Anti-fibril antibodies with engineered fc regions

Abstract

The present invention provides novel antibodies comprising a Fab region and an Fc region, wherein the Fab region has broad specificity for the different types of amyloid fibrils that cause the major forms of human systemic amyloidosis, and the Fc region is engineered to convey additional advantageous properties such as increasing complement activation, increasing binding to Fcγ receptors and / or increasing half life. The present invention also provides humanised Fc engineered monoclonal antibodies which target multiple amyloid fibril types, as well as methods for using such antibodies and uses of the antibodies in therapeutic applications. The present invention further provides novel antibodies comprising a Fab region, wherein the Fab region has broad specificity for the different types of amyloid fibrils.

Description

[0001] Anti-Fibril Antibodies with Engineered Fc Regions

[0002] The present invention provides novel antibodies comprising a Fab region and an Fc region, wherein the Fab region has broad specificity for the different types of amyloid fibrils that cause the major forms of human systemic amyloidosis, and the Fc region is engineered to convey additional advantageous properties such as increasing complement activation, increasing binding to Fey receptors and / or increasing half life. The present invention also provides humanised Fc engineered monoclonal antibodies which target multiple amyloid fibril types, as well as methods for using such antibodies and uses of the antibodies in therapeutic applications. The present invention further provides novel antibodies comprising a Fab region, wherein the Fab region has broad specificity for the different types of amyloid fibrils.

[0003] Introduction

[0004] Amyloidosis is a serious disease caused by extracellular deposition of insoluble abnormal fibrils, derived from aggregation of misfolded autologous proteins [Pepys, M. B. (2006). Annu. Rev. Med., 57, 223-241 ; Pepys, M. B. and P. N. Hawkins (2020). Amyloidosis. Oxford Textbook of Medicine. J. Firth, C. Conlon and T. Cox, Oxford University Press], About 30 different proteins are known to form amyloid fibrils in vivo in humans, each associated with clinically distinct conditions (https: / / doi.org / 10.1080 / 13506129.2020.1835263). Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries. Cardiac transthyretin amyloidosis, known as ATTR, is a fatal disease, predominantly of elderly men, recently recognised to have a prevalence of 3-5% over the age of 75. The diagnosis of all forms of amyloidosis is clinically challenging and usually delayed, contributing, together with the limited efficacy and notable toxicity of many existing treatments, to frequently poor outcomes. Amyloidosis is thus a major unmet medical need.

[0005] Amyloidosis can be acquired as a complication of pre-existing primary disease that produces either an inherently amyloidogenic abnormal protein or greatly increased exposure to a normal but potentially amyloidogenic protein, or it is caused in the elderly by the normal expression of wild type transthyretin, which is inherently amyloidogenic. Hereditary amyloidosis is caused by mutant genes that encode variant proteins that happen to be amyloidogenic. Amyloid deposits can be local, restricted to a particular organ or tissue, or systemic, with amyloid deposits throughout the body except within the brain. Systemic amyloidosis is overwhelmingly either AL or ATTR type; the various hereditary types are rare. Systemic AA amyloidosis, which is a complication of chronic infections and other inflammatory conditions, is now rare in developed countries but remains more prevalent elsewhere.

[0006] The tissue and organ damage that manifests as clinical disease in amyloidosis is directly caused by remorseless accumulation of the extracellular fibrillar amyloid deposits. They disrupt the structure and thus the function of the affected tissues. For reasons that are not known, the normal mechanisms for clearance of debris from the extracellular space remove amyloid deposits very slowly if at all. Existing management of amyloidosis therefore comprises (a) supportive therapy to sustain function of damaged organs, up to and including multiple organ transplantation, and (b) measures to reduce the abundance of the respective amyloid fibril precursor protein and / or stabilise its native fold to prevent fibrillogenesis. The aim is to reduce or arrest the ongoing accumulation of amyloid and hope for the slow spontaneous but ultimately clinically beneficial regression of amyloid that then occurs in some patients. However, the range and efficacy of interventions intended to prevent amyloid formation, are limited and no specific treatments exist for many different types of amyloidosis and for many patients.

[0007] Direct approaches to removal of amyloid deposits in vivo are known in the art, specifically targeting serum amyloid P component (SAP). The depletion of circulating SAP by small molecule drug miridesap [Pepys, M.B., et al., Nature, 2002. 417(6886): p. 254-259] enabled the safe and effective administration of anti-SAP antibodies to target amyloid deposits of all types [Bodin, K., et al., Nature, 2010. 468(7320): p. 93-97], The obligate therapeutic partnership between miridesap and anti-SAP antibody established proof of concept for safe and clinically beneficial amyloid removal by complement activating IgG antibodies in patients with different forms of systemic amyloidosis [Richards, D.B., et al., N. Engl. J. Med., 2015. 373(12): p. 1106-1114, Richards, D.B., et al., Sci. Transl. Med., 2018. 10(422): p. eaan3128.].

[0008] The SAP bound to amyloid fibrils of all types is an attractive target antigen but the actual purpose of antibody immunotherapy is removal of the amyloid fibrils themselves. Unfortunately, amyloid fibrils have long been known to be very poorly immunogenic. Patients with amyloidosis almost never produce specific anti-amyloid fibril antibodies, and experimental animals respond poorly if at all, even when vigorously immunised with xenogeneic fibrils. On the other hand, ex vivo amyloid fibrils of all types share very similar morphology, ultrastructure and protein fold, especially the cross-p core structure that is common to all ex vivo amyloid fibril types, regardless of their completely unrelated protein sequences [Sunde, M., et al., J. Mol. Biol., 1997. 273: p. 729-739],

[0009] We and others have therefore hypothesised that amyloid fibrils may share potentially epitopic structures but, although some putatively cross- reactive antibodies have been claimed, PCT / EP2024 / 066449 was the first disclosure of genuinely broad spectrum anti-amyloid fibril antibodies. The monoclonal antibodies and humanised antibodies reported in PCT / EP2024 / 066449 are capable of binding to multiple types of amyloid fibrils and demonstrating notable amyloid clearance in mice with established systemic AA amyloidosis. PCT / EP2024 / 066449 also highlights that complement activation is a necessary property for in vivo antibody-mediated amyloid removal.

[0010] Given the importance of the interaction between antibody Fc regions and their targets (Fc receptors, C1 q etc) investigators have sought to optimise these effects by engineering the Fc region to bind to a greater or lesser extent to individual targets of the Fc region. Although many Fc mutations have been trialled, there are few systematic comparisons of the activity of the different mutations and predicting the patterns of activity when incorporated into different antibodies can be challenging. Combinations of Fc mutations are especially hard to predict and combinations of mutations that are effective on their own or in other combinations can lead to complete loss of intended function. Additionally, for therapeutic applications, it is important that Fc modifications do not destabilize the antibody structure and many Fc mutations (even single amino acid changes) can lead to reduced thermal stability which can impact immunogenicity, antibody binding, aggregation, storage and drug manufacture. [Hale, G., et al. (2024). mAbs, 16(1). https: / / doi.org / 10.1080 / 19420862.2024.2406539.]

[0011] There remains a need in the art for further and improved broad spectrum anti-amyloid fibril antibodies that can remove established amyloid deposits.

[0012] Summary of the Invention

[0013] In a first aspect, there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils; and the Fc region is an engineered Fc region. In some embodiments, there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils with broad anti-fibril specificity; and the Fc region is an engineered Fc region be engineered to alter one or more properties of the antibody.

[0014] The Fab region of antibodies of the invention may be capable of binding to at least 3, 4, 5, 6, 7, 8, 9, 10 or 11 different types of amyloid fibrils, for example including ALK, ALA, ATTR wild type (ATTRwt), ATTR variant (ATTRv), AA, AApoAl, ALys, AP2m, AGel, AIAPP (Amylin / lslet Amyloid Polypeptide) and AFib amyloid fibrils. The Fab region of antibodies of the invention may be capable of binding to at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils. The antibodies of the invention successfully binds to fibrils which cause or are involved in systemic amyloidosis. The antibodies do not bind to A fibrils present in the CNS and particularly in the brain in patients with Alzheimer’s disease.

[0015] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively. An antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively, each optionally comprising a single amino acid change or double amino acid changes. An antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8, respectively.

[0016] An antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of a sequence having a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 , respectively. An antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 , respectively, each optionally comprising a single amino acid change.

[0017] In one embodiment, the Fab region of an antibody of the invention comprises a heavy chain variable region having a sequence identity of at least 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% with SEQ ID No. 2.

[0018] In one embodiment, the Fab region of an antibody of the invention comprises a light chain variable region having a sequence identity of at least 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% with SEQ ID No. 4.

[0019] In embodiments, the antibodies of the invention are specific for a conformational epitope commonly presented on amyloid fibrils. Thus, the antibody is able to bind to an amyloid-specific epitope independently of the linear polypeptide structure of the fibril.

[0020] The present invention provides humanised isolated monoclonal antibodies or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils with broad anti-fibril specificity; and the Fc region is an Fc region engineered to alter one or more properties of the antibody. A humanised monoclonal antibody or antigen binding portion thereof of the invention may comprise a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 75% with the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively.

[0021] Additionally, or alternatively, a humanised monoclonal antibody or antigen binding portion thereof of the invention may comprise a Fab region wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of a sequence having a sequence identity of at least 87% with the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID No. 11 respectively.

[0022] In another embodiment, an antibody according to the invention may have a single or double amino acid change in one or more CDRs, compared to the SEQ IDs of the CDRs as set forth herein. The single or double amino acid change may be a conservative amino acid substitution.

[0023] In another embodiment, an antibody according to the invention may have a single amino acid change in one or more framework regions, compared to the SEQ IDs of the VH and VL sequences as set forth herein. The single amino acid change may be a conservative amino acid substitution.

[0024] In another embodiment, the antibody according to the invention may have at least one, for example a single, double or triple amino acid change in one or both of the variable regions, compared to the SEQ IDs of the VH and VL sequences as set forth herein. In some embodiments, at least one amino acid change may be in a CDR. In some embodiments, the at least one amino acid change may be in a framework region. The at least one amino acid change may be a conservative amino acid substitution.

[0025] In another embodiment, the antibody according to the invention may have at least one, for example a single, double or triple amino acid change in one of the variable regions, compared to the SEQ IDs of the VH and VL sequences as set forth herein. In some embodiments, the at least one amino acid change may be in a CDR. In some embodiments, the at least one amino acid change may be in a framework region. The at least one amino acid change may be a conservative amino acid substitution.

[0026] In another embodiment, the humanised monoclonal antibody may have human framework regions derived from antibody genes selected from SEQ ID Nos. 12 and 13.

[0027] In some embodiments, the Fab regions of the isolated (humanised) monoclonal antibodies of the invention may be as shown in Table 1. This includes antibodies generated from humanization of 2E5 (Ab04-Ab23, see Examples 1 to 4) and antibodies generated from optimisation rounds of Ab19 (Ab24-52, see Examples 5 and 16).

[0028]

[0029] The monoclonal antibody or antigen binding portion thereof may be selected from an IgG, IgA, or an antigen binding antibody fragment selected from an FAb, F(ab’)2, an scFv, an Fv, or a disulfide-bonded Fv, a human antibody, a chimeric antibody preferably containing a human variable region, a humanized antibody, or a bispecific antibody.

[0030] The antibodies of the invention may comprise an engineered Fc region. An “engineered” Fc region means an Fc region that has been altered from wild type, for example by mutation of one or more amino acids. The Fc region may be engineered to increase complement activation; increase hexamerisation; increase C1 q affinity; increase affinity to human FcgR I; increase affinity to human FcgR II; increase affinity to human FcgR III; increase ADCP; increase affinity to human

[0031] FcRn at acidic pH; increase antibody cellular recycling; and / or increase half-life. In some embodiments, the Fc region may be engineered to increase complement activation. The humanised monoclonal antibody or antigen binding portion thereof may have an Fc region of or derived from the human lgG1 isotype. In a specific embodiment, the antibody is of hlgG1 isotype (human IgG 1 ). In some embodiments, the engineered Fc region is a human IgG Fc region comprising one or more amino acid mutations with respect to a wildtype human IgG Fc region (e.g. SEQ ID NO: 623).

[0032] The engineered Fc region may comprise one or more of the amino acid mutations selected from the group consisting of: G236W, S239D; M252Y; S254T; T256E; S298A, L234Y, L328E, I332E, M428L, H429F; E430G; and N434S (Eu numbering).

[0033] In some embodiments, the engineered Fc region comprises the amino acid mutations (Eu numbering): a)E430G; b)S239D and I332E; c) M428L and N434S; d)L328E; e)L234Y, G236W and S298A; f) H429F; g)M252Y, S254T and T256E h)E430G, S239D and I332E; i) E430G, M428L, and N434S; j) E430G and L328E k)S239D, I332E, M428L and N434S; l) S239D, I332E and H429F; and / or m) M428L, N434S and H429F.

[0034] In some embodiments, the constant chains comprising the engineered Fc regions comprise or consist of the sequences shown in Table 2.

[0035] IMT1-191 comprises a wild type hlgG1 and the Fc region is not modified.

[0036] In one embodiment there is provided an isolated monoclonal antibody, humanised antibody, or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils; and the Fc region is an engineered Fc region comprising the amino acid mutation E430G.

[0037] In one embodiment there is provided an isolated monoclonal antibody, humanised antibody, or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils; and the Fc region is an engineered Fc region comprising the amino acid mutations S239D + I332E (SDIE).

[0038] The engineered Fc regions of the present invention can be combined with any of the Fab regions of the present invention. For example, any Fab region as shown in Table 1 may suitably be combined with any of the constant chains or Fc regions as shown in Table 2. In addition, any Fab region as shown in Table 1 may suitable be combined with a wild-type Fc region, e.g. IMT1-191. In some embodiments, any of Clone P029_Ab40, Clone P029_Ab41 , Clone P029_Ab42, Clone P029_Ab43, Clone P029_Ab44, Clone P029_Ab45, P029_Ab019-39, P029_Ab019-46, P029_Ab019-47, P029_Ab019-48, P029_Ab019-49, P029_Ab049, P029_Ab050, P029_Ab051 or P029_Ab052 may be combined with an unmodified Fc region, such as IMT1-191.

[0039] A humanised monoclonal antibody or antigen binding portion thereof of the invention may also effectively promote regression of systemic murine AA amyloid deposits when administered parenterally to mice with experimentally induced systemic AA amyloidosis.

[0040] A humanised monoclonal antibody or antigen binding portion thereof of the invention may have in vivo efficacy that is complement activation dependent.

[0041] Alternatively, or in addition, a humanised monoclonal antibody or antigen binding portion thereof of the invention may have in vivo efficacy that is Fey receptor binding dependent.

[0042] In a second aspect, the antibodies of the invention are for use in the treatment of systemic amyloidosis, and there is accordingly provided a pharmaceutical composition comprising an antibody as defined herein for use in the treatment of systemic amyloidosis. In a third aspect, there is provided the use of an antibody as defined herein in the manufacture of a composition for the treatment of systemic amyloidosis.

[0043] In a fourth aspect, there is provided an antibody or pharmaceutical composition disclosed herein for use in medicine. There is provided an antibody or pharmaceutical composition disclosed herein for use in treating a disease or disorder. In some embodiments, the disease or disorder is an amyloidosis. In some embodiments, the disease or disorder is systemic amyloidosis.

[0044] There is also provided a method for treating a subject suffering from systemic amyloidosis, comprising administering to a subject in need thereof a composition comprising an antibody specific for amyloid fibrils as described herein. There is also provided a method for treating systemic amyloidosis, comprising administering to a subject in need thereof an antibody or pharmaceutical composition as described herein.

[0045] The antibody or pharmaceutical composition may be co-administered together with a supporting treatment for amyloidosis. Amyloidosis therapy in the prior art typically aims to remove or reduce the presence or production of amyloid precursors, and the present antibody is designed to remove of established amyloid deposits. Together with existing or novel therapies to remove amyloid, the antibodies of the invention may thus provide a more complete treatment for amyloidosis.

[0046] In some embodiments, the antibody or composition may be administered independently of other amyloidosis treatments, for example where the occurrence of amyloid precursor has been minimised and it is desired to deplete established amyloid fibrils,

[0047] In another embodiment, the amyloidosis therapy is selected from any existing systemic AL amyloidosis therapies, including those listed by Bianchi et al., JACC CardioOncol. 2021 Oct; 3(4): 467-487.

[0048] These and other embodiments are further described in the following Detailed Description.

[0049] Brief description of the Figures

[0050] Figure 1. Generation of best-in-class anti-amyloid antibody 2E5 with broad specificity against amyloid deposits. A) Generation of 2E5 antibody through novel mouse fibril immunization strategies. B) Antibody 2E5 at 10 pg / ml specifically binds to ATTR fibrils in ELISA, but not to soluble, globular, human or mouse transthyretin (TTR) that have been immobilised. C) Antibody 2E5 at 10 pg / ml specifically stains tissue deposits of the major forms of human systemic amyloid, AL, ATTR and AA, as well as rare hereditary forms (images labelled AF488). Amyloid location in the same fields is shown by intense fluorescence of Congo red counterstain.

[0051] Figure 2. Anti-amyloid fibril antibody 2E5 binds to mouse AA amyloid and removes amyloid in vivo. A) Antibody 2E5 at 10 pg / ml specifically stains mouse AA amyloid deposits (images labelled AF488) identified by Congo red staining in serial sections. B) Antibody 2E5 removes amyloid in vivo. Liver amyloid load scores in systemic AA amyloidotic mice 16 days after single IP injection of 4.8 mg / mouse 2E5 compared with untreated controls. Mann- Whitney test: Control vs 2E5: p=0.01278

[0052] Figure 3. Binding of Malonate and Citrate to 2E5. A: binding of citrate in antibody binding cleft of 2E5 Fab, crystal structure. B: space and change comparisons between malonate, citrate and TTR C-terminus

[0053] Figure 4. BLI assay of binding of antibody 2E5 to deletions of TTR 99-127. A BLI assay was set up as depicted and deletions of peptide 99-127 tested for binding to 2E5. The results are shown in graphical and check-box form. Deletion of the C-terminus of the peptide abolishes binding to 2E5. Similarly, amidation of the C-terminal amino acid result in loss of binding, indicating that a free C-terminal COOH is essential for binding.

[0054] Figure 5. BLI assay of alanine scan of TTR 99-127. A BLI assay was performed with variants of 99-127 in which C-terminal amino acids were replaced with alanine. The three C-terminal amino acids (P, K, E) are increasingly essential for binding by 2E5.

[0055] Figure 6. Competition ELISA between 2E5 mAb and hSAP for coated ATTR fibrils. A fixed concentration of 2E5 mAb was incubated with increasing concentrations of hSAP within a physiologically relevant window. Binding of hSAP and 2E5 mAb is observed to ATTR fibrils, and the 2E5 binding signal is stable in the presence of bound hSAP, indicating that 2E5 has a nonoverlapping epitope with hSAP on ATTR fibrils.

[0056] Figure 7. Binding to ATTR Fibrils of Humanised Antibodies. ELISA of antibodies binding to ATTR fibrils after initial humanisation experiments, compared to murine 2E5 antibody. A: CDR grafts show 100-fold decrease in binding compared to 2E5. B: Control in absence of ATTR

[0057] Figure 8. CDR grafted variants binding to ATTR fibrils. Elisa of optimised CDR-grafted antibodies binding to 10ug / ml ATTR fibrils.

[0058] Figure 9. Elisa of CDR-grafted antibodies binding to different amyloid fibrils. Elisa plot of interaction of humanized clones to synthetic fibrils and native amyloid. Fibrils are synthetic amyloid derived from the truncated fragment of immunoglobulin light chain (AL55-133) and mutant forms of the transthyretin protein (S52P TTR) and beta2-microglobulin (D76N Abeta2-m) as well as AA (Amyloid A).

[0059] Figure 10. A-E: IMT1-191 binding to different types of amyloid fibrils in ELISA.

[0060] Figure 11. IHC images showing antibody binding to amyloid deposits. (A) IHC images showing IMT1-191 binding to ATTR amyloid deposits in unfixed human heart tissues. (B) IHC images showing the binding of IMT1-191 , NI006 and PRX004 to different types of amyloid deposits in unfixed human tissues from four cases with systemic amyloidosis. All primary antibodies were used at 1 ,g / mL. Congo red solution was used as a standard stain to identify amyloid proteins in tissue samples.

[0061] Figure 12. Monoclonal antibodies binding to non-native forms of Transthyretin variant S52P protein in ELISA. (A) Pre-fibrillar rS52P and (B) ATTR_S52P.

[0062] Figure 13. Binding of anti-ATTR monoclonal antibodies to C1q and Fey receptors

[0063] Figure 14. Activation of the Classical Complement Pathway by antibodies on (A-D) ATTR fibrils and (E-F) pre-fibrillar S52P rTTR

[0064] Figure 15. Phagocytosis of pHrodo labelled ATTR_S52P fibrils by THP-1 Macrophages. (A) Real time fluorescence signal of phagocytosed ATTR induced by 6.2 nM of antibodies. The phagocytosis was compared to the baseline level of phagocytosis without antibody. (B-D) Doseresponse curves of anti-ATTR antibodies to induce ATTR phagocytosis measured by cumulative fluorescence signal in Area Under Curve between 0-3hr (AUCtwhr). (E) Phagocytosis induced by IMT1-191 and IMT1-191-1 compared in Normal Human Serum (NHS) and human serum depleted of C1q protein (C1q-Dpl). Phagocytosis activity was compared to an LALAPG Fc variant with reduced effector functions. (F) Phagocytosis compared at a 0.69 nM concentration of IMT1-191 and IMT1-191-1 antibodies in NHS or C1q-Dpl human serum taken from Panel E. Error bars represent the mean ± SD of triplicate measurements. ****p <0.0001 , ***P=0.0001 , One-Way ANOVA Multiple Comparisons (Sidak's multiple comparisons test).

[0065] Figure 16. Antibody binding to mouse AA amyloid deposits. (A) IMT1-191 and IMT1-19-391 binding to isolated mouse AA (mAA) fibrils in ELISA. (B) IHC images showing IMT1-191 binding to mouse AA amyloid deposits in unfixed liver and spleen tissues. (C) IHC images showing anti- ATTR antibodies binding to mouse AA amyloid deposits in unfixed liver and spleen tissues.

[0066] Figure 17. The effect of Fc modifications on the removal of amyloid from the liver of mice. Amyloid scoring on the effect of antibodies with and without Fc modifications to remove amyloid from the liver of mice in vivo. Semi-quantitative grading scale ranging from 0 (no amyloid) to 5 (severe amyloidosis).

[0067] Figure 18. Sequences of heavy and light chain constant regions, including modifications to engineered Fc regions

[0068] Figure 19. Sequences of variable light regions (VL). For reference the corresponding SEQ ID NOs can be found in Table 1

[0069] Figure 20. Sequences of variable heavy regions (VH). For reference the corresponding SEQ ID NOs can be found in Table 1

[0070] Figure 21. Binding of IMT1-191 and IMT-191-1 to amyloid deposits in human ATTR wildtype and variant tissues in comparison with competitor antibodies ALXN2220 and coramitug. Primary antibodies used at 1 pg / mL. Mayer’s haematoxylin was used as a counterstain. Scale bar, 200 pm.

[0071] Figure 22. Binding of IMT1-191 and IMT-191-1 to amyloid deposits in human ATTR wildtype and variant tissues. Primary antibodies used at 1 pg / mL. Mayer’s haematoxylin was used as a counterstain. Scale bar, 200 pm.

[0072] Figure 23. Binding of IMT1-191 and IMT-191-1 to amyloid deposits in various types of human AL amyloidotic tissues in comparison with birtamimab. Primary antibodies used at 10 pg / mL. Mayer’s haematoxylin was used as a counterstain. Scale bar, 200 pM.

[0073] Figure 24. Binding of IMT1-191 and IMT-191-1 to amyloid deposits in various types of human AL amyloidotic tissues. Primary antibodies used at 10 pg / mL. Mayer’s haematoxylin was used as a counterstain. Scale bar, 200 pM.

[0074] Figure 25. Binding of IMT1-191 and IMT-191-1 to amyloid deposits in a variety of different human amyloid types. Primary antibodies used at 10 pg / mL. Mayer’s haematoxylin was used as a counterstain. Scale bar, 200 pM.

[0075] Figure 26. Binding of IMT1-191 and IMT-191-1 to clinically normal tissues. Antibody staining to clinically normal liver (top panel) and clinically normal heart (middle panel). ATTRwt heart tissue was used as a positive control (bottom panel). Primary antibodies used at 10 pg / mL. Mayer’s haematoxylin was used as a counterstain. Scale bar, 200 pM.

