fracture, optionally a hip fracture;(ii) a nerve injury, optionally a spinal cord injury (SCI);(iii) immobilisation;(iv) bed rest; and / or(v) obesity.

9. The antibody for use, method, or use according to claim 8, wherein the immobilisation is immobilisation of a bone fracture, optionally wherein the immobilisation is immobilisation of a bone fracture by splinting and / or casting.

10. The antibody for use, method, or use according to any of claims 2-9, wherein the antibody preserves or increases muscle strength and / or muscle function, optionally wherein the antibody preserves or increases muscle strength and / or muscle function of a disused muscle or muscle group.

11. The antibody for use, method, or use according to claim 10, wherein the antibody preserves or increases muscle strength and / or muscle function of a muscle or muscle group subjected to immobilisation in an animal model and / or in a subject, optionally wherein muscle strength and / or muscle function is determined by measuring the isometric force generated by muscle contraction induced by electrical stimulation.

12. The antibody for use, method, or use according to claim 11 or claim 10, wherein the antibody preserves or increases muscle strength and / or muscle function following immobilisation for a predetermined period of time without preserving or increasing muscle mass, optionally wherein the predetermined period of time is 1 , 2, 3, or 4 weeks.

13. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a heavy chain variable domain with the following CDRs:CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925 ATL_7952; ATL_7953);ODRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); SEQ ID NO: 16 (ATL_6026; ATL_7925); SEQ ID NO: 96 (ATL_7952); or SEQ ID NO: 97 (ATL_7953); andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953); or SEQ ID NO: 21 (ATL_6026;ATL_7925);or a set of CDRs containing one to six, or one to three amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs, optionally wherein the substitution is at position 62, optionally wherein the substitution is N62A or N62Q; and / or at position 63, optionally wherein the substitution is G63A; and / or at position 64, optionally wherein the substitution is N64A; and / or at position 65, optionally wherein the substitution is T65A or T65S; and / or at position 111 C, optionally wherein the substitution is D111 CE; and / or at position 112D, optionally wherein the substitution is S112DA;optionally wherein the heavy chain variable domain (VH) comprises the following framework sequences: HFWR1 of SEQ ID NO: 41 (ATL_6026) or SEQ ID NO: 95 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955); HFWR2 of SEQ ID NO: 42 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7955); HFWR3 of SEQ ID NO: 43 (ATL_6026); SEQ ID NO: 99 (ATL_7925; ATL_7953); SEQ ID NO: 100 (ATL_7952); or SEQ ID NO: 101 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); and HFWR4 of SEQ ID NO: 44 (ATL_6026); or SEQ ID NO: 103 (ATL_8944;ATL 8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955); or framework sequences with one to nine or one to six mutations, optionally wherein the mutations are substitutions, compared with the framework sequences above, optionally wherein the substitution is at position 5, optionally wherein the substitution is Q5V; and / or at position 53, optionally wherein the substitution is M53A; and / or at position 78, optionally wherein the substitution is M78I or M78A; and / or at position 81 , optionally wherein the substitution is D81 E; and / or at position 89,optionally wherein the substitution is M89A; and / or at position 97, optionally wherein the substitution is D97E; and / or at position 98, optionally wherein the substitution is D98E; and / or at position 99, optionally wherein the substitution is T99A; and / or at position 123, optionally wherein the substitution is M123T.

14. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a heavy chain variable domain with the following CDRs:CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925 ATL_7952; ATL_7953);ODRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7952; ATL_7953);or a set of CDRs containing one to six, or one to three amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs, optionally wherein the substitution is at position 62, optionally wherein the substitution is N62A or N62Q; and / or at position 64, optionally wherein the substitution is N64A; and / or at position 111 C, optionally wherein the substitution is D111CE.

15. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody binds to an epitope that comprises one or more or all of residues Leu 39, Glu40, Val43, Gln44, Lys46, Ala47, Leu59, Phe60, Ile61 , Gln62, Cys63, Gln70, Asp73, Thr74, Arg76, Lys77, Asp80, His81 of 15-PDGH, provided as SEQ ID NO: 82.

16. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a heavy chain variable domain with the following CDRs:CDRH1 comprising an amino acid sequence of SEQ ID NO: 11 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955);CDRH2 comprising an amino acid sequence of SEQ ID NO: 98 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); andCDRH3 comprising an amino acid sequence of SEQ ID NO: 102 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955);optionally wherein the heavy chain variable domain (VH) comprises the following framework sequences:HFWR1 of SEQ ID NO: 95 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); HFWR2 of SEQ ID NO: 42 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); HFWR3 of SEQ ID NO: 101 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); andHFWR4 of SEQ ID NO: 103 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955).

17. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a heavy chain variable domain (VH) with the following framework sequences:HFWR1 of SEQ ID NO: 41 (ATL_6026); SEQ ID NO: 49 (ATL_6027); SEQ ID NO: 57 (ATL_6058; ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928;ATL 7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468;ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 65 (ATL_6074); SEQ ID NO: 73 (ATL_6075); or SEQ ID NO: 95 (ATL_8944; ATL_8945; ATL_8946; ATL_8947;ATL 7925; ATL_7952; ATL_7953; ATL_7955; ATL_7450; ATL_7819; ATL_7820;ATL 7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827;ATL 7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896;ATL 7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919;ATL 7920; ATL_7921 ; ATL_7922; ATL_7923; ATL_7924);HFWR2 of SEQ ID NO: 42 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_6026; ATL 7925; ATL_7952; ATL_7953; ATL_7955; ATL_7450; ATL_7820; ATL_7821 ;ATL 7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829;ATL 7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899;ATL 7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919; ATL_7920;ATL 7921 ; ATL_7922; ATL_7923; ATL_7924); SEQ ID NO: 50 (ATL_6027); SEQ ID NO: 58 (ATL 6058; ATL_7469; ATL_7927); SEQ ID NO: 66 (ATL_6074); SEQ ID NO: 74 (ATL_6075); SEQ ID NO: 113 (ATL_7933; ATL_7956; ATL_7467; ATL_7468; ATL_7470; ATL_7471 ; ATL_7472; ATL_7473; ATL_7926; ATL_7930; ATL_7931 ; ATL_7932); or SEQ ID NO: 153 (ATL_7819); SEQ ID NO: 192 (ATL_7928); or SEQ ID NO: 193 (ATL_7929);HFWR3 of SEQ ID NO: 43 (ATL_6026; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL 7822; ATL_7823; ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893;ATL 7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7922); SEQ ID NO: 51 (ATL_6027); SEQ ID NO: 59 (ATL_6058; ATL_7469); SEQ ID NO: 67 (ATL_6074; ATL_7472); SEQ ID NO: 75 (ATL_6075); SEQ ID NO: 99 (ATL_7925;ATL 7953; ATL_7919); SEQ ID NO: 100 (ATL_7952; ATL_7917; ATL_7920; ATL_7921); SEQ ID NO: 101 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955); SEQ ID NO: 114 (ATL_7933; ATL_7956; ATL_7926; ATL_7928; ATL_7929); SEQ ID NO: 158 (ATL_7824); SEQ ID NO: 159 (ATL_7825; ATL_7918; ATL_7923; ATL_7924); SEQ ID NO: 160 (ATL_7826); SEQ ID NO: 161 (ATL_7827); SEQ ID NO: 194 (ATL_7931); SEQ ID NO: 195 (ATL_7932); SEQ ID NO: 196 (ATL_7467; ATL_7468; ATL_7470;ATL_7471); SEQ ID NO: 197 (ATL_7473); SEQ ID NO: 198 (ATL_7927); or SEQ ID NO: 199 (ATL_7930); andHFWR4 of SEQ ID NO: 44 (ATL_6026); SEQ ID NO:52 (ATL_6027); SEQ ID NO: 60 (ATL 6058; ATL_7933; ATL_7469; ATL_7927); SEQ ID NO: 68 (ATL_6064); SEQ ID NO: 76 (ATL_6075); SEQ ID NO: 103 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL 7925; ATL_7952; ATL_7953; ATL_7955; ATL_7450; ATL_7819; ATL_7820;ATL 7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827;ATL_7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896;ATL 7899; ATL_7900; ATL_7901 ; ATL_7902; ATL_7917; ATL_7918; ATL_7919;ATL 7920; ATL_7921 ; ATL_7922; ATL_7923; ATL_7924); or SEQ ID NO: 115 (ATL_7956; ATL_7467; ATL_7468; ATL_7470; ATL_7471 ; ATL_7472; ATL_7473; ATL 7926; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932),or framework sequences with one to nine or one to five mutations, optionally wherein the mutations are substitutions, compared with the framework sequences above; optionally wherein the substitution is at position 5, optionally wherein the substitution is Q5V; and / or at position 53, optionally wherein the substitution is M53A; and / or at position 78, optionally wherein the substitution is M78I or M78A; and / or at position 81 ; optionally wherein the substitution is D81 E; and / or at position 89, optionally wherein the substitution is M89A; and / or at position 97, optionally wherein the substitution is D97E; and / or at position 98, optionally wherein the substitution is D98E; and / or at position 98, optionally wherein the substitution is D98E; and / or at position 99, optionally wherein the substitution is T99A; and / or at position 123, optionally wherein the substitution is M 123T.

18. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the amino acid sequence selected from the group consisting of:SEQ ID NO: 93; SEQ ID NO: 1 ; SEQ ID NO: 90; SEQ ID NO: 91 ; SEQ ID NO: 92; SEQ ID NO: 118; SEQ ID NO: 119; SEQ ID NO: 120; SEQ ID NO: 121 ; SEQ ID NO: 122; SEQ ID NO: 123; SEQ ID NO: 124; SEQ ID NO: 125; SEQ ID NO: 126; SEQ ID NO: 127; SEQ ID NO: 128; SEQ ID NO: 129; SEQ ID NO: 130; SEQ ID NO: 131 ; SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 178; SEQ ID NO: 179; SEQ ID NO: 180; and SEQ ID NO: 181 ;optionally selected from the group consisting of: SEQ ID NO: 93; SEQ ID NO: 1 ; SEQ ID NO: 90; SEQ ID NO: 91 ; and SEQ ID NO: 92;optionally wherein the antibody comprises a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the amino acid sequence of SEQ ID NO: 93.

19. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL), with the following CDRs:CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_6026; ATL_7925; ATL_7952; ATL_7953;ATL 7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823; ATL_7824;ATL 7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890; ATL_7892;ATL 7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7901 ; ATL_7902;ATL_7917; ATL_7918; ATL_7919; ATL_7920; ATL_7921 ; ATL_7922; ATL_7923;ATL_7924); SEQ ID NO: 27 (ATL_6027); SEQ ID NO: 28 (ATL_6058; ATL_7933;ATL 7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930;ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472;ATL_7473); SEQ ID NO: 29 (ATL_6074); or SEQ ID NO: 30 (ATL_6075);CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7925; ATL_7952; ATL_7953; ATL_7900;ATL_7919; ATL_7923); SEQ ID NO: 31 (ATL_6026; ATL_7450; ATL_7819; ATL_7820; ATL 7821 ; ATL_7822; ATL_7823; ATL_7824; ATL_7825; ATL_7826; ATL_7827;ATL 7829; ATL_7889; ATL_7890; ATL_7892; ATL_7893; ATL_7895; ATL_7896;ATL 7901 ; ATL_7902; ATL_7920); SEQ ID NO: 32 (ATL_6027); SEQ ID NO: 33 (ATL_6058; ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL 7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468;ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 34 (ATL_6074); SEQ ID NO: 35 (ATL_6075); SEQ ID NO: 166 (ATL_7917; ATL_7918); or SEQ ID NO: 167 (ATL_7899; ATL 7921 ; ATL_7922; ATL_7924); andCDRL3 comprising an amino acid sequence of SEQ ID NO: 207 (ATL_8946); SEQ ID NO: 206 (ATL_8944); SEQ ID NO: 107 (ATL_7955; ATL_7925; ATL_7952; ATL_7953; ATL 7902; ATL_7917; ATL_7922; ATL_7923; ATL_7924); SEQ ID NO: 36 (ATL_8947; ATL 6026; ATL_7450; ATL_7819; ATL_7820; ATL_7821 ; ATL_7822; ATL_7823;ATL 7824; ATL_7825; ATL_7826; ATL_7827; ATL_7829; ATL_7889; ATL_7890;ATL 7892; ATL_7893; ATL_7895; ATL_7896; ATL_7899; ATL_7900; ATL_7918); SEQ ID NO: 37 (ATL_6027); SEQ ID NO: 38 (ATL_6058; ATL_7933; ATL_7956; ATL_7470; ATL 7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930; ATL_7931 ; ATL_7932;ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472; ATL_7473); SEQ ID NO: 39 (ATL_6074); SEQ ID NO: 40 (ATL_6075); SEQ ID NO: 168 (ATL_8945; ATL_7901 ; ATL_7919; ATL_7921); or SEQ ID NO: 169 (ATL_7920);or a set of CDRs containing one to four amino acid mutations, such as substitutions, compared with the above set of CDRs.

20. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL) with the following CDRs:CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7955);CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955; ATL_7925; ATL_7952; ATL_7953) or SEQ ID NO: 31 (ATL_6026); andCDRL3 comprising an amino acid sequence of SEQ ID NO: 207 (ATL_8946); SEQ ID NO: 206 (ATL_8944); SEQ ID NO: 107 (ATL_7955; ATL_7925; ATL_7952; ATL_7953); SEQ ID NO: 36 (ATL_8947; ATL_6026); or SEQ ID NO: 168 (ATL_8945; ATL_7901 ; ATL_7919;ATL_7921);or a set of CDRs containing one to four amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs, optionally wherein the substitution is at position 57, optionally wherein the substitution is N57A or N57Q; and / or at position 65, optionally wherein:(i) the substitution is S65N or S65A; and / or at position 109, optionally wherein the substitution is N109A or N109Q; and / or at position 113, optionally wherein the substitution is S113N or S113A; or(ii) the mutations in the light chain CDRs do not include a mutation at position 109 or position 113 in standard IMGT numbering, optionally wherein the mutations do not include a mutation in CDRL3;optionally wherein the light chain variable domain (VL) comprises the following framework sequences: LFWR1 of SEQ ID NO: 45 (ATL_6026) or SEQ ID NO: 104 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955); LFWR2 of SEQ ID NO: 46 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_6026; ATL_7925; ATL_7952; ATL_7953; ATL_7955); LFWR3 of SEQ ID NO: 47 (ATL_6026) or SEQ ID NO: 106 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953; ATL_7955); and LFWR4 of SEQ ID NO: 48 (ATL_6026) or SEQ ID NO: 108 (ATL_8944; ATL_8945; ATL_8946; ATL_8947;ATL_7925; ATL_7952; ATL_7953; ATL_7955); or framework sequences with one to five mutations, optionally wherein the mutations are substitutions, compared with the framework sequences above, optionally wherein the substitution is at position 2, optionally wherein the substitution is A2S; and / or at position 8, optionally wherein the substitution is S8P; and / or at position 52, optionally wherein the substitution is P52L; and / or at position 90, optionally wherein the substitution is V90A; and / or at position 124, optionally wherein the substitution is V124L.

21. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL) with the following CDRs:CDRL1 comprising an amino acid sequence of SEQ ID NO: 26 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955);CDRL2 comprising an amino acid sequence of SEQ ID NO: 105 (ATL_8944; ATL_8945; ATL 8946; ATL_8947; ATL_7955); andCDRL3 comprising an amino acid sequence of SEQ ID NO: 207 (ATL_8946); SEQ ID NO: 107 (ATL_7955); 206 (ATL_8944); SEQ ID NO: 168 (ATL_8945); or SEQ ID NO: 36 (ATL_8947);optionally wherein the light chain variable domain (VL) comprises the following framework sequences: LFWR1 of SEQ ID NO: 104 (ATL_8944; ATL_8945; ATL_8946; ATL_8947;ATL_7955); LFWR2 of SEQ ID NO: 46 (ATL_8944; ATL_8945; ATL_8946; ATL_8947;ATL_7955); LFWR3 of SEQ ID NO: 106 (ATL_8944; ATL_8945; ATL_8946; ATL_8947;ATL_7955); and LFWR4 of SEQ ID NO: 108 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7955).

22. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL) with the following CDRs:CDRL1 comprising an amino acid sequence of SEQ ID NO: 28 (ATL_6058; ATL_7933; ATL_7956);CDRL2 comprising an amino acid sequence of SEQ ID NO: 33 (ATL_6058; ATL_7933; ATL_7956); andCDRL3 comprising an amino acid sequence of SEQ ID NO: 38 (ATL_6058; ATL_7933; ATL_7956);or a set of CDRs containing one, two, or three amino acid mutations, optionally wherein the mutations are substitutions, compared with the above set of CDRs;optionally wherein the light chain variable domain (VL) comprises the following framework sequences: LFWR1 of SEQ ID NO: 61 (ATL_6058; ATL_7933; ATL_7956); LFWR2 of SEQ ID NO: 62 (ATL_6058) or SEQ ID NO: 116 (ATL_7933; ATL_7956); LFWR3 of SEQ ID NO: 63 (ATL_6058) or SEQ ID NO: 117 (ATL_7933; ATL_7956); and LFWR4 of SEQ ID NO: 64 (ATL_6058; ATL_7933; ATL_7956); or framework sequences with one to four mutations, optionally wherein the mutations are substitutions, compared with the framework sequences above, optionally wherein the substitution is at position 49, optionally wherein the substitution is P49A; and / or at position 52, optionally wherein the substitution is R52L; and / or at position 74, optionally wherein the substitution is G74D; and / or at position 90, optionally wherein the substitution is S90T.

23. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL) with the following CDRs:CDRL1 comprising an amino acid sequence of SEQ ID NO: 28 (ATL_7933); CDRL2 comprising an amino acid sequence of SEQ ID NO: 33 (ATL_7933); and CDRL3 comprising an amino acid sequence of SEQ ID NO: 38 (ATL_7933); and wherein the light chain variable domain (VL) comprises the following framework sequences: LFWR1 of SEQ ID NO: 61 (ATL_7933); LFWR2 of SEQ ID NO: 116 (ATL_7933); LFWR3 of SEQ ID NO: 117 ( ATL_7933) ; and LFWR4 of SEQ ID NO: 64 (ATL_7933).

24. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL) with the following framework sequences:LFWR1 of SEQ ID NO: 45 (ATL_6026; ATL_0007450; ATL_0007819;ATL 0007820; ATL_0007821 ; ATL_0007822; ATL_0007823; ATL_0007824; ATL 0007825; ATL_0007826; ATL_0007827; ATL_0007829; ATL_0007892; ATL 0007893; ATL_0007899; ATL_0007900; ATL_0007901 ; ATL_0007902; ATL 0007917); SEQ ID NO: 53 (ATL_6027); SEQ ID NO: 61 (ATL_6058; ATL_7933; ATL 7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929; ATL_7930;ATL 7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469; ATL_7472;ATL_7473); SEQ ID NO: 69 (ATL_6074); SEQ ID NO: 77 (ATL_6075); SEQ ID NO: 104 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952; ATL_7953;ATL 7955; ATL_0007896; ATL_0007920; ATL_0007921 ; ATL_0007922); SEQ ID NO: 163 (ATL 0007889; ATL_0007895; ATL_0007919; ATL_0007924); or SEQ ID NO: 164 (ATL 0007890; ATL_0007918; ATL_0007923);LFWR2 of SEQ ID NO: 46 (ATL_8944; ATL_8945; ATL_8946; ATL_8947;ATL 6026; ATL_7925; ATL_7952; ATL_7953; ATL_7955; ATL_0007450; ATL_0007819; ATL 0007820; ATL_0007821 ; ATL_0007822; ATL_0007823; ATL_0007824;ATL 0007825; ATL_0007826; ATL_0007827; ATL_0007829; ATL_0007889;ATL 0007890; ATL_0007892; ATL_0007893; ATL_0007896; ATL_0007899; ATL 0007900; ATL_0007901 ; ATL_0007902; ATL_0007920); SEQ ID NO: 54 (ATL_6027); SEQ ID NO: 62 (ATL_6058; ATL_7468); SEQ ID NO: 70 (ATL_6074); SEQ ID NO: 78 (ATL_6075); SEQ ID NO: 116 (ATL_7933; ATL_7956; ATL_7467; ATL_7469; ATL_7470; ATL_7471 ; ATL_7472; ATL_7473; ATL_7928; ATL_7929; ATL_7930;ATL 7931 ; ATL_7932); SEQ ID NO: 165 (ATL_0007895; ATL_0007917; ATL_0007918; ATL 0007919; ATL_0007921 ; ATL_0007922; ATL_0007923; ATL_0007924); SEQ ID NO: 200 (ATL_7927); or SEQ ID NO: 201 (ATL_7926);LFWR3 of SEQ ID NO: 47 (ATL_6026; ATL_0007450; ATL_0007819;ATL 0007820; ATL_0007821 ; ATL_0007822; ATL_0007823; ATL_0007824; ATL 0007825; ATL_0007826; ATL_0007827; ATL_0007829; ATL_0007889; ATL 0007890; ATL_0007893; ATL_0007899; ATL_0007900; ATL_0007901 ; ATL 0007902; ATL_0007921); SEQ ID NO: 55 (ATL_6027); SEQ ID NO: 63 (ATL_6058; ATL_7468); SEQ ID NO: 71 (ATL_6074); SEQ ID NO: 79 (ATL_6075); SEQ ID NO: 106 (ATL_8944; ATL_8945; ATL_8946; ATL_8947;ATL_7925; ATL_7952; ATL_7953;ATL 7955; ATL_0007892; ATL_0007895; ATL_0007896; ATL_0007917; ATL_0007918; ATL 0007919; ATL_0007920; ATL_0007922; ATL_0007923; ATL_0007924); or SEQ ID NO: 117 (ATL_7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928;ATL 7929; ATL_7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7469;ATL_7472; ATL_7473); andLFWR4 of SEQ ID NO: 48 (ATL_6026; ATL_0007450; ATL_0007819;ATL 0007820; ATL_0007821 ; ATL_0007822; ATL_0007823; ATL_0007824; ATL 0007825; ATL_0007826; ATL_0007827; ATL_0007829; ATL_0007889; ATL 0007890; ATL_0007892; ATL_0007899; ATL_0007900; ATL_0007901 ; ATL 0007902; ATL_0007922); SEQ ID NO: 56 (ATL_6027); SEQ ID NO: 64 (ATL_6058; ATL 7933; ATL_7956; ATL_7470; ATL_7926; ATL_7927; ATL_7928; ATL_7929;ATL 7930; ATL_7931 ; ATL_7932; ATL_7471 ; ATL_7467; ATL_7468; ATL_7469;ATL_7472; ATL_7473); SEQ ID NO: 72 (ATL_6074; ATL_0007893; ATL_0007895; ATL 0007896; ATL_0007917; ATL_0007918; ATL_0007919; ATL_0007920; ATL 0007921 ; ATL_0007923; ATL_0007924); SEQ ID NO: 80 (ATL_6075); or SEQ ID NO: 108 (ATL_8944; ATL_8945; ATL_8946; ATL_8947; ATL_7925; ATL_7952;ATL 7953; ATL_7955);or framework sequences with one, two, or three mutations, such as substitutions, compared with the framework sequences above.

25. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity with the amino acid sequence selected from the group consisting of: SEQ ID NO: 204; SEQ ID NO: 6; SEQ ID NO: 7; SEQ ID NO: 8; SEQ ID NO: 9; SEQ ID NO: 10; SEQ ID NO: 94; SEQ ID NO: 111 ; SEQ ID NO: 135; SEQ ID NO: 136; SEQ IDNO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140; SEQ ID NO: 141 ; SEQ ID NO: 142; SEQ ID NO: 143; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151 ; SEQ ID NO: 152; SEQ ID NO: 189; SEQ ID NO: 190; SEQ ID NO: 202; SEQ ID NO: 203; and SEQ ID NO: 205; optionally the group consisting of: SEQ ID NO: 6; SEQ ID NO: 8; SEQ ID NO: 94; SEQ ID NO: 111 ; SEQ ID NO: 202; SEQ ID NO: 203; SEQ ID NO: 204; and SEQ ID NO: 205; optionally the group consisting of: SEQ ID NO: 204; SEQ ID NO: 94; SEQ ID NO: 111 ; SEQ ID NO: 202; SEQ ID NO: 203; and SEQ ID NO: 205; optionally the group consisting of SEQ ID NO: 204; SEQ ID NO: 202; SEQ ID NO: 203; and SEQ ID NO: 205; optionally wherein the antibody comprises a light chain variable domain (VL) comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 204; SEQ ID NO: 202; SEQ ID NO: 203; and SEQ ID NO: 205, optionally wherein the antibody comprises a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 204.

26. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises:(a) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 1 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 6; or(b) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 90 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or(c) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 91 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or(d) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 92 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or(e) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity to SEQ ID NO: 94; or(f) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 202; or(g) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 203; or(h) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 204; or(i) a heavy chain variable domain (VH) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 93 and a light chain variable domain (VL) comprising a sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% sequence identity, or that has 100% sequence identity to SEQ ID NO: 205.

27. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises:a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 93; and a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 204.

28. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody comprises a light chain variable domain (VL) comprising CDRL1 , CDRL2, and CDRL3 within a human framework, and / or within a germline framework and / or wherein the antibody comprises a heavy chain variable domain (VH) comprising CDRH1 , CDRH2, and CDRH3 within a human framework, and / or within a germline framework.

29. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody is a human antibody.

30. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein:(a) the antibody binds human PGDH, wherein the antibody binds human PGDH with a kD of at most 106M, 107M, 108M, 109M, preferably at most 109M, as measured by ELISA, and / or wherein the antibody binds human PGDH with an EC50 below 100 nM, below 50 nM, or below 10nM as measured by titration ELISA; and / or(b) the antibody inhibits PGDH as determined using a 15-PGDH enzyme activity assay, and / or wherein the antibody inhibits human PGDH with an IC50 below 200 nM or below 150 nM; and / or(c) the antibody binds human PGDH, wherein the antibody binds human PGDH with a kD of at most 1 E-06M, at most 1 E-07M, at most 1 E-08M, at most 1 E-09M, at most 5E-10M, at most 3E-10M, at most 2.5E-1 OM, at most 2E-1 OM, preferably at most 2E-1 OM, as measured by BLI.31 . The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody:a. alters PGE2 levels in an in vitro cell culture, and / or wherein the antibody alters one or more of autophagy, activity, oxidative stress, and apoptosis of dopaminergic neurons in vitro, and / or wherein the antibody alters microglia inflammatory state in vitro; and / or b. reduces inflammation, optionally neuroinflammation, in an in vitro cell culture, optionally wherein a reduction in inflammation is determined by measuring the levels of one or more pro-inflammatory cytokines, optionally wherein the pro-inflammatory cytokine is IL- 6, IL-1 p, and / or TNFa, and / or wherein an in vitro cell culture comprises cells exposed to a proinflammatory condition, optionally comprising exposure to aSyn fibrils; and / or c. alters 15-PGDH levels in an in vitro cell culture; and / ord. alters phospho-aSyn129 levels in an in vitro cell culture comprising cells exposed to aSyn fibrils; and / ore. alters mitochondrial function in an in vitro cell culture, optionally wherein an alteration in mitochondrial function is determined by measuring the mitochondrial membrane potential (MMP) comprising cells exposed to aSyn fibrils.

32. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody:a. increases the levels of circulating PGE2 in vivo; and / orb. binds 15-PGDH at an allosteric site; and / orc. prevents, inhibits or competes with binding of one or more substrates, optionally PGE2, to the substrate binding site of 15-PGDH; and / ord. decreases the levels of one or more pro-inflammatory cytokines in vivo, optionally wherein the pro-inflammatory cytokine is IL-6, IL-1 p, and / or TNFa, and / or wherein the antibody decreases the levels of one or more pro-inflammatory cytokines in an animal model and / or in a subject exposed to pro-inflammatory conditions, optionally comprising exposure to LPS; and / ore. binds to and / or obstructs one or more residues in the cofactor entry site of 15-PGDH; and / orf. prevents or inhibits entry of NAD+ to the cofactor entry site of 15-PGDH; and / or g. prevents or inhibits closure of the the lid domain of 15-PGDH.

33. The isolated antibody, antibody for use, method, or use according to any preceding claim, wherein the antibody is a monoclonal antibody, and / or wherein the antibody is an IgG 1 , or amodified version thereof, optionally a LALA IgG 1 , optionally wherein the LALA IgG 1 comprises a sequence according to SEQ NO: 87, or wherein the antibody is an isolated VH domain according to any preceding claim.

34. The antibody for use, method, or use according to any one of claims 2-33, wherein the treatment comprises administering to a subject a therapeutically effective amount of a composition comprising the antibody and at least one additional component, optionally wherein the additional component is a pharmaceutically acceptable excipient, vehicle or carrier.

35. The isolated antibody according to any of claims 1 , or 13-33, for use as a medicament, and / or for use in the treatment of a disease or disorder in a subject in need thereof, optionally wherein the disease or disorder is a disease or disorder associated with inflammation and / orneuroinflammation.

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