[0076] Figure 27. Binding and complement activation on cardiac ex vivo ATTRwt amyloid extract. (A) Microscopy images of Congo red stained amyloid extracted from ATTR positive cardiac tissue by collagenase under normal light and (B) cross-polarised light. (C) Antibody binding to 2 pg of coated ATTRwt amyloid extract by ELISA, measured at 100 nM, 1000 nM, and 10 pM concentrations. (D) Matching complement activation measured by the detection of human C3b protein after incubating bound antibodies with 1 % Normal Human Serum for 30 min. Data represents the mean ±SD of 2 technical repeat measurements.

[0077] Figure 28. Phagocytosis of ATTR induced by antibodies in the presence of transthyretin (TTR) aggregates. (A) Negative-EM image of recombinant TTR aggregates showing an isomorphous mix of miss-folded species. (B) Phagocytosis schematic testing effect of aggregates on ATTR phagocytosis. (C and D) Phagocytosis timecourse overlay of IMT1-191-1 and Coramitug / PRX004 antibodies with and without aggregates. (E) Concentration-response curves comparing phagocytosis of IMT1-191-1 and Coram itug / PRX004 in the presence of aggregates. (F-l) Binding of antibodies with and without rTTR aggregates. Phagocytosis data represents the mean ±SD of 3 technical repeat measurements. Binding data are single technical repeat comparisons at each concentration. Figure 29. IMT191-1 accelerates phagocytosis of in vitro ATTR fibrils labelled with pHrodo by mixed cultures of Macrophages and MGCs. (A) Light microscopy image of mixed culture of macrophages and multinucleated giant cells. (B to E) Phagocytosis time course of different antibodies compared with the isotype control antibody (4-4-20 antibody). (F) Phagocytosis comparison induced by antibodies at 1 nM, 10 nM, and 100 nM concentrations. Data represents the mean ±SD of 3 technical repeat measurements.

[0078] Figure 30. Binding to immobilised ATTR fibrils by antibodies with sequence optimisation.

[0079] Binding activity to in vitro ATTR was evaluated by ELISA.

[0080] Figure 31. IMT1-521 and IMT1-521-1 binding and complement activation on ATTR fibrils. (A and B) Binding to ATTR fibrils and ATTR-mediated complement activation induced by the optimised clones detected by C3b deposition by ELISA. (C and D) Binding to ATTR fibrils and complement activation detected by C3b deposition on ATTR fibrils induced by IMT1-521 , IMT1- 521-1 , ALXN2220 (NI006) and coramitug (PRX004).

[0081] Detailed description of the invention

[0082] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art, such as in the arts of peptide chemistry, cell culture and phage display, nucleic acid chemistry and biochemistry. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991).

[0083] It is noted that in this disclosure and particularly in the claims and / or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can have the meaning attributed to it in Patent law; e.g., they can mean "includes", "included", "including", and the like; and that terms such as "consisting essentially of' and "consists essentially of' have the meaning ascribed to them in Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.

[0084] As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0085] Standard techniques are used for molecular biology, genetic and biochemical methods (“Molecular Cloning: A Laboratory Manual”, second edition (Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal Cell Culture” (Freshney, 1987); “Methods in Enzymology” “Handbook of Experimental Immunology” (Weir, 1996); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Current Protocols in Molecular Biology” (Ausubel, 1987); “PCR: The Polymerase Chain Reaction” (Mullis, 1994); “Current Protocols in Immunology” (Coligan, 1991)), which are incorporated herein by reference. These techniques are applicable to the production of the polynucleotides and polypeptides of the invention, and, as such, may be considered in making and practicing the invention. Particularly useful techniques for particular embodiments will be discussed in the sections that follow.

[0086] The term “about” as used herein includes up to and including 10% greater and up to and including 10% lower than the value specified, suitably up to and including 5% greater and up to and including 5% lower than the value specified, especially the value specified. The term “between”, includes the values of the specified boundaries.

[0087] In one embodiment, the antibody is monoclonal and binds to at least two, at least three, at least four, at least five, at least 6, at least 7, at least 8, at least 9 or at least 10 different amyloid fibril types. Advantageously, it binds substantially to all systemic amyloid fibril types.

[0088] In one aspect, the antibody or antibodies of the invention are formulated for intravenous (iv) or intramuscular (im) administration. Antibodies administered iv should extravasate from the circulation in order to enter the interstitial tissue space and bind to their cognate target.

[0089] By “fragment” is meant a portion of a polypeptide or nucleic acid molecule. This portion contains, preferably, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the entire length of the reference nucleic acid molecule or polypeptide. A fragment may contain 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nucleotides or amino acids.

[0090] The terms “isolated,” “purified,” or “biologically pure” refer to material that is free to varying degrees from components which normally accompany it as found in its native state. “Isolate” denotes a degree of separation from original source or surroundings. “Purify” denotes a degree of separation that is higher than isolation. A “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this invention is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography. The term “purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified.

[0091] By “isolated polynucleotide” is meant a nucleic acid (e.g., a DNA) that is free of the genes which, in the naturally-occurring genome of the organism from which the nucleic acid molecule of the invention is derived, flank the gene. The term therefore includes, for example, a recombinant DNA that is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote; or that exists as a separate molecule (for example, a cDNA or a genomic or cDNA fragment produced by PCR or restriction endonuclease digestion) independent of other sequences. In addition, the term includes an RNA molecule that is transcribed from a DNA molecule, as well as a recombinant DNA that is part of a hybrid gene encoding additional polypeptide sequence.

[0092] By an “isolated polypeptide” is meant a polypeptide of the invention that has been separated from components that naturally accompany it. Typically, the polypeptide is isolated when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, a polypeptide of the invention. An isolated polypeptide of the invention may be obtained, for example, by extraction from a natural source, by expression of a recombinant nucleic acid encoding such a polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis.

[0093] Complement

[0094] The complement system is an important component of the innate immune response, functioning as a complex molecular cascade that enhances the ability to clear pathogens, damaged cells or other non-desirable components (such as amyloid fibrils). The complement system works through three primary activation pathways to result in pathogen destruction and inflammation via mechanisms including opsonisation, inflammatory signalling and formation of the membrane attack complex (MAC). The classical complement pathway is most commonly initiated by antibody-antigen complexes and therefore requires specific immune recognition. Key players in the classic complement pathway include C1q, C1r, and C1s proteins.

[0095] The mechanism by which antibodies according to the present invention promote removal of amyloid deposits is postulated to obligatorily involve complement activation by the antibody bound to the amyloid fibrils, leading to recruitment of macrophages that then fuse into multinucleated giant cells (Bodin, K., et al. (2010). "Antibodies to human serum amyloid P component eliminate visceral amyloid deposits." Nature 468(7320): 93-97). These have the unique phenotype that enables them to destroy the extracellular amyloid deposits that are overwhelmingly massive in relation to single cells (Milde, R., et al. (2015). "Multinucleated giant cells are specialized for complement-mediated phagocytosis and large target destruction." Cell Rep. 13(9): 1937-1948). Accordingly, antibody fragments, intact antibodies and any other constructs that do not efficiently activate the classical complement pathway when they have bound to amyloid fibrils, or do not activate it to a sufficient extent, are advantageously modified, or further modified to promote complement activation. In a preferred embodiment, an antibody fragment or derivative is an antibody fragment or derivative which is appropriately modified to (further) activate complement.

[0096] The other two complement activation pathways are the alternative pathway and the lectin pathway. The alternative pathway does not require antibody binding but provides a rapid initial immune response via spontaneous activation on pathogen surfaces. The lectin pathway is another mechanism of pathogen detection and defence, activated when mannose-binding lectins recognise specific sugar structures the pathogen surface.

[0097] The complement system must be tightly controlled to prevent inappropriate activation and accidental damage to healthy cells.

[0098] It has been shown that complement activation is a necessary property for in vivo antibody- mediated amyloid removal (which the inventors have demonstrated to be complement dependent - see Example 1) and the antibodies of the present invention are shown to activate the classical complement pathway via the deposition of C3b and C4b (see Example 9).

[0099] Amyloid

[0100] Amyloidosis and amyloid fibrils are known in the art. About 30 different proteins are known to form amyloid fibrils in vivo in humans, each associated with clinically distinct conditions. For reviews and definitions, see Pepys, M. B. and P. N. Hawkins (2020). Amyloidosis. Oxford Textbook of Medicine. J. Firth, C. Conlon and T. Cox, Oxford University Press], and the Nomenclature Report of the International Society for Amyloidosis (https: / / doi.Org / 10.1080 / 13506129.2020.1835263).

[0101] Amyloid fibrils are aggregates of proteins, which typically assemble in a beta sheet. The termini of proteins can be exposed in beta sheet structures, and it is postulated that exposed termini of the proteins which compose the amyloid fibrils are responsible for the binding of pan-fibril-specific antibodies to the amyloid. In embodiments, the C-termini of the proteins are bound by the antibody; a free C-terminal carboxyl group in the TTR peptide is essential for binding, indicating that a charged ligand is required by 2E5.

[0102] The amyloid epitope formed by the C-terminal amino acids of TTR can be mimicked by both a citrate ion and a malonate ion in space and charge interactions in the antibody binding domain. The structure of the C-terminus of TTR (PKE) is very similar to the structure of citrate and malonate. Citrate forms binding interactions with N30, F90, T91 , Y104, N105 and W106 in the 2E5 binding cleft; citrate and malonate bind in an almost identical fashion, but are not large enough to contact the heavy chain.

[0103] Antibodies

[0104] The term “antibody” as used herein may be used interchangeably with term “immunoglobulin” or “Ig” and means an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments), single chain Fv (scFv) mutants, multispecific antibodies such as bispecific antibodies (including dual binding antibodies), chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity. The term "antibody" can also refer to a Y-shaped glycoprotein with a molecular weight of approximately 150 kDa that is made up of four polypeptide chains: two heavy (H) chains and two light (L) chains. Each chain is divided into a constant region / domain and a variable region / domain. The heavy (H) chain variable domains are abbreviated herein as VH, and the light (L) chain variable domains are abbreviated herein as VL. These domains, domains related thereto and domains derived therefrom, may be referred to herein as immunoglobulin chain variable domains. The VH and VL domains (also referred to as VH and VL regions) can be further subdivided into regions, termed “complementarity determining regions”(“CDRs”), interspersed with regions that are more conserved, termed “framework regions”(“FRs”). The framework and complementarity determining regions have been precisely defined by various numbering conventions such as Kabat numbering (Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition U.S. Department of Health and Human Services, (1991) NIH Publication Number 91-3242), Eu numbering, Chothia numbering (Chothia et al. (1989) Nature 342: 877-883) or IMGT numbering (as summarized by IMGT.org). The variable domains described herein use IMGT numbering unless otherwise indicated. In a conventional antibody, each VH and VL is composed of three CDRs and four FRs, arranged from aminoterminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4. The conventional antibody tetramer of two heavy immunoglobulin chains and two light immunoglobulin chains is formed with the heavy and the light immunoglobulin chains interconnected by e.g. disulphide bonds, and the heavy chains similarly connected.

[0105] A whole antibody thus comprises two Fabs, each Fab comprising a VH-VL domain pair. The heavy chain constant region includes three domains, CH1 , CH2 and CH3. The heavy chain constant region includes the Fc region (see “Fc engineering” below). The light chain constant region is comprised of one domain, CL. The variable domain of the heavy chains and the variable domain of the light chains are binding domains that interact with an antigen. The constant regions of the antibodies typically mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g. effector cells) and the first component (C1q) of the classical complement system.

[0106] The antibodies of the present invention may comprise both a Fab region and an Fc region. An “antibody” may be selected from, but not limited to, an IgG, IgA, or an antigen binding antibody fragment selected from a FAb, F(ab’)2, an scFv, an Fv, or a disulfide-bonded Fv. In certain embodiments, any of the above antibody types or fragments thereof may be prepared from one or more of a mammalian species selected from, but not limited to mouse, rat, rabbit, human. Such antibodies can be humanized for use in humans.

[0107] In certain embodiments, any of the above antibody types or fragments thereof may be provided as heteroconjugates, bispecific, chimeric or humanized molecules having affinity for amyloid fibrils.

[0108] In certain embodiments, any of the aforementioned antibody / antibodies binds to amyloid or amyloid fibrils with a dissociation coefficient (KD) of 100nM or less, 75nM or less, 50nM or less, 25nM or less, such as 10nM or less, 5nM or less, 1 nM or less, or in embodiments 500pM or less, 100pM or less, 50pM or less or 25pM or less, for example as determined by surface plasmon resonance (SPR).

[0109] Antibodies may be monospecific, with narrow or broad specificity; or multispecific, such as bispecific, such that they possess two distinct epitope specificities in a single antibody molecule. The term “specificity” as used herein is the ability of an antibody or antibody binding domain to recognise a particular antigen as a unique molecular entity and distinguish it from another. Specificity therefore refers to the number of different types of antigens or antigenic determinants to which a particular antibody or antigen-binding fragment thereof can bind. An antibody that “specifically binds” to an antigen or an epitope is a term well understood in the art. A molecule is said to exhibit “specific binding” if it reacts more frequently, more rapidly, with greater duration and / or with greater affinity with a particular target antigen or epitope, than it does with alternative targets. An antibody “specifically binds” to a target antigen or epitope if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances. In one embodiment, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g. as measured by a radioimmunoassay (RIA). For example, the present invention, the antibodies of the present invention may specifically bind to multiple amyloid fibres and not to other non-amyloid epitopes, for example because they are specific for a conformational epitope commonly presented on amyloid fibrils.

[0110] The term “affinity” as used herein is a measure of the binding strength between an antigen and an antigen-binding site on the antibody (or antigen-binding fragment thereof). Affinity is represented by the equilibrium constant for the dissociation of an antigen with an antigen-binding polypeptide (KD). The lower the KD value, the stronger the binding strength between an antigen and the antigen-binding site. Alternatively, the affinity can also be expressed as the affinity constant (KA), which is 1 / KD. Any KD value less than 10'6is considered to indicate binding. Affinity can be determined by known methods, depending on the specific antigen of interest. For example. KD may be determined by surface plasmon resonance (e.g. BIACORE). KD may also be determined by Scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, equilibrium dialysis, equilibrium binding, gel filtration, ELISA, or spectroscopy (e.g. using a fluorescence assay) and the different variants thereof known in the art. The antibodies of the invention may bind to certain amyloid or amyloid fibril types with an affinity (KD value) that is at least 10 times, at least 100 times or at least 1000 times greater than to non-amyloid or nonamyloid fibril epitopes, for example as measured by SPR. In some embodiments, the antibodies of the invention may bind to at least 2 different amyloid fibril types or at least 3 different amyloid fibril types with a Kd for each of less than about 10nM, optionally less than about 1nM.

[0111] The term “avidity” as used herein is the measure of the strength of binding between an antibody, or antigen-binding fragment thereof, and the antigen. Avidity is related to both the affinity between an antigen and its antigen-binding site on the antibody and the number of binding sites for that antigen present on the antibody.

[0112] Cocktails of antibodies may be targeted at two or more specific epitopes. Antibody cocktails may be prepared by a mixture of one or more monoclonal antibodies. In one embodiment, an antibody cocktail contains two, three, four or more monoclonal antibodies each of which recognises a plurality of amyloid fibrils. The term "monoclonal antibody" refers to an antibody obtained from a single clone of B lymphocyte derived plasma cells producing a homogeneous antibody of a single heavy and light chain class and epitope specificity.

[0113] Monoclonal antibodies are typically highly specific, and are directed against a single antigenic site (epitope), in contrast to conventional antibodies within an antiserum induced in a whole animal by immunisation with a particular antigen. Such conventional antibodies are derived from many different clones of B lymphocytes which recognise either the same or different epitopes on the immunising antigen, and are known as polyclonal antibodies. In addition to their very restricted specificity, monoclonal antibodies are readily produced in pure form uncontaminated by other immunoglobulins, whereas isolation of specific antibodies from a polyclonal antiserum requires demanding immunopurification procedures. In the invention, the antibodies may bind to multiple different amyloid or amyloid fibril epitopes, and / or the antibodies may bind to one or more epitopes that are shared across multiple different amyloid or amyloid fibril types.

[0114] Monoclonal antibodies may be prepared by the hybridoma method (see Kohler et al., Nature, 256:495-7, 1975), or by recombinant DNA methods. The monoclonal antibodies may even be isolated from phage antibody libraries using well known techniques.

[0115] The monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984)).

[0116] In the hybridoma method, a host animal, typically a mouse, is immunized with the desired antigen to induce generation of clones of B lymphocytes that produce or are capable of producing antibodies that will specifically bind to that antigen. Lymphocytes harvested from the immunised animal are then fused in vitro with a continuous line of myeloma cells grown in vitro to form so- called hybridoma cells. These are then selected by growth in a suitable culture medium that permits survival only of fused cells and not the unfused, parental myeloma cells. Examples of myeloma cells include, but are not limited to, human myeloma and mouse-human heteromyeloma cell lines which have been described for the production of human monoclonal antibodies.

[0117] The culture medium from the growing hybridoma cells may be assayed for monoclonal antibodies directed against the antigen. The binding specificity of the antibodies produced by the cells may be determined by various methods - such as immunoprecipitation or an in vitro binding assay - such as radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA) or immunoradiometric assay (IRMA).

[0118] After hybridoma cells are identified that produce the desired antibodies, the clones may be subcloned by limiting dilution procedures and grown by standard methods. The monoclonal antibodies secreted by the subclones are separated from the culture medium or serum by well- known immunoglobulin purification procedures - such as protein A-Sepharose, gel electrophoresis, dialysis, hydroxyapatite chromatography or affinity chromatography.

[0119] An “epitope” as used herein is the section of the target that is specifically bound by the antibody or antigen-binding fragment thereof. Protein epitopes may be “conformational epitopes” (which comprise amino acids that are not contiguous in a polypeptide sequence, but are brought into the requisite conformation when the polypeptide folds into its 3D structure) or “linear epitopes” (which comprise a contiguous sequence of amino acids in a polypeptide sequence.

[0120] The antibodies of the invention also encompass variants of such antibodies and fragments thereof. Variants include peptides and polypeptides comprising one or more amino acid sequence substitutions, deletions, and / or additions that have the same or substantially the same affinity and specificity of epitope binding as the anti-amyloid antibody or fragments thereof. Such variants may be referred to herein as antibodies comprising one or more amino acid “changes” compared to a reference sequence.

[0121] The deletions, insertions or substitutions of amino acid residues may produce a silent change and result in a functionally equivalent substance. Deliberate ammo acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.

[0122] Homologous substitution (substitution and replacement are both used herein to mean the interchange of an existing amino acid residue, with an alternative residue) may occur i.e. like-for- like substitution such as basic for basic, acidic for acidic, polar for polar etc. Such substitutions may also be referred to as conservative substitutions. Non-homologous substitution may also occur i.e. from one class of residue to another or alternatively involving the inclusion of unnatural amino acids - such as ornithine (hereinafter referred to as Z), diami- nobutyric acid ornithine (hereinafter referred to as B), norleucine ornithine (hereinafter referred to as O), pyriylalanine, thienylalanine, naphthylalanine and phenylglycine.

[0123] Replacements may also be made by unnatural amino acids include; alpha* and alphadisubstituted* amino acids, N-alkyl amino acids*, lactic acid*, halide derivatives of natural amino acids such as trifluorotyrosine*, p-CI-phe- nylalanine*, p-Br-phenylalanine*, p-l-phenylalanine*, L- allyl-glycine*, p-alanine*, L-a-amino butyric acid*, L-y-amino bu- tyric acid*, L-a-amino isobutyric acid*, L-e-amino caproic acid#, 7-amino heptanoic acid*, L-methionine sulfone#*, L- norleucine*, L-norvaline*, p-nitro-L-phenylalanine*, L-hydroxyproline#, L-thioproline*, methyl derivatives of phenylalanine (Phe) such as 4-methyl-Phe*, pentamethyl-Phe*, L-Phe (4-amino)#, L-Tyr (methyl)*, L-Phe (4-isopropyl)*, L-Tic (1 ,2,3,4- tetrahydroisoquinoline-3-carboxyl acid)*, L- diaminopropionic acid# and L-Phe (4-benzyl)*. The notation * has been utilised for the purpose of the discussion above (relating to homologous or non-homologous substitution), to indicate the hydro- phobic nature of the derivative whereas # has been utilised to indicate the hydrophilic nature of the derivative, #* indicates amphipathic characteristics.

[0124] Thus, variants may include peptides and polypeptides comprising one or more amino acid sequence substitutions, deletions, and / or additions to the antibodies and fragments of the invention wherein such substitutions, deletions and / or additions do not cause substantial changes in affinity and specificity of epitope binding. For example, a variant of an antibody or fragment thereof may result from one or more changes to the antibody or fragment thereof, where the changed antibody or fragment thereof has the same or substantially the same affinity and specificity of epitope binding as the starting sequence. Variants may be naturally occurring, such as allelic or splice variants, or may be artificially constructed. Variants may be prepared from the corresponding nucleic acid molecules encoding said variants. Variants of the antibodies or fragments thereof may have changes in light and / or heavy chain amino acid sequences that are naturally occurring or are introduced by in vitro engineering of native sequences using recombinant DNA techniques. Naturally occurring variants include "somatic" variants which are generated in vivo in the corresponding germ line nucleotide sequences during the generation of an antibody response to a foreign antigen.

[0125] Variants of antibodies and binding fragments may also be prepared by mutagenesis techniques. For example, amino acid changes may be introduced at random throughout an antibody coding region and the resulting variants may be screened for binding affinity for amyloid or for another property. Alternatively, amino acid changes may be introduced into selected regions of the antibody, such as in the light and / or heavy chain CDRs, and / or in the framework regions, and the resulting antibodies may be screened for binding to amyloid or some other activity. Amino acid changes encompass one or more amino acid substitutions in a CDR, ranging from a single amino acid difference to the introduction of multiple permutations of amino acids within a given CDR. Also encompassed are variants generated by insertion of amino acids to increase the size of a CDR.

[0126] Amyloid specific antibodies or fragments thereof may be provided with a modified Fc region (also referred to herein as an engineered Fc region) where a naturally-occurring Fc region is modified to increase the half-life of the antibody or fragment in a biological environment, for example, the serum half-life or a half-life measured by an in vitro assay. Fc modification can also be employed to alter antibody biodistribution in vivo, which can direct the antibody to amyloid-bearing tissues. Fc modification or engineering is done with respect to a wild-type Fc sequence, and the change in one or more properties in the resulting antibody comprising the modified or engineered Fc may be with respect to an antibody comprising an unmodified or non-engineered Fc.

[0127] Variants also include antibodies or fragments thereof comprising a modified Fc region, wherein the modified Fc region comprises at least one amino acid modification relative to a wild-type Fc region. The variant Fc region may be designed, relative to a comparable molecule comprising the wild-type Fc region, so as to bind Fc receptors with a greater or lesser affinity. For example, the antibodies and fragments thereof may comprise a modified Fc region. Fc region refers to naturally-occurring or synthetic polypeptides homologous to the IgG C-terminal domain that is produced upon papain digestion of IgG. IgG Fc has a molecular weight of approximately 50 kD. In the antibodies and fragments, an entire Fc region can be used, or only a half-life enhancing portion.

[0128] The antibodies and fragments thereof also encompass derivatives of the antibodies, fragments and sequences disclosed herein. Derivatives include polypeptides or peptides, or variants, fragments or derivatives thereof, which have been chemically modified. Examples include covalent attachment of one or more polymers - such as water soluble polymers, N-linked, or O- linked carbohydrates, sugars, phosphates, and / or other such molecules. The derivatives are modified in a manner that is different from naturally occurring or starting peptide or polypeptides, either in the type or location of the molecules attached. Derivatives further include deletion of one or more chemical groups which are naturally present on the peptide or polypeptide.

[0129] The present invention also encompasses amyloid specific antibodies that include two full length heavy chains and two full length light chains. Alternatively, the antibodies may be constructs such as single chain antibodies or "mini" antibodies that retain binding activity to amyloid. Such constructs may be prepared by methods well known in the art. Advantageously, such fragments are modified to enable complement activation.

[0130] Methods for creating recombinant DNA versions of the antigen-binding regions of antibody molecules which bypass the generation of monoclonal antibodies are contemplated for the amyloid specific antibodies and fragments thereof. DNA is cloned into a plasmid vector system. One example of such a technique uses a bacteriophage lambda vector system having a leader sequence that causes the expressed Fab protein to migrate to the periplasmic space (between the bacterial cell membrane and the cell wall) or to be secreted. One can rapidly generate and screen great numbers of functional Fab fragments for those which bind amyloid. Such amyloid binding agents (Fab fragments with specificity for amyloid) are specifically encompassed within the amyloid specific antibodies and fragments thereof.

[0131] The amyloid binding antibodies and fragments thereof may be humanized or human engineered antibodies. As used herein, "a humanized antibody", or antigen binding fragment thereof, is a recombinant polypeptide that comprises a portion of an antigen binding site from a non-human antibody and a portion of the framework and / or constant regions of a human antibody. A human engineered antibody or antibody fragment is a non-human (e.g., mouse) antibody that has been engineered by modifying (e.g., deleting, inserting, or substituting) amino acids at specific positions so as to reduce or eliminate any detectable immunogenicity of the modified antibody in a human.

[0132] Humanized antibodies include chimeric antibodies and CDR-grafted antibodies. Chimeric antibodies are antibodies that include a non-human antibody variable region linked to a human constant region. Thus, in chimeric antibodies, the variable region is mostly non-human, and the constant region is human. Chimeric antibodies and methods for making them are described in, for example, Proc. Natl. Acad. Sci. USA, 81 : 6841-6855 (1984). Although, they can be less immunogenic than a mouse monoclonal antibody, administrations of chimeric antibodies have been associated with human immune responses (HAMA) to the non-human portion of the antibodies. Chimeric antibodies can also be produced by splicing the genes from a mouse antibody molecule of appropriate antigen-binding specificity together with genes from a human antibody molecule of appropriate biological activity, such as the ability to activate human complement and mediate antibody- dependent cellular phagocytosis (ADCP). One example is the replacement of a Fc region with that of a different isotype.

[0133] CDR-grafted antibodies are antibodies that include the CDRs from a non-human "donor" antibody linked to the framework region from a human "recipient" antibody. Generally, CDR-grafted antibodies include more human antibody sequences than chimeric antibodies because they include both constant region sequences and variable region (framework) sequences from human antibodies. Thus, for example, a CDR-grafted humanized antibody of the invention can comprise a heavy chain that comprises a contiguous amino acid sequence (e.g., about 5 or more, 10 or more, or even 15 or more contiguous amino acid residues) from the framework region of a human antibody (e.g., FR-I, FR-2, or FR-3 of a human antibody) or, optionally, most or all of the entire framework region of a human antibody. CDR-grafted antibodies and methods for making them are described in Nature, 321 : 522-525 (1986). Methods that can be used to produce humanized antibodies also are described in, for example, US 5,721 ,367 and 6,180,377.

[0134] "Veneered antibodies" are non-human or humanized (e.g., chimeric or CDR-grafted antibodies) antibodies that have been engineered to replace certain solvent-exposed amino acid residues so as to reduce their immunogenicity or enhance their function. Veneering of a chimeric antibody may comprise identifying solvent-exposed residues in the non-human framework region of a chimeric antibody and replacing at least one of them with the corresponding surface residues from a human framework region.

[0135] Veneering can be accomplished by any suitable engineering technique.

[0136] Further details on antibodies, humanized antibodies, human engineered antibodies, and methods for their preparation can be found in Antibody Engineering, Springer, New York, NY, 2001.

[0137] Examples of humanized or human engineered antibodies are IgG, IgM, IgE, IgA, and IgD antibodies. The antibodies may be of any class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise a kappa or lambda light chain. For example, a human antibody may comprise an IgG heavy chain or defined fragment, such as at least one of isotypes, lgG1 , lgG2, lgG3 or lgG4. As a further example, the antibodies or fragments thereof can comprise an IgG 1 heavy chain and a kappa or lambda light chain.

[0138] Human antibodies to target amyloid can be produced using transgenic animals that have no endogenous immunoglobulin production and are engineered to contain human immunoglobulin loci, as described in WO 98 / 24893 and WO 91 / 00906.

[0139] Using a transgenic animal described above, an immune response can be produced to a selected antigenic molecule, and antibody producing cells can be removed from the animal and used to produce hybridomas that secrete human monoclonal antibodies. Immunization protocols, adjuvants, and the like are known in the art, and are used in immunization of, for example, a transgenic mouse.

[0140] The development of technologies for making repertoires of recombinant human antibody genes, and the display of the encoded antibody fragments on the surface of filamentous bacteriophage, has provided a means for making human antibodies directly.

[0141] The antibodies produced by phage technology are produced as antigen binding fragments-usually Fv or Fab fragments-in bacteria and thus lack effector functions.

[0142] Effector functions can be introduced by one of two strategies: the fragments can be engineered either into complete antibodies for expression in mammalian cells, or into bispecific antibody fragments with a second binding site capable of triggering an effector function.

[0143] Human antibodies may be generated through the in vitro screening of antibody display libraries (J Mol. Biol. (1991) 227: 381). Various antibody-containing phage display libraries have been described and may be readily prepared. Libraries may contain a diversity of human antibody sequences, such as human Fab, Fv, and scFv fragments, that may be screened against an appropriate target. Phage display libraries may comprise peptides or proteins other than antibodies which may be screened to identify agents capable of selective binding to amyloid.

[0144] Phage-display processes mimic immune selection through the display of antibody repertoires on the surface of filamentous bacteriophage, and subsequent selection of phage by their binding to an antigen of choice. One such method is described in WO 99 / 10494. Anti-amyloid antibodies can be isolated by screening of a recombinant combinatorial antibody library, preferably a scFv phage display library, prepared using human VL and VH cDNAs prepared from mRNA derived from human lymphocytes. Methodologies for preparing and screening such libraries are known in the art. There are commercially available kits for generating phage display libraries.

[0145] The amyloid binding antibodies and fragments thereof may comprise one or more portions that do not bind amyloid but instead are responsible for other functions, such as circulating half-life, direct cytotoxic effect, detectable labelling, or activation of the recipient’s endogenous complement cascade or endogenous cellular cytotoxicity. The antibodies or fragments thereof may comprise all or a portion of the constant region and may be of any isotype, including IgA (e.g., IgAI or lgA2), IgD, IgE, IgG (e.g. lgG1 , lgG2, lgG3 or lgG4), or IgM. In addition to, or instead of, comprising a constant region, antigen-binding compounds of the invention may include an epitope tag, a salvage receptor epitope, a label moiety for diagnostic or purification purposes, or a cytotoxic moiety such as a radionuclide or toxin.

[0146] An anti-amyloid antibody or fragment thereof may be modified in order to increase its serum halflife, for example, by adding molecules - such as PEG or other water soluble polymers, including polysaccharide polymers to increase the half-life.

[0147] Amyloid binding antibodies and fragments thereof may be bispecific. For example, bispecific antibodies may resemble single antibodies (or antibody fragments) but have two different antigen binding sites (variable regions). Bispecific antibodies can be produced by various methods - such as chemical techniques, "polydoma" techniques or recombinant DNA techniques. Bispecific antibodies may have binding specificities for at least two different epitopes, at least one of which is an epitope of amyloid. In the context of the present invention, bispecific (or multispecific) refers to the ability of an antibody of the invention to bind (via one or more antigen -binding regions) one or more amyloid or amyloid fibrils, and additionally bind one (in the case of bispecific) or more (in the case of multispecific) non-amyloid or amyloid fibril epitopes. In the context of the present invention, monospecific means an antibody of the invention specifically binds to only one or more amyloid fibril types (via one or more antigen-binding regions), and does not bind (via any antigenbinding regions) any non-amyloid or amyloid-fibril epitopes.

[0148] Amyloid binding antibodies and fragments may be heteroantibodies. Heteroantibodies are two or more antibodies, or antibody binding fragments (Fab) linked together, each antibody or fragment having a different specificity. As used herein, the term "antibody fragments" refers to portions of an intact full length antibody - such as an antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab’, F(ab’)2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); multispecific antibody fragments such as bispecific, trispecific, and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies); binding-domain immunoglobulin fusion proteins; camelized antibodies; minibodies; chelating recombinant antibodies; tribodies or bibodies; intrabodies; nanobodies; small modular immunopharmaceuticals (SMIP), VHH containing antibodies; and any other polypeptides formed from antibody fragments.

[0149] In the context of the present invention, the terms anti- amyloid antibody and amyloid binding antibody encompass amyloid binding antibody fragments comprising any part of the heavy or light chain sequences of the full length antibodies, and which bind amyloid. The term "antigen binding fragment" or “antigen binding portion” as used herein refers to portions of the antibody capable of binding amyloid, for example any of at least 3 contiguous amino acids (e.g., at least 4, 5, 6, 7, 8, 9 or 10 or more contiguous amino acids, for example from a CDR) of the antibody involved in antigen binding, and encompasses Fab, Fab’, F(ab’)2, and F(v) fragments, or the individual light or heavy chain variable regions or portion thereof. For example, the present invention includes a portion of an antibody that does not comprise the entire antibody sequence, but still comprises a Fab region which specifically binds to amyloid fibrils and an engineered Fc region.

[0150] Anti- amyloid antibodies or antibody fragments thereof typically bind to human amyloid with high affinity (e.g., as determined with BIACORE surface plasmon resonance (SPR)), such as for example with an equilibrium binding dissociation constant (KD) for amyloid of about 15nM or less, 10 nM or less, about 5 nM or less, about 1 nM or less, about 500 pM or less, about 250 pM or less, about 100 pM or less, about 50 pM or less, or about 25 pM or less, about 10 pM or less, about 5 pM or less, about 3 pM or less about 1 pM or less, about 0.75 pM or less, or about 0.5 pM or less. The anti-amyloid antibodies or antibody fragments thereof may bind to at least two or at least three different human amyloid fibril types with high affinity (e.g., as determined with BIACORE surface plasmon resonance (SPR)), such as for example with an equilibrium binding dissociation constant (KD) for at least two or at least three amyloid fibril types of about 15nM or less, 10 nM or less, about 5 nM or less, about 1 nM or less, about 500 pM or less, about 250 pM or less, about 100 pM or less, about 50 pM or less, or about 25 pM or less, about 10 pM or less, about 5 pM or less, about 3 pM or less about 1 pM or less, about 0.75 pM or less, or about 0.5 pM or less.

[0151] The antibodies and antibody fragments described herein can be prepared by any suitable method. Suitable methods for preparing such antibodies and antibody fragments are known in the art. The antibody or antibody fragment may be isolated or purified to any degree.

[0152] The present invention provides an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils with broad anti-fibril specificity; and the Fc region is an Fc region engineered to alter one or more properties of the antibody.

[0153] The Fab region of antibodies of the invention may be capable of binding to at least 3, 4, 5, 6, 7, 8 , 9, 10 or 11 different types of amyloid fibrils, for example including ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils. The Fab region of antibodies of the invention may be capable of binding to at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils. The antibody of the invention successfully binds to fibrils which cause or are involved in systemic amyloidosis. The antibody does not bind to A fibrils present in the CNS and particularly in the brain in patients with Alzheimer’s disease. The antibody of the invention has preferential binding to fully formed amyloid fibrils over pre- fibrillar aggregates (intermediate amorphous aggregate species).

[0154] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively. The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively, each optionally comprising a single or double amino acid change. An antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8, respectively.

[0155] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of a sequence having a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 , respectively. The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 , respectively, each optionally comprising a single amino acid change.

[0156] In one embodiment, there is provided an antibody that comprises a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively, each optionally comprising a single amino acid change.

[0157] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8, respectively. The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8, respectively, each optionally comprising a single amino acid change.

[0158] In one embodiment, there is provided an antibody that comprises a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0159] In one embodiment, there is provided an antibody that comprises a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ I D No 6, SEQ I D No. 7 and SEQ I D NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0160] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 82, SEQ ID No. 83 and SEQ ID NO. 84, respectively. The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 82, SEQ ID No. 83 and SEQ ID NO. 84, respectively, each optionally comprising a single amino acid change.

[0161] In one embodiment, there is provided an antibody that comprises a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 82, SEQ ID No. 83 and SEQ ID NO. 84 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0162] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 85, respectively. The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 85, respectively, each optionally comprising a single amino acid change. In one embodiment, there is provided an antibody that comprises a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 85 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0163] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 6, SEQ ID No. 86 and SEQ ID NO. 8, respectively. The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 86 and SEQ ID NO. 8, respectively, each optionally comprising a single amino acid change.

[0164] In one embodiment, there is provided an antibody that comprises a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 86 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0165] The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99% or 100% with SEQ ID No 6, SEQ ID No. 87 and SEQ ID NO. 8, respectively. The antibody according to the invention may be an antibody or antigen binding portion thereof wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 87 and SEQ ID NO. 8, respectively, each optionally comprising a single amino acid change.

[0166] In one embodiment, there is provided an antibody that comprises a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 87 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0167] In the above aspects of the invention, the antibody can be selected from a human antibody, a chimeric antibody containing a human variable region, a humanized antibody, a bispecific antibody, or a single chain antibody, as well as antigen-binding fragments thereof. In embodiments, the antibody of the invention is specific for a conformational epitope commonly presented on amyloid fibrils. Thus, the antibody is able to bind to an amyloid-specific epitope independently of the linear polypeptide structure of the fibril.

[0168] In embodiments, the conformational epitope is present on at least three different amyloid fibrils. Preferably, it is present on 4, 5, 6, 7, 8, 9, 10 or 11 different amyloid fibrils, selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils.. The confirmational epitope may be present on at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils.

[0169] In embodiments, the epitope is formed at the C-terminus of the proteins which compose the fibrils. In embodiments, the epitope comprises at least one charged amino acid, preferably at least 2 charged amino acids, comprising a charged side-chain. Amino acids with charged side-chains include aspartic acid, histidine, glutamic acid, lysine and arginine.

[0170] In embodiments, the conformational epitope comprises a C-terminal carboxyl group, preferably a free C-terminal carboxyl group.

[0171] In embodiments, the conformational epitope can be mimicked by both malonate and citrate ions.

[0172] Humanisation

[0173] The isolated monoclonal antibodies as described herein can be humanised. The present invention therefore provides a humanised isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils with broad anti-fibril specificity; and the Fc region is an Fc region engineered to alter one or more properties of the antibody.

[0174] Humanised forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. For the most part, humanised antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Some or all of the CDRs of the antibodies described herein may be transferred; for example, it is possible to retain human acceptor CDRs as long as the donor CDR H3 is transferred. The members of the immunoglobulin superfamily all share a similar fold for their polypeptide chain. For example, although antibodies are highly diverse in terms of their primary sequence, comparison of sequences and crystallographic structures has revealed that, contrary to expectation, five of the six antigen binding loops of antibodies (H 1 , H2, L1 , L2, L3) adopt a limited number of main-chain conformations, or canonical structures (Chothia and Lesk (1987) J. Mol. Biol., 196: 901 ; Chothia et al. (1989) Nature, 342: 877). Analysis of loop lengths and key residues has therefore enabled prediction of the mainchain conformations of H1 , H2, L1 , L2 and L3 found in the majority of human antibodies (Chothia et al. (1992) J. Mol. Biol., 227: 799; Tomlinson et al. (1995) EMBO J., 14: 4628; Williams et al. (1996) J. Mol. Biol., 264: 220).

[0175] In a further aspect, the invention provides a method for generating an antibody according to the first aspect of the invention, comprising immunising a mammal in which SAP gene has been deleted.

[0176] In one embodiment, a SAP knockout mouse, which does not express the murine SAP protein, is immunised with human synthetic ATTR fibril material.

[0177] In another embodiment, a SAP knockout mouse, which does not express the murine SAP protein, is immunised with human synthetic ATTR fibril material coated with human SAP.

[0178] The humanised antibody of the invention successfully binds to fibrils which cause or are involved in systemic amyloidosis. The humanised antibody does not bind to Ap fibrils present in the CNS and particularly in the brain in patients with Alzheimer’s disease.

[0179] For example, the humanised monoclonal antibody binds to at least ALK, ATTR wild type and ATTR variant fibrils.

[0180] In another embodiment, the humanised monoclonal antibody binds to at least 4, 5, 6, 7, 8, 9, 10 or 11 types of amyloid fibrils, which are selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils. The humanised monoclonal antibodies of the invention may be capable of binding to at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils. The fibrils may be endogenous amyloid fibrils, e.g. naturally occuring amyloid fibrils or amyloid fibrils formed in vivo.

[0181] In embodiments, the humanised antibody of the invention does not compete with SAP, preferably human SAP, for binding to the amyloid fibrils. Thus, the epitope bound by the antibody of the invention is not identical to the epitope bound by SAP.

[0182] The humanised monoclonal antibody of the invention binds to fibrils which cause or are involved in systemic amyloidosis, but does not bind to soluble, native peptides from which the fibrils are derived. The humanised monoclonal antibody of the invention has preferential binding to fully formed amyloid fibrils over pre-fibrillar aggregates (intermediate amorphous aggregate species).

[0183] In embodiments, the epitope bound by the antibody of the invention comprises the C-terminus of the proteins which compose the fibrils. In embodiments, the epitope comprises at least one charged amino acid, preferably at least 2 charged amino acids, comprising a charged side-chain. Amino acids with charged side-chains include aspartic acid, glutamic acid, lysine and arginine.

[0184] In embodiments, the epitope comprises a C-terminal carboxyl group, preferably a free C-terminal carboxyl group.

[0185] In embodiments, a citrate and / or a malonate ion can be located in the binding site of the antibody according to the invention, when examined by x-ray crystallography.

[0186] The humanized antibody may comprise the CDR sequences as described for the isolated monoclonal antibody above.

[0187] The humanised monoclonal antibody may have human framework regions derived from antibody genes selected from SEQ ID Nos. 12 and 13.

[0188] The isolated humanised monoclonal antibody may have Fab variable domain residues (such as framework residues) mutated to match murine residues. These mutated residues may include VL residues I2, E17, L39, A40, Q44, A49, V101 , N66, T85, F87 and E97 and residues selected from VH residues F37, M39, D57, A80, L55, I66, V25, D85, E69, A45, P46, G47, K48, Y108 and N111 (IMGT numbering).

[0189] The isolated humanised monoclonal antibody may have the VH region comprising the mutations L55K and I66K.

[0190] The isolated humanised monoclonal antibody may have a combination of light and heavy chain Fab variable domain residues (such as framework mutations). The light chain Fab mutations may consist of I2K, L39M, A40Y and N66K and the heavy chain Fab mutations may consist of M39I, L55K, I66K and E69P. The light chain Fab mutations may consist of I2K, A40Y, L39M, Q44E, A49S, N66K, T85N and F87Y, V101T and the heavy chain Fab mutations may consist of M39I, L55K, I66K, V25A, A80T, D85N and E69P. The light chain Fab mutations may consist of I2K, A40Y, N66K, T85N and F87Y and the heavy chain Fab mutations may consist of L55K, I66K, V25A, D85N and E69P. The light chain Fab mutations may consist of I2K, L39M, A40Y, N66K, T85N and F87Y and the heavy chain Fab mutations may consist of M39I, A80T, L55K, I66K, E69P, A45R, P46T, G47E and K48Q. The light chain Fab mutations may consist of I2K, A40Y, N66K, T85N and F87Y and the heavy chain Fab mutations may consist of M39I, A80T, L55K, I66K, V25A, D85N and E69P. The light chain Fab mutations may consist of I2K, L39M, A40Y and N66K and the heavy chain Fab mutations may consist of L55K, I66K, and E69P. The light chain Fab mutations may consist of A40Y and the heavy chain Fab mutations may consist of L55K, I66K, V25A, D85N and E69P. The light chain Fab mutations may consist of A40Y and the heavy chain Fab mutations may consist of L55K and I66K. The light chain Fab mutations may consist of I2K, L39M, A40Y and N66K and the heavy chain Fab mutations may consist of F37R, L55K, D57L, I66K, E69P, Y108V. The light chain Fab mutations may consist of I2K, E17K, L39M, A40Y, N66K and E97K and the heavy chain Fab mutations may consist of L55K, I66K, and E69P. The light chain Fab mutations may consist of I2K, E17R, L39M, A40Y, N66K and E97R and the heavy chain Fab mutations may consist of L55K, I66K, and E69P. The light chain Fab mutations may consist of I2K, E17K, L39M, A40Y, N66K and E97K and the heavy chain Fab mutations may consist of L55K, I66K, E69P and N111 R. The light chain Fab mutations may consist of I2K, E17R, L39M, A40Y, N66K and E97R and the heavy chain Fab mutations may consist of L55K, I66K, E69P and N111 R. The light chain Fab mutations may consist of I2K,L39M,A4OY,N66K and the heavy chain Fab mutations may consist of L55K,I66K,E69P,R95T.

[0191] In embodiments, the humanised monoclonal antibody may be further modified to alter the charge of the immunoglobulin. For example, positive charge in the immunoglobulin may be reduced, for example by reducing positive charge such that the next charge over the Fv region is +4 or less.

[0192] For example, the VL domain may be modified by including mutations Q44E, A49S, V101T, or omitting mutations L39M or I2K and L39M.

[0193] The VH domain may comprise changes including the mutations L55K or I66K, but not both; adding E69P; and mutants at D57E and / or D62E, in HCDR2.

[0194] The VH domain may comprise changes including the mutations M39I, D57E and / or D62E. The VH domain may comprise the mutation M39I. The VH domain may comprise the mutation D57E. The VH domain may comprise the mutation D62E. The VH domain may comprise the mutation D57E and D62E. The VH domain may comprise the mutations M39I and D57E. The VH domain may comprise the mutations M39I and D62E. The VH domain may comprise the mutations M39I and D57E and D62E.

[0195] The VL domain may comprise the mutations I2K, L39M, A40Y, N66K and / or the VH domain may comprise the mutations M39I, L55K, D57E, D62E, l66K and E69P.

[0196] As described above, in some embodiments, the Fab regions of the isolated (humanised) monoclonal antibodies of the invention may be as shown in Table 1.

[0197] Summary of specific Fab regions provided herein

[0198] As set out above, the antibodies of the invention comprise a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils; and the Fc region is an engineered Fc region. Antibodies of the present invention may be humanised antibodies derived from antibody 2E5 (see Examples 1 to 5). Antibodies of the invention may also be affinity matured variants of antibody clones (such as Clone P029_Ab19) originally derived from antibody 2E5.

[0199] The CDR regions of said antibodies may be as defined in above embodiments, and / or in Table 1. The variable domains described herein use IMGT numbering unless otherwise indicated.

[0200] In some embodiments, the humanized antibody according to the invention comprises a Fab region wherein each of CDRH1, CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8 respectively and each of CDRL1, CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0201] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 739 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 740, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740.

[0202] In some embodiments, the humanized antibody according to the invention comprises a Fab region wherein each of CDRH1, CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively and each of CDRL1, CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0203] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 14 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 15, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 14 and the VH domain comprises or consists of the sequence of SEQ ID No. 15.

[0204] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 16 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 17, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 16 and the VH domain comprises or consists of the sequence of SEQ ID No. 17.

[0205] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 18 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 19, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 18 and the VH domain comprises or consists of the sequence of SEQ ID No. 19.

[0206] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 20 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 21 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 20 and the VH domain comprises or consists of the sequence of SEQ ID No. 21.

[0207] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 22 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 23, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 22 and the VH domain comprises or consists of the sequence of SEQ ID No. 23.

[0208] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 24 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 25, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 24 and the VH domain comprises or consists of the sequence of SEQ ID No. 25. In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 26 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 27, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 26 and the VH domain comprises or consists of the sequence of SEQ ID No. 27.

[0209] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 28 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 29, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 28 and the VH domain comprises or consists of the sequence of SEQ ID No. 29.

[0210] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 30 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 31 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 30 and the VH domain comprises or consists of the sequence of SEQ ID No. 31.

[0211] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 32 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 33, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 32 and the VH domain comprises or consists of the sequence of SEQ ID No. 33.

[0212] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 34 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 35, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 34 and the VH domain comprises or consists of the sequence of SEQ ID No. 35.

[0213] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 36 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 37, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 36 and the VH domain comprises or consists of the sequence of SEQ ID No. 37.

[0214] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 38 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 39, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 38 and the VH domain comprises or consists of the sequence of SEQ ID No. 39.

[0215] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 40 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 41 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 40 and the VH domain comprises or consists of the sequence of SEQ ID No. 41.

[0216] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 42 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 43, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 42 and the VH domain comprises or consists of the sequence of SEQ ID No. 43. In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 44 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 45, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 44 and the VH domain comprises or consists of the sequence of SEQ ID No. 45.

[0217] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 46 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 47, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 46 and the VH domain comprises or consists of the sequence of SEQ ID No. 47.

[0218] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 48 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 49, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 48 and the VH domain comprises or consists of the sequence of SEQ ID No. 49.

[0219] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 50 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 51 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 50 and the VH domain comprises or consists of the sequence of SEQ ID No. 51.

[0220] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 52 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 53, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 52 and the VH domain comprises or consists of the sequence of SEQ ID No. 53.

[0221] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 54 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 55, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 54 and the VH domain comprises or consists of the sequence of SEQ ID No. 55.

[0222] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 56 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 57, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 56 and the VH domain comprises or consists of the sequence of SEQ ID No. 57.

[0223] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 58 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 59, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 58 and the VH domain comprises or consists of the sequence of SEQ ID No. 59.

[0224] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 60 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 61 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 60 and the VH domain comprises or consists of the sequence of SEQ ID No. 61. In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 62 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 63, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 62 and the VH domain comprises or consists of the sequence of SEQ ID No. 63.

[0225] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 64 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 65, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 64 and the VH domain comprises or consists of the sequence of SEQ ID No. 65.

[0226] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 70 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 71 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 70 and the VH domain comprises or consists of the sequence of SEQ ID No. 71.

[0227] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 74 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 75, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 74 and the VH domain comprises or consists of the sequence of SEQ ID No. 75.

[0228] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 76 comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 77, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 76 and the VH domain comprises or consists of the sequence of SEQ ID No. 77.

[0229] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 660 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 661 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 660 and the VH domain comprises or consists of the sequence of SEQ ID No. 661.

[0230] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 662 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 663, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 662 and the VH domain comprises or consists of the sequence of SEQ ID No. 663.

[0231] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 664 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 665, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 664 and the VH domain comprises or consists of the sequence of SEQ ID No. 665.

[0232] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 721 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 722, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 721 and the VH domain comprises or consists of the sequence of SEQ ID No. 722. In some embodiments, the humanized antibody according to the invention comprises a Fab region wherein each of CDRH1, CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 82, SEQ ID No. 83 and SEQ ID NO. 84 respectively and each of CDRL1, CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0233] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 72 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 73, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 72 and the VH domain comprises or consists of the sequence of SEQ ID No. 73.

[0234] In some embodiments, the humanized antibody according to the invention comprises a Fab region wherein each of CDRH1, CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 85 respectively and each of CDRL1, CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0235] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 78 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 79, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 78 and the VH domain comprises or consists of the sequence of SEQ ID No. 79.

[0236] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 80 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 81 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 80 and the VH domain comprises or consists of the sequence of SEQ ID No. 81. In some embodiments, the humanized antibody according to the invention comprises a Fab region wherein each of CDRH1, CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 86 and SEQ ID NO. 8 respectively and each of CDRL1, CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0237] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 66 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 67, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 66 and the VH domain comprises or consists of the sequence of SEQ ID No. 67.

[0238] In some embodiments, the humanized antibody according to the invention comprises a Fab region, wherein each of CDRH1, CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 87 and SEQ ID NO. 8 respectively and each of CDRL1, CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

[0239] In such embodiments, antibodies may comprise a Fab region in which the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 68 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 69, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 68 and the VH domain comprises or consists of the sequence of SEQ ID No. 69.

[0240] In the above embodiments, the sequence variation allowed by the “at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence identify” may occur outside the CDR regions in the framework regions. For example, antibodies may comprise a Fab region in which each of CDRL1, CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively and the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 22; and each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 23.

[0241] Fc engineering

[0242] Antibodies of the invention comprise a Fab region that comprises a binding site which specifically binds to amyloid fibrils (for example any of the Fab regions disclosed herein) and an engineered Fc region.

[0243] The “Fc region” or “Fc domain” (fragment crystallizable region) is the C-terminal region of an immunoglobulin heavy chain which comprises the CH2 and CH3 domains (or constructs that contain the CH2 and CH3 domains). Typically an Fc region when part of an antibody is a dimer comprising two paired heavy chain CH2 and CH3 regions. The term “Fc domain” includes wild type Fc regions (such as wildtype human IgG Fc region (e.g. SEQ ID NO: 623)) and engineered or Fc regions. An “engineered” Fc region is an Fc region that has been modified from wild type, for example by one or more amino acid changes or mutations, to alter one or more properties of the antibody. Unless otherwise indicated, residue numbering for the constant regions and Fc regions follows the Eu numbering convention.

[0244] The Fc region plays an important role in immune responses and in the ability of therapeutic antibodies to engage with immune effector mechanisms. For example, the Fc region of an antibody enables immune cell engagement since the Fc region is able to bind to and interact with Fc receptors on various cells of the immune system such as macrophage, neutrophils and natural killer (NK) cells. The binding of the Fc region to Fc receptors enables immune cells to recognize and respond to “antibody-tagged” targets. These interactions enable or upregulate critical immune responses such as inflammatory response modulation, phagocytosis, antibody-dependent cellular cytotoxicity and activation of the complement system via Fc region binding to C1q. The Fc region additionally mediates isotype-specific functions since different antibody classes have distinct Fc regions that determine their specific interaction capabilities with components of the immune system and immunological roles.

[0245] There are a number of Fc receptors found on cells of the immune system. The most extensively studied class is IgG Fc receptor gamma (FcyR or FcgR). There are a number of FcyR subtypes, including the following:

[0246] Other types of Fc receptor are well known, such as the FcRn which is thought to be responsible for the relatively long half life of IgG.

[0247] Given the importance of the interaction between Fc regions and their targets (Fc receptors, C1q etc) investigators have sought to optimise these effects by engineering the Fc region to bind to a greater or lesser extent to individual targets of the Fc region. The most common method of Fc engineering is glycosylation modifications to reduce fucosylation of the Fc region, which has been found to increase affinity for FcyRIII which leads to increased ADCC potency. Other Fc engineering techniques include mutations that modify the binding of the IgG to one of more Fc receptors, for example for the purpose of enhancing complement dependent cytotoxicity (CDC), ADCC or antibody-dependent cell-mediated phagocytosis (ADCP). Although many Fc mutations have been trialled, there are few systematic comparisons of the activity of the different mutations and predicting the patterns of activity when incorporated into different antibodies can be challenging. Combinations of Fc mutations are especially hard to predict and combinations of mutations that are effective on their own or in other combinations can lead to complete loss of intended function. Additionally, for therapeutic applications, it is important that Fc modifications do not destabilize the antibody structure and many Fc mutations (even single amino acid changes) can lead to reduced thermal stability which can impact immunogenicity, antibody binding, aggregation, storage and drug manufacture. [Hale, G., et al. (2024). mAbs, 16(1). https: / / doi.org / 10.1080 / 19420862.2024.2406539.]

[0248] Different Fc regions may have different allotypes. Allotypes are inherited genetic variations in the Fc region, for example as resulting from polymorphisms in immunoglobulin genes. Allotypes are generally caused by single nucleotide polymorphisms in genes encoding antibodies and do not normally affect the structure or function of the antibody. The skilled person could apply the same Fc mutations described in the engineered Fc regions of the invention to different Fc allotypes and would expect the same effect. Summary of specific engineered Fc regions provided herein

[0249] In some embodiments the antibodies of the invention comprise an engineered Fc region of the antibody which is derived from human I gG 1 isotype. In some embodiments the antibodies of the invention comprise an engineered Fc region derived from mouse lgG2 isotype. In this context “derived from” means the wild type Fc region on which the Fc engineering is performed is a human IgG 1 isotype or mouse lgG2 isotype respectively. An Fc region that is “derived from” a wild type Fc region may have one or more amino acid sequence changes (for example 1 , 2, 3, 4 or 5 or more amino acid changes) relative to the wild type sequence to confer one or more properties to an antibody comprising the modified Fc region.

[0250] The Fc regions of the antibodies of the invention are engineered to convey certain properties on the antibodies.

[0251] The Fc regions may be engineered to increase complement activation compared to a wild-type Fc region.

[0252] Complement activation may be increased, for example, by increasing affinity of the Fc region to C1q compared to a wild-type Fc region. Engineered Fc regions that may increase complement activation compared to a wild-type Fc region by increasing affinity to C1q include Fc regions comprising the mutation E430G (either alone or in combination with other mutations), Fc regions comprising the mutation H429F (either alone or in combination with other mutations), Fc regions comprising the mutations E430G + S239D + I332E (“SDIE"), Fc regions comprising the mutations S239D + I332E (“SDIE”) + H429F, or Fc regions comprising the mutations M428L + N434S (LS) + H429F. An antibody comprising one or more Fc modifications for the purposes of increasing affinity of the Fc region to C1 q has increased affinity of the Fc region to C1 q compared to an antibody that lacks the same one or more Fc modifications when tested under the same or substantially the same conditions. In some embodiments, an antibody comprising one or more Fc modifications for the purposes of increasing affinity of the Fc region to 01 q has increased affinity of the Fc region to 01 q compared to an antibody that comprises the corresponding wild type Fc region when tested under the same or substantially the same conditions. For an example, see Example 8. Complement activation may also be increased by increasing ADCP compared to a wild-type Fc region, for example by engineering the Fc region to increase the capacity of the Fc region to be recognised by phagocytes, or increasing the capacity of the Fc region to activate the phagocytes. Engineered Fc regions that may increase complement activation compared to a wildtype Fc region by increasing ADCP compared to a wild-type Fc region include Fc regions comprising the mutations S239D + I332E (SDIE), Fc regions comprising the mutation L328E (either alone or in combination with other mutations), Fc regions comprising the mutations L234Y + G236W + S298A, Fc regions comprising the mutations E430G + S239D + I332E (SDIE), Fc regions comprising the mutations E430G + L328E, Fc regions comprising the mutations S239D + I332E (SDIE) + M428L + N434S (LS), or Fc regions comprising the mutations S239D - I332E (SDIE) + H429F. An antibody comprising one or more Fc modifications for the purposes of increasing complement activation has increased complement activation compared to an antibody that lacks the same one or more Fc modifications when tested under the same or substantially the same conditions. In some embodiments, an antibody comprising one or more Fc modifications for the purposes of increasing complement activation has increased complement activation compared to an antibody that comprises the corresponding wild type Fc region when tested under the same or substantially the same conditions. For an example, see Example 9.

[0253] Complement activation may also be increased by engineering Fc regions to increase hexamerisation compared to a wild-type Fc region by improving the suitability of Fc regions to specifically interact with other Fc regions to oligomerise and form a hexamer, which is a large complex aggregate (preferably comprising 6 antibodies). Antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell killing. Engineered Fc regions that may increase complement activation compared to a wild-type Fc region by increasing hexamerisation compared to a wild-type Fc region include Fc regions comprising the mutation E430G (either alone or in combination with other mutations), Fc regions comprising the mutation H429F (either alone or in combination with other mutations), Fc regions comprising the mutations E430G + S239D + I332E (SDIE), Fc regions comprising the mutations E430G + M428L + N434S (LS), Fc regions comprising the mutations E430G + L328E, Fc regions comprising the mutations S239D + I332E (SDIE) + H429F, or Fc regions comprising the mutations M428L - N434S (LS) + H429F. An antibody comprising one or more Fc modifications for the purposes of increasing hexamerisation has increased hexamerisation compared to an antibody that lacks the same one or more Fc modifications when tested under the same or substantially the same conditions. In some embodiments, an antibody comprising one or more Fc modifications for the purposes of increasing hexamerisation has increased hexamerisation compared to an antibody that comprises the corresponding wild type Fc region when tested under the same or substantially the same conditions.

[0254] The Fc regions may be engineered to increase affinity to one or more Fc receptors, such as human FcgR I, human FcgR II (or one or more subtypes thereof), human FcgR III (or one or more subtypes thereof, preferably human FcgR Illa) and / or human FcRn compared to a wild type Fc region. The Fc regions may be engineered to increase affinity to human FcgR I as compared to a wild type Fc region. Engineered Fc regions that may increase affinity to human FcgR I include Fc regions comprising the mutations S239D + I332E (SDIE), Fc regions comprising the mutation L328E (alone or in combination with other mutations), Fc regions comprising the mutations E430G + S239D - I332E (SDIE), Fc regions comprising the mutations E430G + L328E , Fc regions comprising the mutations S239D - I332E (SDIE) + M428L - N434S (LS) or Fc regions comprising the mutations S239D - I332E (SDIE) + H429F. The Fc regions may be engineered to increase affinity to human FcgR II as compared to a wild type Fc region. Engineered Fc regions that may increase affinity to human FcgR II include Fc regions comprising the mutations S239D + I332E (SDIE), Fc regions comprising the mutation L328E (alone or in combination with other mutations), Fc regions comprising the mutations E430G + S239D - I332E (SDIE), Fc regions comprising the mutations E430G + L328E , Fc regions comprising the mutations S239D - I332E (SDIE) + M428L - N434S (LS) or Fc regions comprising the mutations S239D - I332E (SDIE) + H429F.

[0255] The Fc regions may be engineered to increase affinity to human FcgR III (preferably human FcgR Illa) as compared to a wild type Fc region. Engineered Fc regions that may increase affinity to human FcgR II include Fc regions comprising the mutations S239D + I332E (SDIE), Fc regions comprising the mutations L234Y + G236W+ S298A, Fc regions comprising the mutations E430G + S239D - I332E (SDIE), Fc regions comprising the mutations S239D - I332E (SDIE) + M428L - N434S (LS), or Fc regions comprising the mutations S239D - I332E (SDIE) + H429F.

[0256] The Fc regions may be engineered to increase affinity to human FcRn at acidic pH as compared to a wild type Fc region. Engineered Fc regions that may increase affinity to human FcRn at acidic pH include Fc regions comprising the mutations M428L - N434S (LS), Fc regions comprising the mutations M252Y - S254T - T256E, Fc regions comprising the mutations E430G + M428L - N434S (LS), Fc regions comprising the mutations S239D - I332E (SDIE) + M428L - N434S (LS), or Fc regions comprising the mutations M428L - N434S (LS) + H429F.

[0257] An antibody comprising one or more Fc modifications for the purposes of increasing affinity to one or more Fc receptors has increased affinity to one or more Fc receptors compared to an antibody that lacks the same one or more Fc modifications when tested under the same or substantially the same conditions. In some embodiments, an antibody comprising one or more Fc modifications for the purposes of increasing affinity to one or more Fc receptors has increased affinity to one or more Fc receptors compared to an antibody that comprises the corresponding wild type Fc region when tested under the same or substantially the same conditions. For an example, see Example 8. The Fc regions may be engineered to increase half-life of the antibody as compared to wild type Fc regions. For example this may be via engineering the Fc region to increase binding to FcRn and therefore increasing antibody cellular recycling. The prolonged halflives of IgGs depend on the intracellular trafficking function of neonatal Fc receptor (FcRn), which rescues internalized IgGs from lysosomal degradation and recycles them back to circulation. Engineered Fc regions that may increase half-life include Fc regions comprising the mutations M428L - N434S (LS), Fc regions comprising the mutations M252Y - S254T - T256E, Fc regions comprising the mutations E430G + M428L - N434S (LS), Fc regions comprising the mutations S239D - I332E (SDIE) + M428L - N434S (LS), or Fc regions comprising the mutations M428L - N434S (LS) + H429F. An antibody comprising one or more Fc modifications for the purposes of increasing half-life has increased half-life compared to an antibody that lacks the same one or more Fc modifications when tested under the same or substantially the same conditions. In some embodiments, an antibody comprising one or more Fc modifications for the purposes of increasing half-life has increased half-life compared to an antibody that comprises the corresponding wild type Fc region when tested under the same or substantially the same conditions. Increased half-life can be measured, for example, by measuring the effect of mutations on antibody half-life in mice that express the human neonatal Fc receptor (FcRn) in place of the mouse FcRn. In some embodiments the engineered Fc region comprises one or more of the amino acid mutations selected from the group consisting of: G236W, S239D; M252Y; S254T; T256E; S298A, L234Y, L328E, I332E, M428L, H429F; E430G; and N434S (Eu numbering).

[0258] The engineered Fc region of the antibodies of the invention may comprise one or more of the Fc mutations described as A to M in Table 3.

[0259] Table 3: Mutation(s) in engineered Fc regions

[0260] Name of engineered Fc Mutation(s) in Fc region (Eu numbering)

[0261] A IMT1-191-1 E430G

[0262] B IMT1-191-2 S239D and I332E (SDIE)

[0263] C IMT1-191-3 M428L and N434S (LS)

[0264] D IMT1-191-4 L328E

[0265] E IMT1-191-5 L234Y and G236W and S298A

[0266] F IMT1-191-7 H429F

[0267] G IMT1-191-10 M252Y and S254T and T256E

[0268] H IMT1-191-12 E430G and S239D and I332E (SDIE)

[0269] I IMT1-191-13 E430G and M428L and N434S (LS)

[0270] J IMT1-191-14 E430G and L328E

[0271] K IMT1-191-23 S239D and I332E (SDIE) and M428L and N434S (LS)

[0272] L IMT1-191-27 S239D and I332E (SDIE) and H429F

[0273] M IMT1-19-37 M428L and N434S (LS) and H429F

[0274] The mentioned mutations in the Fc region are with respect to a wild type Fc region of a corresponding allotype. For example. The mentioned mutations in the Fc region may be with respect to a wild type huma IgG 1 Fc region. In some embodiments, the antibody comprises an engineered Fc region comprising the amino acid mutation E430G, optionally wherein the Fc region does not comprise any other amino acid mutations.

[0275] In some embodiments, the antibody comprises an engineered Fc region comprising the amino acid mutations S239D and I332E, optionally wherein the Fc region does not comprise any other amino acid mutations.

[0276] In some embodiments, the antibody comprises an engineered Fc region comprising the amino acid mutations M428L and N434S, optionally wherein the Fc region does not comprise any other amino acid mutations.

[0277] In some embodiments, the antibody comprises an engineered Fc region comprising the amino acid mutation L328E, optionally wherein the Fc region does not comprise any other amino acid mutations.

[0278] In some embodiments, the antibody comprises an engineered Fc region comprising the amino acid mutations L234Y and G236W and S298A, optionally wherein the Fc region does not comprise any other amino acid mutations.

[0279] In some embodiments, the antibody comprises an engineered Fc region comprising the amino acid mutation H429F, optionally wherein the Fc region does not comprise any other amino acid mutations.

[0280] In some embodiments, the antibody comprises an engineered Fc region comprising the amino acid mutation M252Y and S254T and T256E, optionally wherein the Fc region does not comprise any other amino acid mutations.

[0281] The mutations that occur in the engineered Fc region may be in the CH2 domain and or the CH3 domain. The antibodies of the present invention may comprise an engineered Fc region comprising one or more sequences selected from the group consisting of SEQ ID NO: 93 to 103. The antibodies of the present invention may comprise an engineered Fc region comprising a CH2 domain comprising or consisting of a sequence selected from the group consisting of SEQ ID NO: 93 to 97. The antibodies of the present invention may comprise an engineered Fc region comprising a CH3 domain comprising or consisting of a sequence selected from the group consisting of SEQ ID NO: 98 to 103, optionally further comprising a lysine (K) residue at the C- terminus. The C-terminus of the lgG1 constant domain is sometimes considered to end with “PGK”, however the C-terminal lysine (K) is often cleaved during protein expression (known as lysine clipping). This can result in increased product heterogeneity and a potential charge change to the antibody through the loss of the basic lysine. Therefore the C-terminal lysine is often removed from the C-terminus of the constant domain (as in the CH3 sequences provided herein). The C-terminal G may also be removed in the same fashion (not shown in the CH3 sequences provided herein).

[0282] In some embodiments, the antibodies of the invention comprise a Fab region (for example any Fab region disclosed herein) and a constant region comprising the engineered Fc regions which comprise or consist of the sequences shown in Table 2.

[0283] In some embodiments, the antibodies of the invention comprise a Fab region (for example any Fab region disclosed herein, for example as defined by heavy and light chain variable region pairings disclosed herein, or a Fab region comprising the 6 CDRs of any HCDR1 , HCDR2, HCDR3, LCDR1 , LCDR2 and LCDR3 groups disclosed herein) and the engineered Fc region comprises: a. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 99; b. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 98; c. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 100 ; d. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 95 and a CH3 domain comprising or consisting of SEQ ID NO: 98 ; e. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 96 and a CH3 domain comprising or consisting of SEQ ID NO: 98 ; f. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 101 ; g. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 97 and a CH3 domain comprising or consisting of SEQ ID NO: 98; h. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 99; i. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 95 and a CH3 domain comprising or consisting of SEQ ID NO: 99; j. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 102; k. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 100; l. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 101 ; or m. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 103. The constant region of the antibodies of the invention may further comprise a CH1 domain, optionally a CH1 domain comprising or consisting of the sequence of SEQ ID NO: 92.

[0284] Generally, an antibody may comprise, in its heavy a chain, a CH1 , a CH2 and a CH3 domain in an N to C terminal direction. In some embodiments, the antibody may comprise a heavy chain comprising, in an N to C terminal direction, a VH domain, a CH1 domain, a CH2 domain and a CH3 domain. In some embodiments, the antibody may comprise a heavy chain comprising, in an N to C terminal direction, a VH domain, a heavy chain CH1 domain, a CH2 domain connected covalently to the CH1 domain by a Hinge (Hinge-CH2), and a CH3 domain and a light chain comprising, in an N to C terminal direction, a VL domain and a light chain CH1 domain.

[0285] Any of the constant regions or engineered Fc regions disclosed herein may be combined with any of the Fab regions disclosed herein to form an antibody falling inside the scope of the present invention. For example, any of the Fab regions of Table 1 may be combined with any of the constant regions (comprising an engineered Fc region) of Table 2.

[0286] Summary of specific antibodies provided herein

[0287] Any of the constant regions or engineered Fc regions disclosed herein may be combined with any of the Fab regions disclosed herein to form an antibody falling inside the scope of the present invention. For example, any of the Fab regions of Table 1 may be combined with any of the constant regions (comprising an engineered Fc region) of Table 2.

[0288] For example, in some embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0289] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0290] For example, in some embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0291] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 14 and the VH domain comprises or consists of the sequence of SEQ ID No. 15, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0292] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 16 and the VH domain comprises or consists of the sequence of SEQ ID No. 17, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0293] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 18 and the VH domain comprises or consists of the sequence of SEQ ID No. 19, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0294] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 20 and the VH domain comprises or consists of the sequence of SEQ ID No. 21 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0295] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 22 and the VH domain comprises or consists of the sequence of SEQ ID No. 23, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0296] In one embodiment there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740, and an engineered Fc region comprising the amino acid mutation E430G (alone or in combination with other Fc mutations).

[0297] In one embodiment there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740, and an engineered Fc region comprising the amino acid mutations S239D and I332E (SDIE) (alone or in combination with other Fc mutations).

[0298] In one embodiment there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 22 and the VH domain comprises or consists of the sequence of SEQ ID No. 23, and an engineered Fc region comprising the amino acid mutation E430G (alone or in combination with other Fc mutations).

[0299] In one embodiment there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 22 and the VH domain comprises or consists of the sequence of SEQ ID No. 23, and an engineered Fc region comprising the amino acid mutations S239D and I332E (SDIE) (alone or in combination with other Fc mutations).

[0300] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 24 and the VH domain comprises or consists of the sequence of SEQ ID No. 15, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0301] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 26 and the VH domain comprises or consists of the sequence of SEQ ID No. 27, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0302] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 28 and the VH domain comprises or consists of the sequence of SEQ ID No. 29, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0303] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 30 and the VH domain comprises or consists of the sequence of SEQ ID No. 31 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0304] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 32 and the VH domain comprises or consists of the sequence of SEQ ID No. 33, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0305] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 34 and the VH domain comprises or consists of the sequence of SEQ ID No. 35, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0306] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 36 and the VH domain comprises or consists of the sequence of SEQ ID No. 37, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0307] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 38 and the VH domain comprises or consists of the sequence of SEQ ID No. 39, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0308] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 40 and the VH domain comprises or consists of the sequence of SEQ ID No. 41 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0309] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 42 and the VH domain comprises or consists of the sequence of SEQ ID No. 43, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0310] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 44 and the VH domain comprises or consists of the sequence of SEQ ID No. 45, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0311] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 46 and the VH domain comprises or consists of the sequence of SEQ ID No. 47, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0312] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 48 and the VH domain comprises or consists of the sequence of SEQ ID No. 49, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0313] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 50 and the VH domain comprises or consists of the sequence of SEQ ID No. 51 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0314] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 52 and the VH domain comprises or consists of the sequence of SEQ ID No. 53, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0315] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 54 and the VH domain comprises or consists of the sequence of SEQ ID No. 55, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0316] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 56 and the VH domain comprises or consists of the sequence of SEQ ID No. 57, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0317] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 58 and the VH domain comprises or consists of the sequence of SEQ ID No. 59, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0318] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 60 and the VH domain comprises or consists of the sequence of SEQ ID No. 61 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0319] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 62 and the VH domain comprises or consists of the sequence of SEQ ID No. 63, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0320] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 64 and the VH domain comprises or consists of the sequence of SEQ ID No. 65, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0321] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 70 and the VH domain comprises or consists of the sequence of SEQ ID No. 71 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0322] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 74 and the VH domain comprises or consists of the sequence of SEQ ID No. 75, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0323] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 76 and the VH domain comprises or consists of the sequence of SEQ ID No. 77, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0324] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 660 and the VH domain comprises or consists of the sequence of SEQ ID No. 661 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0325] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 662 and the VH domain comprises or consists of the sequence of SEQ ID No. 663, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0326] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 664 and the VH domain comprises or consists of the sequence of SEQ ID No. 665, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0327] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 721 and the VH domain comprises or consists of the sequence of SEQ ID No. 722, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0328] In other embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 82, SEQ ID No. 83 and SEQ ID NO. 84 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0329] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 72 and the VH domain comprises or consists of the sequence of SEQ ID No. 73, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0330] In other embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ I D No 6, SEQ ID No. 7 and SEQ ID NO. 85 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0331] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 78 and the VH domain comprises or consists of the sequence of SEQ ID No. 79, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0332] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 80 and the VH domain comprises or consists of the sequence of SEQ ID No. 81 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0333] In other embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ I D No 6, SEQ ID No. 86 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0334] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 66 and the VH domain comprises or consists of the sequence of SEQ ID No. 67, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE). In other embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ I D No 6, SEQ ID No. 87 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0335] In such embodiments there is provided an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 68 and the VH domain comprises or consists of the sequence of SEQ ID No. 69, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0336] As described elsewhere herein, any of the constant regions or engineered Fc regions disclosed herein may be combined with any of the Fab regions disclosed herein to form an antibody falling inside the scope of the present invention. For example, any of the Fab regions of Table 1 may be combined with any of the constant regions (comprising an engineered Fc region) of Table 2. In order to obtain a complete antibody sequence in this manner a Fab from Table 1 (such as Clone P029_Ab19) and a engineered Fc taken from Table 2 such as (IMT1-191-1) are combined together to form full heavy and light antibody chains. A complete antibody will normally comprise two copies of the heavy chain and two copies of the light chain. In this example, to make the heavy chain the VH region of Clone P029_Ab19 (SEQ ID NO: 23) is concatemerized with the constant heavy region (CH1+CH3+CH3) of IMT1-191 -1 (SEQ ID NO: 92 + 93 + 99 = 106) to give the heavy chain [Clone P029_Ab19, VH+ IMT1-191-1 CH1CH2CH3] (SEQ ID NO: 159). To make the light chain the VL region of Clone P029_Ab19 (SEQ ID NO: 22) is concatemerized with the constant light region (CL) of IMT1-191-1 (SEQ ID NO: 104) to give the light chain [Clone P029_Ab19, VL + CL] (SEQ ID NO: 628). The resulting heavy chain SEQ ID NO: 159 is paired with the resulting light chain SEQ ID NO: 628 (two copies of each) to give the full antibody Clone P029_Ab19 x IMT1-191-1. In some embodiments there is provided a humanised isolated monoclonal antibody, respectively comprising the heavy chain and light chain sequence of: a. SEQ ID NOs: 155 and 624, 191 and 624, 227 and 624, 263 and 624, 299 and 624,

[0337] 335 and 624, 371 and 624, 407 and 624, 443 and 624, 479 and 624, 515 and 624,

[0338] 551 and 624, 587 and 624: b. SEQ ID NOs: 156 and 625, 192 and 625, 228 and 625, 264 and 625, 300 and 625,

[0339] 336 and 625, 372 and 625, 408 and 625, 444 and 625, 480 and 625, 516 and 625,

[0340] 552 and 625, 588 and 625; c. SEQ ID NOs: 157 and 626, 193 and 626, 229 and 626, 265 and 626, 301 and 626,

[0341] 337 and 626, 373 and 626, 409 and 626, 445 and 626, 481 and 626, 517 and 626,

[0342] 553 and 626, 589 and 626; d. SEQ ID NOs: 158 and 627, 194 and 627, 230 and 627, 266 and 627, 302 and 627,

[0343] 338 and 627, 374 and 627, 410 and 627, 446 and 627, 482 and 627, 518 and 627,

[0344] 554 and 627, 590 and 627; e. SEQ ID NOs: 159 and 628, 195 and 628, 231 and 628, 267 and 628, 303 and 628,

[0345] 339 and 628, 375 and 628, 411 and 628, 447 and 628, 483 and 628, 519 and 628,

[0346] 555 and 628, 591 and 628; f. SEQ ID NOs: 160 and 629, 196 and 629, 232 and 629, 268 and 629, 304 and 629,

[0347] 340 and 629, 376 and 629, 412 and 629, 448 and 629, 484 and 629, 520 and 629,

[0348] 556 and 629, 592 and 629; g. SEQ ID NOs: 161 and 630, 197 and 630, 233 and 630, 269 and 630, 305 and 630,

[0349] 341 and 630, 377 and 630, 413 and 630, 449 and 630, 485 and 630, 521 and 630,

[0350] 557 and 630, 593 and 630; h. SEQ ID NOs: 162 and 631 , 198 and 631, 234 and 631 , 270 and 631, 306 and 631,

[0351] 342 and 631 , 378 and 631, 414 and 631, 450 and 631 , 486 and 631 , 522 and 631,

[0352] 558 and 631, 594 and 631 ; i. SEQ ID NOs: 163 and 632, 199 and 632, 235 and 632, 271 and 632, 307 and 632,

[0353] 343 and 632, 379 and 632, 415 and 632, 451 and 632, 487 and 632, 523 and 632,

[0354] 559 and 632, 595 and 632; j. SEQ ID NOs: 164 and 633, 200 and 633, 236 and 633, 272 and 633, 308 and 633,

[0355] 344 and 633, 380 and 633, 416 and 633, 452 and 633, 488 and 633, 524 and 633,

[0356] 560 and 633, 596 and 633; k. SEQ ID NOs: 165 and 634, 201 and 634, 237 and 634, 273 and 634, 309 and 634,

[0357] 345 and 634, 381 and 634, 417 and 634, 453 and 634, 489 and 634, 525 and 634,

[0358] 561 and 634, 597 and 634; l. SEQ ID NOs: 166 and 635, 202 and 635, 238 and 635, 274 and 635, 310 and 635,

[0359] 346 and 635, 382 and 635, 418 and 635, 454 and 635, 490 and 635, 526 and 635,

[0360] 562 and 635, 598 and 635; m. SEQ ID NOs: 167 and 636, 203 and 636, 239 and 636, 275 and 636, 311 and 636,

[0361] 347 and 636, 383 and 636, 419 and 636, 455 and 636, 491 and 636, 527 and 636,

[0362] 563 and 636, 599 and 636; n. SEQ ID NOs: 168 and 637, 204 and 637, 240 and 637, 276 and 637, 312 and 637,

[0363] 348 and 637, 384 and 637, 420 and 637, 456 and 637, 492 and 637, 528 and 637,

[0364] 564 and 637, 600 and 637; o. SEQ ID NOs: 69 and 638, 205 and 638, 241 and 638, 277 and 638, 313 and 638, 349 and 638, 385 and 638, 421 and 638, 457 and 638, 493 and 638, 529 and 638, 565 and 638, 601 and 638; p. SEQ ID NOs: 170 and 639, 206 and 639, 242 and 639, 278 and 639, 314 and 639,

[0365] 350 and 639, 386 and 639, 422 and 639, 458 and 639, 494 and 639, 530 and 639,

[0366] 566 and 639, 602 and 639; q. SEQ ID NOs: 171 and 640, 207 and 640, 243 and 640, 279 and 640, 315 and 640,

[0367] 351 and 640, 387 and 640, 423 and 640, 459 and 640, 495 and 640, 531 and 640,

[0368] 567 and 640, 603 and 640; r. SEQ ID NOs: 172 and 641 , 208 and 641, 244 and 641 , 280 and 641, 316 and 641,

[0369] 352 and 641 , 388 and 641, 424 and 641, 460 and 641 , 496 and 641 , 532 and 641,

[0370] 568 and 641, 604 and 641 ; s. SEQ ID NOs: 173 and 642, 209 and 642, 245 and 642, 281 and 642, 317 and 642,

[0371] 353 and 642, 389 and 642, 425 and 642, 461 and 642, 497 and 642, 533 and 642,

[0372] 569 and 642, 605 and 642; t. SEQ ID NOs: 174 and 643, 210 and 643, 246 and 643, 282 and 643, 318 and 643,

[0373] 354 and 643, 390 and 643, 426 and 643, 462 and 643, 498 and 643, 534 and 643,

[0374] 570 and 643, 606 and 643; u. SEQ ID NOs: 175 and 644, 211 and 644, 247 and 644, 283 and 644, 319 and 644,

[0375] 355 and 644, 391 and 644, 427 and 644, 463 and 644, 499 and 644, 535 and 644,

[0376] 571 and 644, 607 and 644; v. SEQ ID NOs: 176 and 645, 212 and 645, 248 and 645, 284 and 645, 320 and 645,

[0377] 356 and 645, 392 and 645, 428 and 645, 464 and 645, 500 and 645, 536 and 645,

[0378] 572 and 645, 608 and 645; w. SEQ ID NOs: 177 and 646, 213 and 646, 249 and 646, 285 and 646, 321 and 646,

[0379] 357 and 646, 393 and 646, 429 and 646, 465 and 646, 501 and 646, 537 and 646,

[0380] 573 and 646, 609 and 646; x. SEQ ID NOs: 178 and 647, 214 and 647, 250 and 647, 286 and 647, 322 and 647,

[0381] 358 and 647, 394 and 647, 430 and 647, 466 and 647, 502 and 647, 538 and 647,

[0382] 574 and 647, 610 and 647; y. SEQ ID NOs: 179 and 648, 215 and 648, 251 and 648, 287 and 648, 323 and 648, 359 and 648, 395 and 648, 431 and 648, 467 and 648, 503 and 648, 539 and 648, 575 and 648, 611 and 648; z. SEQ ID NOs: 180 and 649, 216 and 649, 252 and 649, 288 and 649, 324 and 649,

[0383] 360 and 649, 396 and 649, 432 and 649, 468 and 649, 504 and 649, 540 and 649,

[0384] 576 and 649, 612 and 649; aa. SEQ ID NOs: 181 and 650, 217 and 650, 253 and 650, 289 and 650, 325 and 650,

[0385] 361 and 650, 397 and 650, 433 and 650, 469 and 650, 505 and 650, 541 and 650,

[0386] 577 and 650, 613 and 650; bb. SEQ ID NOs: 182 and 651 , 218 and 651, 254 and 651 , 290 and 651, 326 and 651,

[0387] 362 and 651 , 398 and 651, 434 and 651, 470 and 651 , 506 and 651 , 542 and 651,

[0388] 578 and 651, 614 and 651 ; cc. SEQ ID NOs: 183 and 652, 219 and 652, 255 and 652, 291 and 652, 327 and 652,

[0389] 363 and 652, 399 and 652, 435 and 652, 471 and 652, 507 and 652, 543 and 652,

[0390] 579 and 652, 615 and 652; dd. SEQ ID NOs: 184 and 653, 220 and 653, 256 and 653, 292 and 653, 328 and 653,

[0391] 364 and 653, 400 and 653, 436 and 653, 472 and 653, 508 and 653, 544 and 653,

[0392] 580 and 653, 616 and 653; ee. SEQ ID NOs: 185 and 654, 221 and 654, 257 and 654, 293 and 654, 329 and 654,

[0393] 365 and 654, 401 and 654, 437 and 654, 473 and 654, 509 and 654, 545 and 654,

[0394] 581 and 654, 617 and 654; ff. SEQ ID NOs: 186 and 655, 222 and 655, 258 and 655, 294 and 655, 330 and 655,

[0395] 366 and 655, 402 and 655, 438 and 655, 474 and 655, 510 and 655, 546 and 655,

[0396] 582 and 655, 618 and 655; gg. SEQ ID NOs: 187 and 656, 223 and 656, 259 and 656, 295 and 656, 331 and 656,

[0397] 367 and 656, 403 and 656, 439 and 656, 475 and 656, 511 and 656, 547 and 656,

[0398] 583 and 656, 619 and 656; hh. SEQ ID NOs: 188 and 657, 224 and 657, 260 and 657, 296 and 657, 332 and 657,

[0399] 368 and 657, 404 and 657, 440 and 657, 476 and 657, 512 and 657, 548 and 657,

[0400] 584 and 657, 620 and 657; ii. SEQ ID NOs: 189 and 658, 225 and 658, 261 and 658, 297 and 658, 333 and 658,

[0401] 369 and 658, 405 and 658, 441 and 658, 477 and 658, 513 and 658, 549 and 658,

[0402] 585 and 658, 621 and 658; jj. SEQ ID NOs: 190 and 659, 226 and 659, 262 and 659, 298 and 659, 334 and 659,

[0403] 370 and 659, 406 and 659, 442 and 659, 478 and 659, 514 and 659, 550 and 659,

[0404] 586 and 659, or 622 and 659; kk. SEQ ID NOs: 669 and 666, 670 and 666, 671 and 666, 672 and 666, 673 and 666,

[0405] 674 and 666, 675 and 666, 676 and 666, 677 and 666, 678 and 666, 679 and 666,

[0406] 680 and 666, 681 and 666;

[0407] II. SEQ ID NOs: 682 and 667, 683 and 667, 684 and 667, 685 and 667, 686 and 667,

[0408] 687 and 667, 688 and 667, 689 and 667, 690 and 667, 691 and 667, 692 and 667,

[0409] 693 and 667, 694 and 667; mm. SEQ ID NOs: 695 and 668, 696 and 668, 697 and 668, 698 and 668, 699 and 668, 700 and 668, 701 and 668, 702 and 668, 703 and 668, 704 and 668, 705 and 668, 706 and 668, 707 and 668; nn. SEQ ID NOs: 725 and 723, 726 and 723, 727 and 723, 728 and 723, 729 and 723,

[0410] 730 and 723, 731 and 723, 732 and 723, 733 and 723, 734 and 723, 735 and 723,

[0411] 736 and 723, 737 and 723; or oo. SEQ ID NOs: 743 and 741 , 744 and 741, 745 and 741 , 746 and 741, 747 and 741,

[0412] 748 and 741 , 749 and 741, 750 and 741, 751 and 741 , 752 and 741 , 753 and 741,

[0413] 754 and 741, 755 and 741.

[0414] It will be understood that a complete antibody will normally comprise two copies of the heavy chain and two copies of the light chain. Each of these heavy or light chain sequences can be made as described above by concatemerising the Fab and Fc sequences provided herein.

[0415] Heavy chain = VH + CH1 + CH2 + CH3

[0416] Light chain = VL + CL

[0417] Additional Fc engineered anti-amyloid antibodies

[0418] The engineered Fc regions described herein may be applied to other anti-amyloid antibodies, even if they do not share the pan-fibril binding property of other antibodies described herein.

[0419] The present invention also provides an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 88 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 89, and the Fc region is an engineered Fc region (such as an engineered Fc region described herein, for example in Table 2).

[0420] The present invention also provides an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of the sequence of SEQ ID No. 88 and the VH domain comprises or consists of the sequence of SEQ ID No. 89, and the Fc region is an engineered Fc region (such as an engineered Fc region described herein, for example in Table 2). The present invention also provides an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 88 and the VH domain comprises or consists of the sequence of SEQ ID No. 89, and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0421] The present invention also provides an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 90 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 91 , and the Fc region is an engineered Fc region (such as an engineered Fc region described herein, for example in Table 2).

[0422] The present invention also provides an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of the sequence of SEQ ID No. 90 and the VH domain comprises or consists of the of SEQ ID No. 91 , and the VH domain comprises or consists of the sequence of SEQ I D No. 91 and the Fc region is an engineered Fc region (such as an engineered Fc region described herein, for example in Table 2).

[0423] The present invention also provides an isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region in which the VL domain comprises or consists of the sequence of SEQ ID No. 90 and the VH domain comprises or consists of the sequence of SEQ ID No. 91 , and an engineered Fc region comprising an amino acid mutation(s) selected from the group consisting of E430G; S239D and I332E (SDIE); M428L and N434S (LS); L328E; L234Y and G236W and S298A; H429F; M252Y and S254T and T256E; E430G and S239D and I332E (SDIE); E430G and M428L and N434S (LS); E430G and L328E; S239D and I332E (SDIE) and M428L and N434S (LS); S239D and I332E (SDIE) and H429F; and M428L and N434S (LS) and H429F. Preferably the amino acid mutation is E430G, or S239D and I332E (SDIE).

[0424] Additional antibodies

[0425] In one aspect of the invention, any Fab region as shown in Table 1 may suitably be combined with a wild-type Fc region, e.g. IMT1-191.

[0426] IMT1-191 (or the Fc region thereof) comprises a wild type hlgG1 and the Fc region is not modified.

[0427] In some embodiments, any of P029_Ab019-39, P029_Ab019-46, P029_Ab019-47, P029_Ab019- 48, P029_Ab019-49, P029_Ab049, P029_Ab050, P029_Ab051 or P029_Ab052 may be combined with an unmodified Fc, such as IMT1-191.

[0428] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 72 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 73.

[0429] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 74 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 75;

[0430] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 76 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 77;

[0431] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 78 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 79;

[0432] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 80 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 81 ;

[0433] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 660 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 661 ;

[0434] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 662 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 663; or

[0435] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 664 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 665.

[0436] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 56 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 57.

[0437] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 58 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 59.

[0438] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 60 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 61.

[0439] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 62 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 63.

[0440] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 64 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 65.

[0441] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 721 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 722.

[0442] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein the VL domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 739 and the VH domain comprises or consists of a sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% sequence identity with SEQ ID No. 740.

[0443] In one embodiment the invention therefore provides a humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein: a. the VL domain comprises or consists of the sequence of SEQ ID No. 72 and the VH domain comprises or consists of the sequence of SEQ ID No. 73; b. the VL domain comprises or consists of the sequence of SEQ ID No. 74 and the VH domain comprises or consists of the sequence of SEQ ID No. 75; or c. the VL domain comprises or consists of the sequence of SEQ ID No. 76 and the VH domain comprises or consists of the sequence of SEQ ID No. 77; d. wherein the VL domain comprises or consists of the sequence of SEQ ID No. 78 and the

[0444] VH domain comprises or consists of the sequence of SEQ ID No. 79; e. wherein the VL domain comprises or consists of the sequence of SEQ ID No. 80 and the

[0445] VH domain comprises or consists of the sequence of SEQ ID No. 81; f. the VL domain comprises or consists of the sequence of SEQ ID No. 660 and the VH domain comprises or consists of the sequence of SEQ ID No. 661; g. the VL domain comprises or consists of the sequence of SEQ ID No. 662 and the VH domain comprises or consists of the sequence of SEQ ID No. 663; h. the VL domain comprises or consists of the sequence of SEQ ID No. 664 and the VH domain comprises or consists of the sequence of SEQ ID No. 665; i. the VL domain comprises or consists of the sequence of SEQ ID No. 56 and the VH domain comprises or consists of the sequence of SEQ ID No. 57; j. the VL domain comprises or consists of the sequence of SEQ ID No. 58 and the VH domain comprises or consists of the sequence of SEQ ID No. 59; k. the VL domain comprises or consists of the sequence of SEQ ID No. 60 and the VH domain comprises or consists of the sequence of SEQ ID No. 61; l. the VL domain comprises or consists of the sequence of SEQ ID No. 62 and the VH domain comprises or consists of the sequence of SEQ ID No. 63; m. the VL domain comprises or consists of the sequence of SEQ ID No. 64 and the VH domain comprises or consists of the sequence of SEQ ID No. 65; n. the VL domain comprises or consists of the sequence of SEQ ID No. 721 and the VH domain comprises or consists of the sequence of SEQ ID No. 722; or o. the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740.

[0446] The humanised monoclonal antibodies of this aspect may bind to at least 3, 4, 5, 6, 7, 8, 9, 10 or 11 different types of amyloid fibrils, selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils. The humanised monoclonal antibodies of the invention may be capable of binding to at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils. The fibrils may be endogenous amyloid fibrils, e.g. naturally occuring amyloid fibrils or amyloid fibrils formed in vivo. The humanised monoclonal antibodies of this aspect may also have any of the features of the antibodies of the first aspect.

[0447] In some embodiments, the invention provides a humanised monoclonal antibody, respectively comprising the heavy and light chain sequence of: SEQ ID NOs: 119 and 624, 120 and 625, 121 and 626, 122 and 627, 123 and 628, 124 and 629, 125 and 630, 126 and 631 , 127 and 632, 128 and 633, 129 and 634, 130 and 635, 131 and 636, 132 and 637, 133 and 638, 134 and 639, 135 and 640, 136 and 641 , 137 and 642, 138 and 643, 139 and 644, 140 and 645, 141 and 646, 142 and 647, 143 and 648, 144 and 649, 145 and 650, 146 and 651 , 147 and 652, 148 and 653, 149 and 654, 150 and 655, 151 and 656, 152 and 657, 708 and 666, 709 and 667, 710 and 668, 724 and 723, 140 and 645, 141 and 646, 142 and 647, 143 and 648, 144 and 649, 742 and 741.

[0448] Pharmaceutical Composition

[0449] Provided here are pharmaceutical compositions comprising an antibody or antigen binding portion thereof of the invention and optionally one or more pharmaceutically acceptable excipients.

[0450] A pharmaceutical composition may comprise, in addition to the antibody, one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those skilled in the art. Suitable materials will be sterile and pyrogen-free, with a suitable isotonicity and stability. Examples include sterile saline (e.g. 0.9% NaCI), water, dextrose, glycerol, ethanol or the like or combinations thereof. Such materials should be non-toxic and should not interfere with the efficacy of the active compound. The precise nature of the carrier or other material will depend on the route of administration, which may be by infusion, injection or any other suitable route, as discussed below. Suitable materials will be sterile and pyrogen free, with a suitable isotonicity and stability. Examples include sterile saline (e.g. 0.9% NaCI), water, dextrose, glycerol, ethanol or the like or combinations thereof. The composition may further contain auxiliary substances such as wetting agents, emulsifying agents, pH buffering agents or the like.

[0451] Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington’s Pharmaceutical Sciences, 18thedition, Mack Publishing Company, Easton, Pa., 1990.

[0452] The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0453] In some embodiments, the antibodies may be provided in a lyophilized form for reconstitution prior to administration. For example, lyophilized reagents may be re-constituted in sterile water and mixed with saline prior to administration to a subject.

[0454] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

[0455] Formulations may be in the form of liquids, solutions, suspensions, emulsions, and the like.

[0456] Optionally, other therapeutic or prophylactic agents may be included in a pharmaceutical composition or formulation.

[0457] The pharmaceutical compositions comprising the active compounds may be formulated in suitable dosage unit formulations appropriate for the intended route of administration.

[0458] Formulations suitable for oral administration (e.g. by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.

[0459] A tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surfaceactive or dispersing or wetting agents (e.g. sodium lauryl sulfate); and preservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[0460] Formulations suitable for parenteral administration (e.g. by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal), include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other micro particulate systems which are designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer’s Solution, or Lactated Ringer’s Injection. Typically, the concentration of the active compound in the solution is from about 1 ng / ml to about 10 pg / ml, for example from about 10 ng / ml to about 1 pg / ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.

[0461] Compositions may be prepared in the form of a concentrate for subsequent dilution, or may be in the form of divided doses ready for administration. Alternatively, the reagents may be provided separately within a kit, for mixing prior to administration to a human or animal subject.

[0462] Medical uses and methods of treatment

[0463] The present invention provides the antibodies or antibody binding portion thereof of the invention, or the composition or pharmaceutical compositions of the invention, for use in medicine.

[0464] The present invention also provides the antibodies or antibody binding portion thereof of the invention, or the composition or pharmaceutical compositions of the invention, for use in in the treatment of a disease or disorder. In some embodiments, the disease or disorder is amyloidosis. In some embodiments, the disease or disorder is systemic amyloidosis.

[0465] The present invention provides a method of treating a disease or disorder, the method comprising administering a therapeutically effective amount of an antibody or antibody binding portion thereof of the invention, or of the composition or pharmaceutical composition of the invention, to a subject in need thereof. In some embodiments, the disease or disorder is amyloidosis. In some embodiments, the disease or disorder is systemic amyloidosis. The present invention provides the use of an antibody or antibody binding portion thereof of the invention, or a composition or pharmaceutical composition of the invention, for use in the manufacture of a medicament for the treatment of a disease or disorder. In some embodiments, the disease or disorder is amyloidosis. In some embodiments, the disease or disorder is systemic amyloidosis.

[0466] T reatment may be any treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition or delay of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, cure or remission (whether partial or total) of the condition, preventing, delaying, abating or arresting one or more symptoms and / or signs of the condition or prolonging survival of a subject or patient beyond that expected in the absence of treatment. Treatment in humans may be preferred.

[0467] Treatment as a prophylactic measure (i.e. prophylaxis) is also included. For example, a subject susceptible to or at risk of the occurrence or re-occurrence of amyloidosis may be treated as described herein. Such treatment may prevent or delay the occurrence or re-occurrence of amyloidosis in the subject.

[0468] In particular, treatment may include inhibiting and / or reducing amyloid deposition, including complete amyloid deposition reversal.

[0469] Antibodies may be administered as described herein in therapeutically-effective amounts.

[0470] The term “therapeutically-effective amount” as used herein, pertains to that amount of an active compound, or a combination, material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0471] It will be appreciated that appropriate dosages of the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the administration. The selected dosage level will depend on a variety of factors including, but not limited to, the route of administration, the time of administration, the rate of excretion of the active compound, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of active compounds and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve concentrations of the active compound at a site of therapy without causing substantial harmful or deleterious side-effects.

[0472] In general, a suitable dose of the active compound is in the range of about 100 pg to about 250 mg per kilogram body weight of the subject per day. Where the active compound is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

[0473] Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals). Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the physician. Multiple doses of antibody may be administered, for example 2, 3, 4, 5 or more than 5 doses may be administered.

[0474] Other aspects of the invention

[0475] The present invention also provides one or more polynucleotide sequences encoding one or more sequences of the antibodies disclosed herein. The present invention also provides vectors (i.e. expression vectors) comprising one or more of the polynucleotide sequences disclosed herein. The present invention also provides host cells comprising one or more of the vectors or expression vectors disclosed herein.

[0476] In some embodiments, there is provided a polynucleotide sequence or pair of polynucleotide sequences encoding an antibody or antigen binding portion thereof of the invention.

[0477] In some embodiments, there is provided a polynucleotide sequence encoding a heavy chain variable region, a light chain variable region, a heavy chain or a light chain of an antibody or antigen binding portion thereof of the invention.

[0478] In some embodiments, there is provided a polynucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 755.

[0479] In some embodiments, there is provided a pair of polynucleotide sequences, wherein the first member of the pair encodes a heavy chain variable region of an antibody or antigen binding portion thereof of the invention, and the second member of the pair encodes a light chain variable region of an antibody or antigen binding portion thereof of the invention.

[0480] In some embodiments, there is provided a pair of polynucleotide sequences, wherein the first member of the pair encodes a heavy chain sequence of an antibody or antigen binding portion thereof of the invention and the second member of the pair encodes a light chain sequence of an antibody or antigen binding portion thereof of the invention.

[0481] In some embodiments, there is provided vector, in particular an expression vector, comprising a polynucleotide sequence or pair of polynucleotide sequences as disclosed herein. In some embodiments, there is provided a pair of expression vectors collectively comprising a pair of polynucleotide sequences as disclosed herein. The invention also provides a host cell comprising a polynucleotide sequence or pair of polynucleotide sequences as disclosed herein, or comprising a vector or expression vector or pair of vectors or expression vectors as disclosed herein, optionally wherein the host cell is a recombinant host cell. In some embodiments, the host cell is a host cell selected from the group consisting of a Chinese hamster ovary (CHO) cell and a HEK293 cell.

[0482] The present invention also provides methods for making the antibodies and antigen-binding fragments thereof disclosed herein.

[0483] In one embodiment, a method for producing an antibody or antigen-binding fragment thereof of the disclosure is provided, comprising culturing a host cell of the disclosure in a cell culture medium. In some embodiments, the method comprises culturing the host cell under conditions to allow for the production of the antibody or antigen-fragment thereof encoded by a vector or expression vector (or pair thereof) present in the host cell. In some embodiments, the methods comprise a step of isolating the antibody or antigen-binding fragment thereof from the culture medium. The method may comprise the further step of formulating the isolated antibody or antigen-binding fragment thereof with one or more pharmaceutically acceptable carriers, for example to provide a pharmaceutical composition. The present invention extends to antibodies or antigen-binding fragments thereof, and pharmaceutical compositions, obtained or obtainable by the methods disclosed herein.

[0484] Identity

[0485] Amino acid or nucleic acid sequences are said to be the same as or “identical” to other amino acid or nucleic acid sequences if they share 100% sequence identity over their entire length. Residues in sequences are numbered from left to right, i.e. from N- to C- terminus for polypeptides; from 5’ to 3’ terminus for polynucleotides. Changes (such as insertions, deletions or substitutions) in a second sequence as compared to a first sequence will result in reduced % sequence identity. An “insertion” is the addition of an amino acid or nucleic acid into the sequence of the first polypeptide or polynucleotide. A “deletion” is the removal of an amino acid or nucleic acid from the sequence of the first polypeptide or polynucleotide. A “substitution” is swapping one amino acid or nucleic acid residue in the first polypeptide or polynucleotide sequence with a different amino acid or nucleic acid residue in the second polypeptide or polynucleotide sequence. For example, if two identical sequences (100% sequence identity) are each 8 amino acids in length, then one substitution in the second sequence results in a reduced % sequence identity (87.5% identical). For example, if a first sequence differs from a second sequence by “a single amino acid change” this means that the second sequence has one amino acid substitution as compared to the first sequence, or the second sequence has had one amino acid inserted into the sequence compared to the first sequence, or the second sequence has had one amino acid deleted from the sequence compared to the first sequence. Nucleic acid molecules useful in the methods of the invention include any nucleic acid molecule that encodes a polypeptide of the invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. Nucleic acid molecules useful in the methods of the invention include any nucleic acid molecule that encodes a polypeptide of the invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having “substantial identity” to an endogenous sequence are typically capable of hybridizing with at least one strand of a doublestranded nucleic acid molecule. By “hybridize” is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol. 152:507).

[0486] For example, stringent salt concentration will ordinarily be less than about 750 mM NaCI and 75 mM trisodium citrate, preferably less than about 500 mM NaCI and 50 mM trisodium citrate, and more preferably less than about 250 mM NaCI and 25 mM trisodium citrate. Low stringency hybridization can be obtained in the absence of organic solvent, e.g., formamide, while high stringency hybridization can be obtained in the presence of at least about 35% formamide, and more preferably at least about 50% formamide. Stringent temperature conditions will ordinarily include temperatures of at least about 30° C, more preferably of at least about 37° C, and most preferably of at least about 42° C. Varying additional parameters, such as hybridization time, the concentration of detergent, e.g., sodium dodecyl sulfate (SDS), and the inclusion or exclusion of carrier DNA, are well known to those skilled in the art. Various levels of stringency are accomplished by combining these various conditions as needed. In a preferred: embodiment, hybridization will occur at 30° C in 750 mM NaCI, 75 mM trisodium citrate, and 1 % SDS. In a more preferred embodiment, hybridization will occur at 37° C in 500 mM NaCI, 50 mM trisodium citrate, 1% SDS, 35% formamide, and 100 .mu.g / ml denatured salmon sperm DNA (ssDNA). In a most preferred embodiment, hybridization will occur at 42° C in 250 mM NaCI, 25 mM trisodium citrate, 1% SDS, 50% formamide, and 200 pg / ml ssDNA. Useful variations on these conditions will be readily apparent to those skilled in the art.

[0487] For most applications, washing steps that follow hybridization will also vary in stringency. Wash stringency conditions can be defined by salt concentration and by temperature. As above, wash stringency can be increased by decreasing salt concentration or by increasing temperature. For example, stringent salt concentration for the wash steps will preferably be less than about 30 mM NaCI and 3 mM trisodium citrate, and most preferably less than about 15 mM NaCI and 1.5 mM trisodium citrate. Stringent temperature conditions for the wash steps will ordinarily include a temperature of at least about 25 °C, more preferably of at least about 42° C, and even more preferably of at least about 68 °C. In a preferred embodiment, wash steps will occur at 25° C in 30 mM NaCI, 3 mM trisodium citrate, and 0.1% SDS. In a more preferred embodiment, wash steps will occur at 42 °C in 15 mM NaCI, 1.5 mM trisodium citrate, and 0.1 % SDS. In a more preferred embodiment, wash steps will occur at 68° C in 15 mM NaCI, 1.5 mM trisodium citrate, and 0.1% SDS. Additional variations on these conditions will be readily apparent to those skilled in the art. Hybridization techniques are well known to those skilled in the art and are described, for example, in Benton and Davis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad. Sci., USA 72:3961 , 1975); Ausubel et al. (Current Protocols in Molecular Biology, Wiley Interscience, New York, 2001); Berger and Kimmel (Guide to Molecular Cloning Techniques, 1987, Academic Press, New York); and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York.

[0488] By “substantially identical” is meant a polypeptide or nucleic acid molecule exhibiting at least 90% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). Preferably, such a sequence is at least 91%, more preferably 92% or 93%, and more preferably 94%, 95%, 96%, 97%, 98% or even 99% and up to 100% identical at the amino acid level or nucleic acid to the sequence used for comparison.

[0489] In the foregoing embodiments, “at least 90%” is to be understood as 90% or more, optionally 91% or more, 92% or more, optionally 93% or more, optionally 94% or more, optionally 95% or more, optionally 96% or more, optionally 97% or more, optionally 98% or more, or optionally 99% or more, up to 100% identity with the recited SEQ ID. Sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e-3and e-100indicating a closely related sequence.

[0490] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50. Modifications of the above embodiments, further embodiments and modifications thereof will be apparent to the skilled person on reading this disclosure, and as such these are within the scope of the present invention.

[0491] All documents and sequence database entries mentioned in this specification are incorporated herein by reference in their entirety for all purposes.

[0492] The invention is further described below, with reference to the following examples.

[0493] EXAMPLES

[0494] Example 1 : Antibody 2E5 production

[0495] Antibody 2E5 was produced by immunisation of a SAP- / - mouse (Bickerstaff et al., Nat Med 1999 Jun;5(6):694-7) using a synthetic human ATTR amyloid fibril immunogen by a variation of the classic hybridoma approach, originally developed by Milstein and Koehler (Figure 1A).

[0496] ATTR fibrils in PBS were mixed with the adjuvant RIBI and injected at two-weekly intervals with 50 .g ATTR in week zero, followed by 25 .g ATTR in week two and 25 .g ATTR complexed with SAP in week 4.

[0497] This approach provided a range of monoclonal antibodies, including 2E5. ELISA screening confirmed specific binding to human ATTR fibrils but not to globular human TTR, the fibril precursor protein, or to mouse TTR (Figure 1 B). 2E5 also shows unprecedented specific binding to all the major types of human systemic amyloid (Figure 1 C) and to experimentally induced [Bodin, K., et al., Nature, 2010. 468(7320): p. 93-97, Botto, M., et al., Nature Med., 1997. 3(8): p. 855-859] mouse AA amyloid deposits (Figure 2A). The original 2E5 mouse monoclonal isotype was lgG2c, which is homologous to human lgG1 and potently complement activating. Complement activation is a necessary property for in vivo antibody-mediated amyloid removal which we have demonstrated to be complement dependent [Bodin, K., et al., Nature, 2010. 468(7320): p. 93-97, Richards, D.B., et al., N. Engl. J. Med., 2015. 373(12): p. 1106-1114, Milde, R., et al., Cell Rep., 2015. 13(9): p. 1937-1948], Indeed, administration of 2E5 to mice with established systemic AA amyloidosis, produced notable amyloid clearance (Figure 2B).

[0498] Example 2: Binding of 2E5 to the TTR peptide

[0499] Crystal structure data from 2E5 showed both malonate and citrate ions locating in the binding cleft of the antibody, adopting a structure which mimics the C-terminal structure of TTR polypeptides. In order to identify the epitope to which 2E5 binds, peptide truncation studies and alanine scans were preformed using an TTR peptide (99-127) previously shown to behave as an analogue for the full-length TTR protein.

[0500] Peptides were synthesised with a biotin-SGSG N-terminal tag, based on the human TTR sequence as follows: - huTTR 99-127

[0501] - huTTR 105-115

[0502] - huTTR 113-127

[0503] - huTTR 118-127

[0504] - huTTR 123-127

[0505] - huTTR 99-127 T123A

[0506] - huTTR 99-127 N124A

[0507] - huTTR 99-127 P125A

[0508] - huTTR 99-127 K126A

[0509] - huTTR 99-127 E127A

[0510] - huTTR 99-127 amidated C-Term

[0511] A stock solution (4mg / ml) of each peptide was prepared, dissolving 2mg of peptide in 500ul of:

[0512] - 50% acetonitrile

[0513] - 10% glacial acetic acid

[0514] - 40% H2O

[0515] The peptides were diluted to 10ug / ml in PBS for mapping using a bio-layer interferometry (BLI) biosensor.

[0516] 2E5-1 B7 antibody (murine lgG2a) was prepared by recombinant expression, and diluted to 40ug / ml in PBS for BLI

[0517] The binding of the antibody to each of the peptides was analysed by pre-soaking the streptavidin BLI biosensors for 10min in PBS + 0.1 % BSA, equilibrating the peptides and mAb to room temperature, and performing BLI measurement using a Blitz instrument (Blitz pro software), applying advanced kinetics as follows:

[0518] 1. 30sec baseline (PBS)

[0519] 2. 60sec Loading biotinylated peptide at 10ug / ml onto streptavidin biosensor

[0520] 3. 30sec baseline (PBS)

[0521] 4. 120sec Association, 2E5-1 B7 at 40ug / ml

[0522] 5. 120sec Dissociation in PBS A reference run was performed using huTTR 99-127 peptide at Step 2 (above), and association with PBS only at Step 4 (above).

[0523] Binding affinity data was calculated within the Blitz pro software, and the raw BLI trace data exported for plotting.

[0524] The results show that deletion of the C-terminus of the 99-127 peptide abolishes binding of the antibody to the peptide. Thus, whilst peptides 99-127, 113-127, 118-127 and 123-127 retain identical binding properties (Figure 4), the 105-115 truncation and 99-127 E127A failed to be bound by 2E5.

[0525] Moreover, amidation of the C-terminus and removal of the carboxyl group results in loss of binding, indicating that the charged nature of the acidic C-terminus is essential for binding.

[0526] Performing an alanine scan of the C-terminus (Figure 5) showed that T123A and N124A variants retained normal binding, but that binding was progressively reduced in P125A, K126A and E127A variants. Accordingly, binding of 2E5 to the TTR peptide is dependent on the presence of charged amino acids at the C-terminus of the protein fibril.

[0527] Example 3: 2E5 does not compete with SAP for binding to fibrils

[0528] In order to determine whether 2E5 and SAP bind to the same epitope in amyloid fibrils, a competition assay was conducted to assay binding of 2E5 at 0.01 .g / ml to 0.5 ig coated ATTR fibrils in the presence of SAP at a varying concentration of 0.08 to 50 pg / ml, and in the presence of an irrelevant control antibody. Antibody detection was conducted through the Fc domain using anti-mouse Fc HRP. 2E5 was found to bind to fibrils in a SAP-independent manner, indicating that SAP and 2E5 do not compete for the same epitope on ATTR fibrils.

[0529] The results are shown in Figure 6.

[0530] Example 4: CDR Grafting of 2E5

[0531] Initial CDR grafting experiments produced three humanised antibodies, as illustrated in table 4:

[0532] TABLE 4 Original 3 CDR grafts (Batch 1)

[0533] Antibodies 1-3 were tested by ELISA to determine binding to amyloid TTR fibrils in comparison to murine 2E5. All of the CDR-grafted antibodies showed about 100 fold decrease in binding. See Figure 7 A and B.

[0534] A sequence and structural analysis of 2E5 was performed, to identify the key residues responsible for providing structure to the CDRs in the murine framework. Key residues were identified and mutated back to murine residues. 20 humanised antibodies were generated, and tested by ELISA.

[0535] The results are shown in Figure 8.

[0536] Results were ranked as shown in Table 5.

[0537]

[0538] The 6 most promising antibodies show strong binding to fibrils, comparable to murine 2E5 (See

[0539] Figure 4). P029_Ab004, 006, 008, 016, 019 and 021 were selected for further development.

[0540] Example 5: Charge reduction in humanised antibodies

[0541] As shown in Table 6, the higher affinity humanised antibodies were associated with a high positive charge. In order to reduce this charge to a charge which is considered more suitable for pharmaceutical development, further modifications were carried out to the humanised clones, as shown in Table 7. This included removal of positively charged residues by substituting them with non-positively charged residues observed at high frequency in human antibodies. The addition of negatively charged residues was also employed to reduce overall positive charge. In addition to charge, mutations were made in isomerization sites to improve developability of the antibody in

[0542] CDR-H2 (Details described in Table 6).

[0543] Antibodies P029_Ab0019 and P029_Ab0008 were chosen as the base clones for modification.

[0544] Antibody Net charge across Fv

[0545] P029 Ab004 8

[0546] P029_Ab005 0

[0547] P029_Ab006 6

[0548] P029_Ab007 5

[0549] P029_Ab008 4

[0550] P029_Ab009 5

[0551] P029_Ab010 4

[0552] P029_Ab011 3 PO29_AbO12 5

[0553] P029_Ab013 5

[0554] P029_Ab014 2

[0555] P029_Ab015 3

[0556] P029_Ab016 7

[0557] P029_Ab017 6

[0558] P029_Ab018 8

[0559] P029_Ab019 7

[0560] P029_Ab020 5

[0561] P029_Ab021 6

[0562] PO29_AbO22 2

[0563] P029_Ab023 2

[0564] Table 6

[0565] Clone VL changes VH changes

[0566] Table 7 The results of the modification procedure are shown in table 8. Net charge was reduced to or below +4 in several instances. To determine whether the broad reactivity of 2E5 was maintained to different amyloid types following humanization, the interaction of the humanized clones to synthetic fibrils and native amyloid was determined by ELISA. This includes synthetic amyloid derived from the truncated fragment of immunoglobulin light chain (AL55-133) and mutant forms of the transthyretin protein (S52P TTR) and beta2-microglobulin (D76N Abeta2-m) as well as AA (Amyloid A) present in the spleen extract from mice. ELISA characterization confirmed that humanized 2E5 clones were able to interact with these amyloid forms in a dose-dependent manner (Fig 9).

[0567] Example 6: IMT1-191 has broad reactivity to different human amyloid types

[0568] Antibody 2E5 shows specific binding to all the major types of human systemic amyloid. To evaluate the conservation of the pan-fibril binding property after humanisation, the humanised 2E5 antibody clone P029_Ab019, referred to in this example as “IMT1-191” (meaning an antibody with the Fab region of P029_Ab019 and a wild type Fc region), was tested for its binding to various amyloid fibrils using ELISA and immunohistochemistry (IHC).

[0569] Briefly, different types of amyloid fibrils at 1 pg were coated on ELISA plates overnight followed by washing with 10 mM Tris, 140 mM NaCI and 2 mM CaCI2, pH 8.0 buffer (TC buffer). Thereafter wash steps were performed in TC buffer supplemented with 0.1 % Tween 20 and a final 250 mM concentration of salt (Wash buffer). IMT1-191 was incubated for 1 hour in 3 % milk, 0.1 % Tween 20 prepared in TC buffer (Blocking buffer). The plates were washed in Wash buffer prior to the addition of anti-human-Fc-HRP followed by chromogenic substrate solution TMB for signal detection at A450 nm using a spectrophotometer.

[0570] ELISA characterization confirmed that IMT1-191 bound in a dose-dependent manner to diverse types of amyloid fibrils, including in vitro assembled ATTR fibrils derived from recombinant transthyretin protein with the S52P mutation, in vitro assembled AL fibrils derived from the truncated fragment of recombinant immunoglobulin light chain (AL55-133), in vitro assembled Abeta2-m fibrils derived from recombinant beta2-microglobulin protein with the D76N mutation (D76N Abeta2-m), as well as in vitro assembled AIAPP fibrils derived from recombinant islet amyloid polypeptide, or amylin. No signal was detected in the control condition where no amyloid fibril was coated (Figure 10A-E).

[0571] To confirm the binding of IMT1-191 to native amyloids, binding of IMT1-191 to frozen unfixed human amyloidosis diseased tissues was determined using IHC. The Human-on-Human kit (Vector Labs) was used for staining human tissues with human antibodies according to manufacturer’s protocol. Briefly, the slides were defrosted and air-dried at room temperature. After blocking of endogenous peroxidase activity and a subsequent protein block, primary antibodies were applied at 1 pg / mL and 10 pg / mL using a kit-specific diluent mixture. Detection was performed using an HRP-conjugated secondary antibody used at 1 :50 followed by colorimetric detection using a DAB kit. Mayer’s haematoxylin was used for counterstaining. Adjacent sections were stained with alkaline alcoholic Congo red solution, a standard stain used to identify amyloid proteins in tissue samples. Slides were dehydrated, coverslipped using a non-aqueous mounting medium and imaged with a Qlmaging Retiga 2000R CCD camera on an Olympus BX50 microscope.

[0572] IHC characterization confirmed that IMT1-191 bound to wild type ATTR (ATTRwt) and hereditary ATTR (ATTRv) S77Y amyloid deposits in human heart tissues (Figure 11 A). Strong binding to a variety of different human amyloid types, including AApoAl and AL(A) in spleen, AFib in kidney and AA in liver was also observed (Figure 11 B). Staining of ALXN2220 (NI006) and coramitug (PRX004) (known anti-amyloid antibodies) to the same sets of amyloidotic tissues were also performed in parallel. ALXN2220 (NI006) and coramitug (PRX004) only showed binding to the ATTR tissues. While IMT1-191 and ALXN2220 (NI006) showed equivalent binding to ATTR deposits, coramitug (PRX004) appeared to have reduced binding to both ATTRwt and ATTRv (S77Y) deposits. Minimal binding signal was detected by ALXN2220 (NI006) and coramitug (PRX004) to other amyloid types in human tissues other than ATTR. These results demonstrated that IMT1-191 bound to a broad range of human amyloid fibrils, providing its key characteristic for drug development in multiple systemic amyloidosis. It is a unique property that antibodies that bind to a single amyloid target, such as ALXN2220 (NI006) and coramitug (PRX004), do not have.

[0573] Example 7: Binding characteristic of IMT1-191 and its variant to ATTR fibrils

[0574] The binding affinities of IMT1-191 (in this example meaning an antibody with the Fab region of P029_Ab019 and a wild type Fc region) and a sequence variant with a E430G substitution in the Fc domain, IMT1-191-1 (in this example meaning an antibody with the Fab region of P029_Ab019 and an engineered Fc region IMT1-191-1), to immobilised ATTR fibrils were determined by surface plasmon resonance (SPR) using Biacore T200. Briefly, ATTR S52P was immobilised on a biosensor chip through amine coupling. Binding kinetics were measured with the humanised antibodies at concentration ranges from 3.0 to 0.1 nM diluted in Phosphate- Buffered Saline (PBS) and injected at 50 .L / min over the biosensor chip for 5 min for on-rate (ka), followed by PBS only to determine the dissociation rate (kd). The equilibrium dissociation constant for the binding (KD) was derived from the Two State Reaction model using the Biacore T200 evaluation software version 3.2.1. The results showed that IMT1-191 and IMT 1-191-1 bound to in vitro ATTR fibrils with KD of 0.8 and 0.07 nM respectively (Table 9). The results demonstrated that, surprisingly, the Fc modification did not impact the binding to ATTR.

[0575] Further characterisation on the binding to different forms of TTR using ELISA as described in Example 6 showed that coramitug (PRX004) and ALXN220 (NI006) bound strongly to the pre- fibrillar recombinant TTR (rTTR) variants S52P in its amorphous aggregated form with EC50values of 0.04 nM and 0.4 nM, respectively. By contrast, IMT1-191 binding was reduced, and did not reach saturation when measured at an identical concentration range (Figure 12A). However, to ATTR S52P fibrils, IMT1-191 and Fc variants IMT1-191-1 , IMT1-191-4, IMT1- 191-5, IMT1-191-7 bound with EC50values ranging from 1.40 - 0.35 nM. By contrast, coramitug (PRX004) and ALXN2220 (NI006) had lower binding responses (Figure 12B). These results demonstrated the unique property of IMT1-191 to bind preferentially to ATTR_S52P fibrils over the pre-fibrillar S52P rTTR in its amorphous aggregated form. This property is thought to confer the advantage of the effective removal of ATTR fibrils.

[0576] Table 9: Binding of IMT1-191 and variants to immobilised ATTR_S52P fibrils

[0577] Example 8: Binding of IMT1-191 and variants to Fey receptors and C1q

[0578] Fc effector functions of antibodies can be optimised by engineering the Fc region to enhance the bindings to specific Fc receptors and / or C1q. The Fc mutation E430G introduced in IMT1- 191-1 (in this example meaning an antibody with the Fab region of P029_Ab019 and an engineered Fc region IMT1-191-1) is known to enhance binding to C1q. The Fc mutation S239E-I332E (SDIE) introduced in IMT1-191-2 (in this example meaning an antibody with the Fab region of P029_Ab019 and an engineered Fc region IMT1-191-2) is known to enhance binding to FcyRI (CD64), FcyRII (CD32) and FcyRIII (CD16). Two different ELISA methods were used to determine the binding of IMT1-191 and the variants to recombinant human Fey receptors (Gamma Proteins Ltd) and native C1 q (Complement Technologies). For Fey receptor interactions, the Fey receptors were biotinylated and diluted in Blocking buffer before being captured on Streptavidin coated plates. The plates were washed 3 times in Blocking buffer, then varying amounts of the biotinylated receptors (2.5 - 10.0 pug) were added and allowed to bind with Streptavidin for 2 hr. Thereafter, the plates were washed and antibodies added at concentrations that ranged between (10 iM - 0.01 nM). Bound antibodies were detected enzymatically using a Goat F(ab’)2 fragment specific to the heavy and light chain F(ab’)2 region of the test antibodies. For binding to C1q, the same assay regime was used as described for the complement activation assays in Example 9, where antibodies were allowed to bind first to coated ATTR_S52P before being exposed to 0.5 % human serum for 30 min at 37 °C. C1 q molecules bound to antibodies after incubation in human serum were then detected enzymatically using a secondary antibody to C1 q.

[0579] IMT1-191 and IMT1-191-2 bound to FcyRI (CD64) stronger than IMT1-191-1 , suggesting the E430G mutation reduced binding to FcyRI. IMT1-191 and variants bound stronger to FcyRI than PRX004 and NI006 at the same concentration of 0.01 nM (Figure 13). All monoclonal antibodies tested (1 .M) had similar binding to FcyRII (CD32a 167R, CD32a 167H and CD32b), except NI006 showing higher binding. For FcyRIII (CD16), the Fc mutation SDIE on IMT1-191-2 led to increased binding to the CD16a 176Val allotypic variant compared to other anti-ATTR antibodies at 10 nM. The binding of all tested anti-ATTR antibodies to CD16a 176Phe and CD16b were comparable. The signal of binding to C1 q by different monoclonal antibodies IMT1-191 , IMT1-191-2, PRX004, and NI006 was comparable to no antibody control. However, binding of IMT1-191-1 to C1q was significantly increased due to the E430G Fc mutation. The results confirmed that the E430G C1 q binding and SDIE FcyR binding enhancement mutations led to improved binding of IMT1-191-1 to C1q and IMT1-191-2 to FcyRIII (176Val), respectively.

[0580] Example 9: Complement activation of IMT1-191 and variants

[0581] It is hypothesized that the removal of amyloid by IMT1-191 is dependent on complement activation. Complement activation by antibodies leads to the deposition of C3b and C4b complement proteins in human serum. An ELISA-based assay was established to determine the complement activity. Briefly, a high density of either synthetic ATTR_S52P fibrils or pre- fibrillar forms of ATTR diluted in water at 20 .g / mL was coated on plates overnight at 37°C. The plates were washed and blocked as described in Example 6, prior to a 1-hour incubation with the tested primary antibodies at room temperature. The plates were washed again, and the sample primed by washing once with verinyl containing GVB++ (with Ca2+and Mg2+ions) buffer and then incubated with 0.5% human serum in the GVB++ buffer for 30 min prior to further washing. The deposition of C3b and C4b complement proteins in the incubated human serum were detected using their corresponding detection antibodies (Abeam: ab231078 or ab278018) at 1 |ig / mL in ELISA.

[0582] Upon binding to ATTR_S52P fibrils, IMT1-191 mediated the deposition of C3b and C4b through activation of the classical complement whereas PRX004 and NI006 showed much lower responses (Figure 14A and 14B). IMT1-191-1 and IMT1-191-12 have Fc mutations that improve binding for C1 q. These variants showed increased C3b and C4b depositions compared to IMT1-191 with the wildtype Fc, as well as IMT 1-191-2 that has the Fc mutations to improve FcyR binding (Figure 14C and 14D). Removal of the Fc effector function with the Fc silent mutation in IMT1-191- LALAPG resulted in significant reduction in the detections of C3b and C4b.

[0583] In the presence of the pre-fibrillar S52P rTTR, IMT1-191 and IMT1-191-1 did not mediate C3b deposition through complement (Figure 14E). Although PRX004 bound strongly to both pre- fibrillar S52P rTTR and ATTR_S52P fibrils (Example 7), it showed minimal complement activation. NI006 elicited low level of complement activation to the pre-fibrillar S52P rTTR and minimal activity to ATTR_S52P fibrils (Figure 14F).

[0584] These results showed that IMT1-191 and its variants, including IMT1-191-1 , had the unique property to selectively mediate complement activation on ATTR_S52P fibrils, but not on the amorphous aggregated pre-fibrillar S52P rTTR.

[0585] Example 10: Phagocytosis of amyloid by IMT1-191 and its variants

[0586] Prior work has shown the removal of amyloid deposits in vivo by antibodies is dependent on complement proteins C1q and 03 (Bodin, K., et al., 2010). To determine whether IMT1-191 and its variants could drive phagocytosis of ATTR_S52P fibrils and whether this effect could be enhanced with Fc modifications designed to improve effector functions, an in vitro assay was established to observe the phagocytosis of the labelled ATTR fibrils.

[0587] ATTR fibrils were labelled with pHrodo® Orange intracellular pH indicator (Sartorius UK Limited). Fibrils were characterised by Negative Stain cryo-EM for structural integrity after labelling. Phagocytosis can be tracked over time through fluorescence live imaging as the pHrodo label on the ATTR fibrils fluoresce in acidic intracellular environment once phagocytosed. Macrophages were generated from a monocytic cell line THP-1 (ATCC®). Monocytes were cultured in culture medium (RPMI-1640 ATCC® medium with Pen-Step antibiotics and 10 % Heat-Inactivated Foetal Bovine Serum) supplemented with 50 - 100 nM of Phorbol 12- myristate 13-acetate (PMA) in UpCell™ culture dishes (ThermoFisher Scientific) for 12-48 hr at 37 °C / 5% CO2. The PMA was removed from the culture dishes and adherent macrophages allowed to recover for 48 hr to obtain THP-1 macrophages in an ‘MO Like’ state. 20,000 macrophage cells were added to each well of a 384-well microplate and left to recover overnight at 37 °C / 5% CO2before being used in phagocytosis assays.

[0588] Antibodies were first incubated with ~ 40.0 ng of labelled ATTR_S52P fibrils and allowed to bind for 1 hr at 37 °C, 5 % CO2. After 1 hr, a 1 % final v / v of Normal Human Serum (Complement Technologies) was added to the Antibodies / ATTR protein mix to provide a source of complement, and antibodies were given 30 min at 37 °C, 5 % CO2to activate the classical complement pathway. The opsonised ATTR fibrils were subsequently presented to the THP-1 macrophages. Fluorescence images were captured using a live cell imaging IncuCyte system (Sartorius) every 20 min using a 20X objective and the images were processed using IncuCyte S3 software.

[0589] Live imaging of THP-1 macrophages showed that IMT1-191 (at 6 nM) accelerated the rate of phagocytosis of labelled ATTR fibrils when compared with an isotype control antibody and the baseline level of phagocytosis without antibody (Figure 15A). The effect of antibody concentration on phagocytosis was quantified by calculating the area under the curve (AUC) for fluorescence intensity over time at each antibody concentration. The time-window selected was based on the time taken for phagocytosis to reach saturation and was typically at 2 - 3 hr. The analysis revealed a clear concentration-dependent effect of IMT1-191 on phagocytosis, with increasing antibody concentrations resulting in higher AUC values (Figure 15B). The data fitted to a sigmoidal dose-response curve yielded an EC50value of 0.51 nM nanomolar, indicating a potent effect of antibody IMT1-191 on phagocytosis. The calculated AUC and EC50values of IMT 1-191 were comparable with another anti-TTR antibody, PRX004 (EC5O = 1.0 nM). Notably, the phagocytosis activity of the ALXN220 (NI006) antibody was comparable with the isotype control antibody, consistent with the reduced binding of this antibody to the in vitro ATTR_S52P fibrils (Figure 12B). Collectively, these results demonstrated that the accelerated phagocytosis of ATTR fibrils by antibodies was mediated through specific binding to the ATTR fibrils.

[0590] Testing the effect of Fc modifications showed that increasing the affinity of the IMT1-191 antibody for complement C1q protein (IMT1-191-1) increased phagocytosis potency (Figure 15C). This was reflected in a greater overall level of phagocytosis of labelled ATTR by THP-1 macrophages than either the IMT1-191 antibody or other anti-TTR antibodies PRX004 and NI006 that lack Fc modifications (Figure 15C and 15D). Reducing the effector functions of IMT1-191 through Fc silencing with LALAPG (IMT1-191-LALAPG) reduced phagocytosis activity to a level comparable with the isotype control IgG.

[0591] To investigate if the phagocytosis activity of IMT1-191 and IMT1-191-1 antibodies was dependent on C1 q, phagocytosis was compared in conditions with either Normal Human Serum (NHS) or human serum with C1q depleted. The results showed that when C1q was depleted from the human serum, the phagocytosis activity of both antibodies was significantly reduced to a level comparable with the Fc effector function-disabled IMT1-191-LALAPG (Figure 15E and 15F). These results show that phagocytosis is dependent on the Fc domain of antibodies and 01 q, and that the potency could be enhanced through Fc modifications, in particular modifications that increase affinity for 01 q.

[0592] Example 11 : Cross-reactivity of IMT1-191 and its variant to mouse AA amyloid

[0593] Antibody 2E5 shows specific binding to experimentally induced mouse AA amyloid deposits. To evaluate the conservation of mouse AA amyloid cross-reactivity after humanisation, IMT1- 191 and IMT1-19-391 were tested for the binding to mouse AA amyloid using ELISA and I HO.

[0594] Briefly, for the ELISA, AA amyloid fibrils extracted from amyloidotic mouse spleens were diluted in water and coated on 96-well microplates at 37°C overnight. Plate was blocked for 2 hours in Tris-calcium buffer (10 mM Tris, 140 mM NaCI, 2 mM CaCI2, pH 8.0) with 3% milk and 0.1 % Tween 20 at room temperature. Primary antibodies were titrated in same buffer and incubated for 1 hour at room temperature. Primary antibodies were detected by HRP- conjugated anti-human IgG Fey secondary antibody, followed by TMB substrate. Absorbance was measured at 450 nm using a spectrophotometer.

[0595] For IHC, the Human-on-Human kit (Vector Labs) was used for staining mouse tissues with human antibodies according to manufacturer’s protocol. Briefly, the slides were defrosted and air-dried at room temperature. After blocking of endogenous peroxidase activity and a subsequent protein block, primary antibodies were applied 10 pg / mL using a kit-specific diluent mixture. Detection was performed using an HRP-conjugated secondary antibody used at 1 :25 followed by colorimetric detection using a DAB kit. Mayer’s haematoxylin was used for counterstaining. Adjacent sections were stained with alkaline alcoholic Congo red solution. Slides were dehydrated, coverslipped using a non-aqueous mounting medium and imaged with a Qlmaging Retiga 2000R CCD camera on an Olympus BX50 microscope. ELISA characterization confirmed that IMT1-191 and I MT1- 19-391 (also named P029_Ab019- 39) bound in a dose-dependent manner to isolated AA fibrils extracted from amyloidotic mouse spleens. No signal was detected in the control condition where no amyloid fibril was coated (Figure 16A).

[0596] To confirm the binding of IMT1-191 to native amyloids, binding of IMT1-191 to frozen unfixed mouse AA amyloidotic tissues was determined using IHC. IHC characterization confirmed that IMT1-191 showed cross reactivity to mouse AA amyloidotic tissues in spleen and liver (Figure 16B). Staining of ALXN2220 (NI006) and coramitug (PRX004) to the same sets of amyloidotic tissues were also performed in parallel. No staining was shown by ALXN2220 (NI006) and coramitug (PRX004) to mouse AA tissues (Figure 16C). The results of cross-reactivity of IMT1- 191 and IMT1-19-391 support the use of a mouse AA in vivo model for proof-of-concept studies described in Example 12.

[0597] Example 12: In vivo efficacy study IMT1-191 and variants in mouse AA amyloid model

[0598] To determine the efficacy of IMT1-191 in removing AA amyloid from the liver of mice, in vivo studies were performed. In addition, the effect of modifications to the Fc region of IMT1-191 was also assessed in vivo to determine if efficacy is increased by modifications that enhance complement activation or Fey receptor mediated phagocytosis.

[0599] For induction of AA amyloidosis, 10- to 12-week-old female C57BL / 6 mice were randomly assigned to groups of 12 mice. On day 1 , mice were intravenously infused with 0.2 ml of crude homogenate from amyloid-loaded spleens containing preformed AA amyloid fibrils (i.e. AEF, Amyloid Enhancing Factor). Mice then received a subcutaneous injection of 0.4 ml of casein (10% w / v solution in 0.05M NaHCO3). On days 2-5 and 8-12, mice received additional subcutaneous injections of 0.4 ml of casein. After the induction of AA amyloidosis, on day 26, animals were injected intraperitoneally with antibodies and monitored for welfare until day 54 when the animals were sacrificed by cervical dislocation. The liver, spleen, kidney and heart were dissected out and fixed in 10% neutral buffered formalin for at least 24 hours. Fixed tissues were then dehydrated, embedded in paraffin blocks and sectioned at 6 pm thickness. For the histochemical staining tissue sections were deparaffinised, rehydrated and stained with Mayer’s haematoxylin (counterstain) followed by alkaline alcoholic Congo red solution. Slides were dehydrated and coverslipped using a non-aqueous mounting medium. Stained tissue sections were then examined using a cross-polarised light microscope and the applegreen birefringence of the Congo-red stained amyloid was scored separately by two scientists with extensive knowledge of the model and scoring system. These scientists were blinded to the experiments groups to which the samples belonged. The induction of the AA amyloid model resulted in the deposition of amyloid in the liver of mice. This amyloid was depleted from the liver by IMT1-191. The E430G modification in the Fc region of IMT-191-1 increased the ability to activate complement as shown in Example 9. This E430G modification resulted in a modest improvement in the depletion of amyloid when compared to IMT1-191 treated mice (Figure 17). The S293D / I332E (SDIE) modification in IMT1-191-2 enhanced affinity to Fey receptors, increasing macrophage mediated phagocytosis of amyloid fibrils. This SDIE modification led to modest improvements over IMT1-191 and IMT1-191-1 in amyloid removal from the liver of mice with AA amyloidosis. All other tested modifications, despite comparable binding to immobilised ATTR fibrils in vitro, resulted in reduced removal of amyloid from the liver. IMT1-191-LALAPG is Fc effector function disabled. The loss of amyloid removal after this modification confirmed that the Fc effector functions including complement activation and Fey receptor binding are essential for the removal of amyloid.

[0600] Table 10: Modifications to IMT1-191 Fc and their potential effects on IMT1-191 effector function Example 13 - Specific binding of IMT1-191 and its variants to patient-derived ex vivo amyloids by IHC and ELISA

[0601] IMT1-191 has broad reactivity to different human amyloid types. To further evaluate its specificity and reactivity to different types of human amyloid, IMT1-191 (in this example meaning an antibody with the Fab region of P029_Ab019 and a wild type Fc region) and IMT1- 191-1 (in this example meaning an antibody with the Fab region of P029_Ab019 and an engineered Fc region IMT1 -191-1) were tested for their binding to a broad panel of amyloidotic tissues from amyloidosis patients and non-amyloidotic tissues from individuals free from amyloidosis.

[0602] Briefly, unfixed frozen 6-pm tissue sections were thawed at room temperature and briefly rehydrated in Tris-NaCI buffer with CaCI2(TC buffer). Endogenous peroxidase activity was quenched using BLOXALL Endogenous Blocking solution (#SP-6000, Vector Laboratories). Sections were washed for 5 min in TC buffer and incubated for 20 min at room temperature in Protein Block (#HOH-3000, Vector Laboratories). Antibody solutions (prepared according to #HOH-3000) were applied at a final concentration of either 1 pg / mL or 10 pg / mL to the sections and incubated for 60 min at room temperature. After the sections were washed for 2 x 5 min in TC buffer, HRP labelled anti-goat IgG diluted 1 / 50 (#HCH-3000, Vector Laboratories) was added to the sections and incubated for 13 min at room temperature. Sections were washed for 2 x 5 min in TC buffer and antibody staining was visualised with DAB substrate (#HCH-3000, Vector Laboratories). Sections were counterstained with Mayer’s haematoxylin (#51275, Sigma) and adjacent sections were stained with Congo red (Puchtler’s method). Sections were mounted with DPX mounting medium (#06522, Sigma) and slides were imaged using a Leica DM LB fluorescence microscope equipped with a Infinity 2 camera.

[0603] Strong binding was observed for IMT1-191 and IMT1-191-1 used at 1 pg / mL to tissue sections from wild-type and several variant forms of ATTR amyloidosis patients (Figure. 21 and 22). Apart from the heart tissue which was analysed for all six cases, spleen tissue was further tested for two cases with a variant form of ATTR amyloidosis. In addition to ATTR amyloid, IMT1-191 and IMT1-191-1 also bind to amyloid deposits in various tissues of six human AL amyloidosis patients at a concentration of 10 pg / mL (Figure. 23 and 24). Moreover, IMT1-191 and IMT1-191-1 bind to a wide range of different human amyloid types, including AApoAl, AA, Ap2M, AFib, and AGel (Figure. 25). Importantly, IMT1-191 and IMT1-191-1 do not bind to non- amyloidotic liver and heart tissue from individuals free from amyloidosis (Figure. 26). To ensure that data generated using in vitro generated amyloid fibrils was representative of natural amyloid fibrils, ATTR fibrils were obtained from a human heart following transplant surgery. Binding characterisation to collagenase extracted ex vivo cardiac ATTRwt (Figure. 27A and B) was determined by ELISA. Briefly, the amount of protein in the extract sample was determined by bicinchoninic acid assay (BCA), then diluted in water and a 2 pg amount applied to each well of a 384-well microplate. The extract was allowed to dry to the plate overnight at 37 °C to immobilise the amyloid. After blocking the plate in 3 % dried milk prepared in TrisCalcium buffer supplemented with 0.1 % Tween 20 solution for a minimum of 1 hr, antibodies are added and given 1 hr to bind prior to washing the plate to remove unbound antibodies. The antibodies remaining bound were detected through their Fc domain by using an antihuman IgG Fey secondary antibody.

[0604] Clear binding was observed for IMT1-191 and IMT1-191-1 to coated ex vivo ATTRwt at both 100 nM, 1 pM and 10 pM concentrations. Furthermore, both antibodies were noticeably more reactive than the Coram itug / PRX004 antibody and an isotype control antibody with no reported reactivity to ATTR (Figure. 27), supporting observations in Example 6 that Coramitug / PRX004 was less sensitive to ATTR assessed by IHC. These results demonstrate antibodies of the invention bind to both ex vivo ATTRwt fibrils as well as in vitro generated fibrils, with clear implications for their use in treating patients.

[0605] To test whether IMT1-191 could activate complement when bound to the ex vivo amyloid extract, antibodies were allowed to bind as before, but were subsequently incubated with 1 % Normal Human Serum for 30 min. The plates were washed to remove soluble proteins and complement activation detected using a mouse monoclonal antibody (clone 7C12) specific to C3b (abeam, ab231078). The results show that increased C3b was deposited on the cardiac ATTRwt extract after opsonization with IMT1-191 as compared with the Coramitug / PRX004 antibody and isotype control, respectively. Furthermore, IMT1-191-1 showed a clear increase in the amount of C3b deposited on ex vivo cardiac ATTRwt extract compared with IMT1-191 , Coramitug / PRX004, and the isotype for all concentrations tested.

[0606] Example 14 - Pre-fi brillar aggregates interference studies in binding and phagocytosis

[0607] During amyloid formation, the native TTR protein unfolds and aggregates to drive fibril growth. IMT1-191 (in this example meaning an antibody with the Fab region of P029_Ab019 and a wild type Fc region) and its variants have preferential binding to end-stage amyloid fibrils over intermediate amorphous aggregate species as described in Example 7. This unique property is crucial in targeting the pathological species of amyloids for removal when administered in the body to avoid the sink effect caused by the circulating pre-fibrillar aggregates or off- pathway misfolded forms of TTR.

[0608] To mimic a physiological environment whereby antibodies may encounter pre-fibrillar aggregates prior to exposure to amyloid in tissues, antibodies were incubated with aggregates before adding to the TH P-1 macrophage in vitro culture for the ATTR fibrils phagocytosis assays. Briefly, antibodies were incubated with 10 pg / mL of pre-fibrillar aggregated rTTR (S52P variant) protein (Figure. 28A) before adding in vitro ATTR fibrils labelled with pHrodo(Orange) dye (Sartorius, 4766) to detect phagocytosis by THP-1 macrophages (Figure. 28B). The results show that while both IMT1-191-1 (in this example meaning an antibody with the Fab region of P029_Ab019 and an engineered Fc region IMT1-191-1) and Coramitug / PRX004 had comparable phagocytosis at low nanomolar concentrations in the absence of aggregates, the activity of PRX004 was substantially reduced in the presence of aggregates as compared with IMT1-191-1 (Figure 28C-E).

[0609] To investigate if the differences in phagocytosis activity were induced by the binding interference to ATTR fibrils by the pre-fibrillar rTTR aggregates, the binding of antibodies to coated ATTR was compared in the presence and absence of 0.5 pg (at 10 pg / mL) rTTR aggregates at a 1 :1 ratio by weight to the coated ATTR using ELISA. Consistent with its reduced phagocytosis activity, binding was most reduced for Coramitug / PRX004 in the presence of aggregates, whereas IMT1-191 and IMT1-191-1 showed no binding interference in the presence of aggregated rTTR. (Figure 28F-I). Potency and phagocytosis of antibodies of the invention is therefore superior to other known antibodies in the presence of aggregates, which is a good indicator of performance in vivo.

[0610] Collectively, these results confirm that the conformationally selective binding of the IMT1-191 variable region is beneficial in binding and facilitating the phagocytosis of ATTR fibrils by THP- 1 macrophages in the presence of aggregates of TTR and demonstrates the antibodies of the invention display preferential binding to amyloid fibrils over pre-fibrillar aggregate species.

[0611] Example 15 - IMT1-191 induces phagocytosis of ATTR by primary macrophage and MGC

[0612] In vivo, the removal of amyloid deposits by the immune system is associated with the formation of macrophages and multi-nucleated giant cells (MGCs) around the amyloid deposits (Fontana et al., NEJM, 2023). To test whether IMT1-191 (in this example meaning an antibody with the Fab region of P029_Ab019 and a wild type Fc region) and it’s variants such as IMT1-191-1 (in this example meaning an antibody with the Fab region of P029_Ab019 and an engineered Fc region IMT1 -191-1) can drive the phagocytosis of amyloid by physiologically relevant immune cells, macrophages and MGCs were produced in vitro from frozen monocytes (Cambridge bioscience, CAT: MONF05-14P) to make the experiment as close to physiological as possible.

[0613] Briefly, monocytes were recovered in Minimum Essential Medium (MEM) supplemented with non-essential amino acids and 35 ng / mL of recombinant macrophage colony stimulating factor (Sartorius; CYK-0100-0031) referred to herein as differentiation medium and cultured in a glass chamber slide system (ThermoFisher; 177372PK). Monocytes were given 3 days to differentiate into macrophages prior to non-adherent cells being washed from the vessel surface. The differentiated macrophages were incubated for a further 4 days in differentiation medium supplemented with 7 ng / mL of recombinant lnterleukin-4 (IL-4) cytokine (Sartorius; CYK-0100- 1006) to drive fusion.

[0614] The final culture contained a mix of MGCs and single macrophage cells (Figure. 29A). Tracking phagocytosis of ATTR labelled with pHrodo(Orange) by the mixed macrophage / MGC cultures in the presence of antibody showed a clear acceleration of phagocytosis for the IMT1- 191 , IMT1-191-1 , and Coramitug / PRX004 antibodies compared with the isotype control antibody. Quantification of the phagocytosis activities by measuring the Area Under the Curves (AUCs) showed a concentration dependent increase in phagocytosis for all antibodies, with phagocytosis most enhanced by IMT1-191-1 (Figure. 29B-F).

[0615] When macrophages cannot efficiently clear large targets individually, they fuse to form MGCs, which have enhanced capacity for phagocytosis and extracellular digestion of large deposits due to their large size and increased membrane surface area. Without being bound by theory, we hypothesise that the selectivity of antibodies of the invention (such as IMT1-191) for fibrils and its activation of the relevant mechanism of action, namely complement activation to harness the enhanced phagocytic activity of MGCs toward complement-opsonized targets compared to single macrophages (Milde et al., Cell Reports, 2015), will translate to phagocytic advantage in the clearance of amyloid fibrils, especially with increased amyloid burden.

[0616] To test the above hypothesis and to differentiate between antibodies that activate complement (such as antibodies of the invention) and those that do not activate complement or having only weak activation (PRX004 or NI006), higher burden amyloid fibrils should be generated by conjugating ATTR fibrils to large microparticles using beads. Beads of 12 mm size or larger (to mimic heavy ATTR deposition) are then added to the phagocytosis assay described above with MGCs. The strong potency of phagocytosis of ATTR induced by antibodies of the invention (such as IMT1-191 and IMT1-191-1 and other variants) will be further enhanced under conditions of greater amyloid burden and appropriate cellular activities involving MGCs due to their abilities to activate complement, whereas the competitor antibodies will not. Example 16 - Antibody optimisation and characterisation

[0617] Selected amino acid substitutions were incorporated to optimise antibodies of the invention, for example to derisk potential sequence liabilities and improve developability of the antibody. Antibodies IMT1-191 (in this example meaning an antibody with the Fab region of P029_Ab019 and a wild type Fc region) and IMT1-191-1 (in this example meaning an antibody with the Fab region of P029_Ab019 and an engineered Fc region IMT1-191-1) were used as the base clones for modification.

[0618] Table 12: Table of optimised sequences with amino acid substitutions

[0619] To characterise the binding to ATTR fibrils of the optimised sequences, a panel of antibodies optimised with single, double or triple amino acid residue substitutions were screened (Table 12).

[0620] Antibodies were tested on 0.5 pg coated ATTR fibrils by ELISA as described in Example 13, and compared with antibodies IMT1-191 and IMT1-191-1.

[0621] The binding profiles of the antibodies with double substitutions, including IMT1-461 , IMT1- 471 , IMT1-491 , IMT1-501 , IMT1-511 was comparable and at least as strong when compared to the parent antibody, suggesting that the point mutations do not affect the binding of the antibody to ATTR fibrils (Figure. 30). Furthermore, it was surprisingly found that IMT1-521 and IMT1-521-1 with triple amino acid modifications (M39I, D57E, D62E), including a double substitution within CDRH2, showed no differences in binding to ATTR compared with IMT1- 191 and IMT1-191-1 (Figure. 31A).

[0622] Next, to test whether IMT1-521 (in this example meaning an antibody with the Fab region of P029_Ab052 and a wild type Fc region) and IMT1-521-1 (in this example meaning an antibody with the Fab region of P029_Ab052 and an engineered Fc region IMT1-191-1) can activate complement when bound to ATTR fibrils, antibodies were allowed to bind to the fibrils first prior to being incubated with 0.5% human serum for 30 min at 37 °C. The deposition of C3b complement proteins in the incubated human serum was detected using an anti-C3b detection antibody (abeam; ab231078) at 1 pg / mL. The results showed that the deposition of C3b was similar between antibodies IMT1-521 and IMT1-191 , as well as between IMT1-521-1 and IMT1-191-1 (Figure. 31 B). Furthermore, a slight increase in deposited C3b was observed for antibodies IMT1-191-1 and IMT1-521-1 over IMT1-191 and IMT1-521. IMT1-521 and IMT1- 521-1 were tested against other anti-ATTR antibodies for ATTR binding and ATTR-mediated complement activation (Figure. 31C and D). While the binding of IMT1-521 and IMT1-521-1 was comparable to coramitug (PRX004), both antibodies showed significantly stronger binding than ALXN2220 (NI006). Furthermore, both IMT1-521 and IMT1-521-1 show a significant increase in the deposition of C3b compared with coramitug (PRX004) and ALXN2220 (NI006).

[0623] Last, to characterise the protein expression and purity of the optimised antibodies, they were expressed transiently in the Chinese Hamster Ovary (CHO) cell line at a 100 mL scale and purified by protein A affinity chromatography. Comparing the protein production yields of the sequence optimised antibodies IMT1-521 and IMT1-521-1 with IMT1-191 and IMT1-191 -1 showed that IMT1-521 and IMT1-521-1 clones had higher yields, demonstrating that the optimisation improved protein expression. Additionally, antibodies exhibited high purity at concentrations >10 mg / mL as determined by SDS-PAGE and size exclusion chromatography (Table 13).

[0624] Table 13: Protein expression yield and purity of sequence optimised monoclonal antibodies

[0625] Taken together, these results show that antibodies with optimised sequences IMT1-521 and IMT1-521-1 have a trio of advantageous properties. Firstly, they maintain comparable binding to ATTR fibrils as parent antibodies IMT1-191 and IMT1-191-1 , even though residues in the CDR regions have been altered. Secondly they also have the additional advantageous ability of activating complement. Thirdly, they have an advantageous manufacturing profile, with higher protein production yields than parent antibodies.

[0626] Sequence Listing

[0627] The following table (Table 11) provides a summary of the SEQ ID NOs as provided in the ST26 sequence listing and the accompanying Figures. In the case of any discrepancy between the sequences in the sequence listing and those in Figures 18 to 20, the sequences in the Figures should prevail.

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

Claims

1. Claims1. An isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils; and the Fc region is an engineered Fc region.

2. An isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to at least 3 different types of amyloid fibrils, selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils; and the Fc region is an engineered Fc region.

3. An isolated monoclonal antibody or antigen binding portion thereof according to claim 1 or 2, which binds to at least 4, 5, 6, 7, 8, 9, 10 or 11 different types of amyloid fibrils, selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils.

4. An isolated monoclonal antibody or antigen binding portion thereof according to claim 3, which binds to at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils.

5. An isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region specifically binds to amyloid fibrils and wherein: a. each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of i. A sequence having a sequence identity of at least 75% with SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively; or ii. the sequence of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively, each optionally comprising a single or double amino acid change; and / or b. each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of i. a sequence having a sequence identity of at least 87% with SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively; or ii. the sequence of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 , respectively, each optionally comprising a single amino acid change; and the Fc region is an engineered Fc region.

6. The isolated monoclonal antibody or antigen binding portion thereof of any previous claim, wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

7. The isolated monoclonal antibody or antigen binding portion thereof of any previous claim, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ I D No 6, SEQ I D No. 738 and SEQ I D NO. 8 respectively.

8. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 4 to 6, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ I D No 6, SEQ I D No. 738 and SEQ I D NO.8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

9. An isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region specifically binds to amyloid fibrils and wherein: a. each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of i. A sequence having a sequence identity of at least 87% with SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively; or ii. the sequence of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8, respectively, each optionally comprising a single amino acid change; and / or b. each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of i. a sequence having a sequence identity of at least 87% with SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively; or ii. the sequence of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 , respectively, each optionally comprising a single amino acid change; and the Fc region is an engineered Fc region.

10. The isolated monoclonal antibody or antigen binding portion thereof of claim 39 whereina. each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequence of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively, each optionally comprising a single amino acid change, and CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequence of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively, each optionally comprising a single amino acid change; or b. each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of a sequence having a sequence identity of at least 87% with SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively and CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain have a sequence identity of at least 87% with SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

11. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 or10, wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

12. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to11 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively.

13. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to12, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

14. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 11 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 82, SEQ ID No 83 and SEQ ID No 84 respectively.

15. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to11 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavychain comprises or consists of the sequences of SEQ ID No 6 , SEQ ID No 7 and SEQ ID No 85 respectively.

16. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 11 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6 , SEQ ID No 86 and SEQ ID No 8 respectively.

17. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 11 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6 , SEQ ID No 87 and SEQ ID No 8 respectively.

18. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 11 or 14, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 82, SEQ ID No. 83 and SEQ ID NO. 84 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ I D No 9, SEQ I D No. 10 and SEQ ID NO. 11 respectively.

19. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 11 or 15, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 85 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ I D No 9, SEQ I D No. 10 and SEQ ID NO. 11 respectively.

20. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 11 or 16, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 86 and SEQ I D NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

21. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 11 or 17, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 87 and SEQ I D NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domainof the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

22. The isolated monoclonal antibody or antigen binding portion thereof of any of claims 9 to 17 wherein the heavy chain variable region comprises or consists of a sequence having a sequence identity of at least 70% with SEQ ID No. 2 and / or the light chain variable region comprises or consists of a sequence having a sequence identity of at least 70% with SEQ ID No. 4.

23. An isolated monoclonal antibody or antigen-binding fragment thereof according to any preceding claim, which a. binds to an epitope present in the amyloid fibril but does not bind to the native peptide from which the fibril is formed; and / or b. has preferential binding to amyloid fibrils over pre-fibrillar aggregate species; and / or c. does not bind to A fibrils present in the CNS and / or the brain in patients with Alzheimer’s disease; and / or d. does not compete with SAP for binding to fibrils.

24. An isolated monoclonal antibody or antigen-binding fragment thereof according to claim 23, wherein the epitope is present in at least 3 amyloid fibrils selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, A 2m, AGel, AIAPP and AFib amyloid fibrils.

25. An isolated monoclonal antibody or antigen-binding fragment thereof according to claim 23 or claim 24, wherein the epitope comprises the C-terminus of the fibril.

26. An isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 23 to 25, wherein the epitope comprises at least one charged amino acid.

27. An isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 23 to 26, wherein the epitope comprises a C-terminal carboxyl group.

28. An isolated monoclonal antibody or antigen-binding fragment thereof according to any one of claims 23 to 27, wherein a citrate ion and / or a malonate ion can be located within the antibody binding site when examined by x-ray crystallography.

29. The isolated monoclonal antibody or antigen binding portion thereof according to any preceding claim wherein the antibody is selected from an IgG, IgA, or an antigen binding antibody fragment selected from a Fab, F(ab’)2, an scFv, an Fv, or a disulfide-bonded Fv, a human antibody, a chimeric antibody preferably containing a human variable region, a humanized antibody, or a bispecific antibody.

30. The isolated monoclonal antibody or antigen binding portion thereof according to any previous claim, wherein the antibody is a humanised antibody.

31. The humanised antibody of claim 30, wherein each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

32. The humanised antibody of any of claims 30 or 31 , wherein each of CDRHI , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8 respectively.

33. The humanised antibody of any of claims 30 to 32, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 738 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

34. The humanised antibody of any of claims 30 or 31 , wherein each of CDRHI , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 8 respectively.

35. The humanised antibody of any of claims 30 to 31 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ I D No 6, SEQ I D No. 7 and SEQ I D NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

36. The humanised antibody of any of claims 30 to 31 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 82, SEQ ID No 83 and SEQ ID No 84 respectively.

37. The humanised antibody of any of claims 30 to 31 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6 , SEQ ID No 7 and SEQ ID No 85 respectively.

38. The humanised antibody of any of claims 30 to 31 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6 , SEQ ID No 86 and SEQ ID No 8 respectively.

39. The humanised antibody of any of claims 30 to 31 , wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6 , SEQ ID No 87 and SEQ ID No 8 respectively.

40. The humanised antibody of any of claims 30 to 31 or 36, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 82, SEQ ID No. 83 and SEQ ID NO. 84 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

41. The humanised antibody of any of claims 30 to 31 or 37, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 7 and SEQ ID NO. 85 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

42. The humanised antibody of any of claims 30 to 31 or 38, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 86 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

43. The humanised antibody of any of claims 30 to 31 or 39, wherein each of CDRH1 , CDRH2 and CDRH3 in the variable domain of the heavy chain comprises or consists of the sequences of SEQ ID No 6, SEQ ID No. 87 and SEQ ID NO. 8 respectively and each of CDRL1 , CDRL2 and CDRL3 in the variable domain of the light chain comprises or consists of the sequences of SEQ ID No 9, SEQ ID No. 10 and SEQ ID NO. 11 respectively.

44. A humanised monoclonal antibody according to any of claims 30 to 43, wherein the human framework regions are derived from antibody genes selected from SEQ ID Nos. 12 and 13.

45. A humanised monoclonal antibody according to any one of claims 30 to 44, wherein the framework residues mutated to match murine residues include residues are selected from VL residues I2, E17, L39, A40, Q44, A49, V101, N66, T85, F87 and E97 and residues selected from VH residues F37, M39, D57, A80, L55, I66, V25, D85, E69, A45, P46, G47, K48, Y108 and N111 (IMGT numbering).

46. A humanised monoclonal antibody according to any one of claims 30 to 45, wherein the VH region comprises the mutations L55K and I66K.

47. A humanised monoclonal antibody according to any one of claims 30 to 45, wherein the VH region comprises the mutations M39I, D57E and / or D62E.

48. A humanised monoclonal antibody according to any one of claims 30 to 45, wherein the VH region comprises the mutations: a. M39I; b. D57E; c. D62E; d. D57E and D62E; e. M39I and D57E; f. M39I and D62E; or g. M39I and D57E and D62E.

49. A humanised monoclonal antibody according to any one of claims 30 to 48, which comprises a combination of light and heavy chain framework mutations comprising: a. light chain framework mutations consisting of I2K, L39M, A40Y and N66K and heavy chain framework mutations consisting of M39I, L55K, I66K and E69P; b. light chain framework mutations consisting of I2K, A40Y, N66K, T85N and F87Y and heavy chain framework mutations consisting of L55K, I66K, V25A, D85N and E69P; c. light chain framework mutations consisting of I2K, L39M, A40Y, N66K, T85N and F87Y and heavy chain framework mutations consisting of M39I, A80T, L55K, I66K, E69P, A45R, P46T, G47E and K48Q;d. light chain framework mutations consisting of I2K, A40Y, N66K, T85N and F87Y and heavy chain framework mutations consisting of M39I, A80T, L55K, I66K, V25A, D85N and E69P; e. light chain framework mutations consisting of I2K, L39M, A40Y and N66K and heavy chain framework mutations consisting of L55K, I66K, and E69P; f. light chain framework mutations consisting of A40Y and heavy chain framework mutations consisting of L55K, I66K, V25A, D85N and E69P; g. light chain framework mutations consisting of A40Y and heavy chain framework mutations consisting of L55K and I66K; h. light chain framework mutations consisting of I2K, L39M, A40Y and N66K and heavy chain framework mutations consisting of F37R, L55K, D57L, I66K, E69P, Y108V; i. light chain framework mutations consisting of I2K, E17K, L39M, A40Y, N66K and E97K and heavy chain framework mutations consisting of L55K, I66K, and E69P; j. light chain framework mutations consisting of I2K, E17R, L39M, A40Y, N66K and E97R and heavy chain framework mutations consisting of L55K, I66K, and E69P; k. light chain framework mutations consisting of I2K, E17K, L39M, A40Y, N66K and E97K and heavy chain framework mutations consisting of L55K, I66K, E69P and N111R; or l. light chain framework mutations consisting of I2K, E17R, L39M, A40Y, N66K and E97R and heavy chain framework mutations consisting of L55K, I66K, E69P and N111R.

50. A humanised monoclonal antibody according to claim 30 to 49, wherein: a. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 14 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 15; b. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 16 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 17; c. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 18 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 19; d. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 20 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 21;e. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 22 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 23; f. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 24 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 25; g. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 26 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 27; h. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 28 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 29; i. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 30 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 31; j. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 32 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 33; k. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 34 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 35; l. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 36 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 37; m. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 38 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 39; n. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 40 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 41; o. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 42 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 43; p. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 44 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 45;130q. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 46 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 47; r. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 48 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 49; s. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 50 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 51 ; t. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 52 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 53; u. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 54 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 55; v. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 56 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 57; w. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 58 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 59; x. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 60 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 61 ; y. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 62 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 63; z. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 64 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 65; aa. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 70 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 71 ; bb. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 74 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 75;131cc. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 76 comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 77; dd. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 660 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 661 ; ee. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 662 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 663; ff. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 664 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 665; gg. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 721 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 722; or hh. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 739 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 740.

51. A humanised monoclonal antibody according to claims 30 to 49, wherein: a. the VL domain comprises or consists of the sequence of SEQ ID No. 14 and the VH domain comprises or consists of the sequence of SEQ ID No. 15; b. the VL domain comprises or consists of the sequence of SEQ ID No. 16 and the VH domain comprises or consists of the sequence of SEQ ID No. 17; c. the VL domain comprises or consists of the sequence of SEQ ID No. 18 and the VH domain comprises or consists of the sequence of SEQ ID No. 19; d. the VL domain comprises or consists of the sequence of SEQ ID No. 20 and the VH domain comprises or consists of the sequence of SEQ ID No. 21 ; e. the VL domain comprises or consists of the sequence of SEQ ID No. 22 and the VH domain comprises or consists of the sequence of SEQ ID No. 23; f. the VL domain comprises or consists of the sequence of SEQ ID No. 24 and the VH domain comprises or consists of the sequence of SEQ ID No. 25; g. the VL domain comprises or consists of the sequence of SEQ ID No. 26 and the VH domain comprises or consists of the sequence of SEQ ID No. 27; h. the VL domain comprises or consists of the sequence of SEQ ID No. 28 and the VH domain comprises or consists of the sequence of SEQ ID No. 29;132i. the VL domain comprises or consists of the sequence of SEQ ID No. 30 and the VH domain comprises or consists of the sequence of SEQ ID No. 31; j. the VL domain comprises or consists of the sequence of SEQ ID No. 32 and the VH domain comprises or consists of the sequence of SEQ ID No. 33; k. the VL domain comprises or consists of the sequence of SEQ ID No. 34 and the VH domain comprises or consists of the sequence of SEQ ID No. 35; l. the VL domain comprises or consists of the sequence of SEQ ID No. 36 and the VH domain comprises or consists of the sequence of SEQ ID No. 37; m. the VL domain comprises or consists of the sequence of SEQ ID No. 38 and the VH domain comprises or consists of the sequence of SEQ ID No. 39; n. the VL domain comprises or consists of the sequence of SEQ ID No. 40 and the VH domain comprises or consists of the sequence of SEQ ID No. 41; o. the VL domain comprises or consists of the sequence of SEQ ID No. 42 and the VH domain comprises or consists of the sequence of SEQ ID No. 43; p. the VL domain comprises or consists of the sequence of SEQ ID No. 44 and the VH domain comprises or consists of the sequence of SEQ ID No. 45; q. the VL domain comprises or consists of the sequence of SEQ ID No. 46 and the VH domain comprises or consists of the sequence of SEQ ID No. 47; r. the VL domain comprises or consists of the sequence of SEQ ID No. 48 and the VH domain comprises or consists of the sequence of SEQ ID No. 49; s. the VL domain comprises or consists of the sequence of SEQ ID No. 50 and the VH domain comprises or consists of the sequence of SEQ ID No. 51; t. the VL domain comprises or consists of the sequence of SEQ ID No. 52 and the VH domain comprises or consists of the sequence of SEQ ID No. 53; u. the VL domain comprises or consists of the sequence of SEQ ID No. 54 and the VH domain comprises or consists of the sequence of SEQ ID No. 55; v. the VL domain comprises or consists of the sequence of SEQ ID No. 56 and the VH domain comprises or consists of the sequence of SEQ ID No. 57; w. the VL domain comprises or consists of the sequence of SEQ ID No. 58 and the VH domain comprises or consists of the sequence of SEQ ID No. 59; x. the VL domain comprises or consists of the sequence of SEQ ID No. 60 and the VH domain comprises or consists of the sequence of SEQ ID No. 61; y. the VL domain comprises or consists of the sequence of SEQ ID No. 62 and the VH domain comprises or consists of the sequence of SEQ ID No. 63; z. the VL domain comprises or consists of the sequence of SEQ ID No. 64 and the VH domain comprises or consists of the sequence of SEQ ID No. 65;aa. the VL domain comprises or consists of the sequence of SEQ ID No. 70 and the VH domain comprises or consists of the sequence of SEQ ID No. 71; bb. the VL domain comprises or consists of the sequence of SEQ ID No. 74 and the VH domain comprises or consists of the sequence of SEQ ID No. 75; cc. the VL domain comprises or consists of the sequence of SEQ ID No. 76 and the VH domain comprises or consists of the sequence of SEQ ID No. 77; dd. the VL domain comprises or consists of the sequence of SEQ ID No. 660 and the VH domain comprises or consists of the sequence of SEQ ID No. 661; ee. the VL domain comprises or consists of the sequence of SEQ ID No. 662 and the VH domain comprises or consists of the sequence of SEQ ID No. 663; ff. the VL domain comprises or consists of the sequence of SEQ ID No. 664 and the VH domain comprises or consists of the sequence of SEQ ID No. 665; or gg. the VL domain comprises or consists of the sequence of SEQ ID No. 721 and the VH domain comprises or consists of the sequence of SEQ ID No. 722; or hh. the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740.

52. A humanised monoclonal antibody according to claims 30 to 50, wherein the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 739 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 740, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740.

53. A humanised monoclonal antibody according to claims 30 to 50, wherein the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 66 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 67, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 66 and the VH domain comprises or consists of the sequence of SEQ ID No. 67.

54. A humanised monoclonal antibody according to any one of claims 30 to 50, wherein the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 68 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 69, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 68 and the VH domain comprises or consists of the sequence of SEQ ID No. 69.

55. A humanised monoclonal antibody according to any one of claims 30 to 50, wherein the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 72 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 73, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 72 and the VH domain comprises or consists of the sequence of SEQ ID No. 73.

56. A humanised monoclonal antibody according to any one of claims 30 to 50, wherein: a. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 78 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 79, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 78 and the VH domain comprises or consists of the sequence of SEQ ID No. 79; or b. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 80 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 81 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 80 and the VH domain comprises or consists of the sequence of SEQ ID No. 81.

57. A humanised monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site which specifically binds to amyloid fibrils, wherein: a. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 14 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 15; b. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 16 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 17; c. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 18 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 19; d. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 20 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 21 ;135e. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 22 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 23; f. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 24 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 25; g. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 26 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 27; h. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 28 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 29; i. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 30 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 31; j. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 32 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 33; k. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 34 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 35; l. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 36 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 37; m. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 38 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 39; n. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 40 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 41; o. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 42 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 43; p. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 44 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 45;136q. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 46 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 47; r. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 48 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 49; s. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 50 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 51 ; t. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 52 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 53; u. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 54 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 55; v. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 56 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 57; w. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 58 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 59; x. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 60 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 61 ; y. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 62 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 63; z. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 64 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 65; aa. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 66 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 67; bb. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 68 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 69;137cc. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 70 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 71 ; dd. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 74 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 75; or ee. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 76 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 77; ff. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 72 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No.

73. gg. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 78 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 79; hh. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 80 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 81 ; ii. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 660 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 661 ; jj. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 662 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 663; kk. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 664 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 665; orII. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 721 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 722; or mm. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 739 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 740; and the Fc region is an engineered Fc region.

58. The humanised antibody according to any of claims 30 to 57, wherein the antibody is of hlgG1 isotype.13859. The antibody or antigen binding portion thereof of any previous claim, wherein the Fab region comprises a binding site which specifically binds to at least 3, 4, 5, 6, 7, 8, 9, 10 or 11 different types of amyloid fibrils, selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils.

60. The antibody or antigen binding portion thereof of claim 59, wherein the binding site specifically binds to at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils.

61. An isolated monoclonal antibody or antigen binding portion thereof comprising a Fab region and an Fc region, wherein the Fab region specifically binds to amyloid fibrils, wherein: a. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 88 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 89, optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 88 and the VH domain comprises or consists of the sequence of SEQ ID No. 89; or b. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 90 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 91 , optionally wherein the VL domain comprises or consists of the sequence of SEQ ID No. 90 and the VH domain comprises or consists of the sequence of SEQ ID No. 91 ; and the Fc region is an engineered Fc region.

62. The isolated monoclonal antibody according to any preceding claim wherein the Fc region of the antibody is derived from mouse lgG2 isotype.

63. The isolated monoclonal antibody according to any preceding claim wherein the Fc region of the antibody is derived from human lgG1 isotype64. The isolated monoclonal antibody according to any preceding claim wherein the Fc region is engineered to: a. increase complement activation; b. increase hexamerisation; c. increase C1q affinity; d. increase affinity to human FcgR I;139e. increase affinity to human FcgR II; f. increase affinity to human FcgR III; g. increase ADCP; h. increase affinity to human FcRn at acidic pH; i. increase antibody cellular recycling; and / or j. increase half-life.

65. The isolated monoclonal antibody of any previous claim, wherein the engineered Fc region is a human IgG Fc region comprising one or more amino acid mutations with respect to a wildtype human IgG Fc region (e.g. SEQ ID NO: 623).

66. The isolated monoclonal antibody of claim 65, wherein the human IgG Fc region is a human lgG1 Fc region.

67. The isolated monoclonal antibody of any previous claim, wherein the engineered Fc region comprises one or more of the amino acid mutations selected from the group consisting of: G236W, S239D; M252Y; S254T; T256E; S298A, L234Y, L328E, I332E, M428L, H429F; E430G; and N434S (Eu numbering).

68. The isolated monoclonal antibody of any previous claim, wherein the engineered Fc region comprises the amino acid mutations (Eu numbering): a. E430G; b. S239D and I332E; c. M428L and N434S; d. L328E; e. L234Y, G236W and S298A; f. H429F; g. M252Y, S254T and T256E h. E430G, S239D and I332E; i. E430G, M428L, and N434S; j. E430G and L328E k. S239D, I332E, M428L and N434S; l. S239D, I332E and H429F; and / or m. M428L, N434S and H429F.14069. The isolated monoclonal antibody of any previous claim, wherein the engineered Fc region comprises one or more sequences selected from the group consisting of SEQ ID NO: 93 to 103.

70. The isolated monoclonal antibody of any previous claim, wherein the engineered Fc region comprises a CH2 domain comprising or consisting of a sequence selected from the group consisting of SEQ ID NO: 93 to 97.

71. The isolated monoclonal antibody of any previous claim, wherein the engineered Fc region comprises a CH3 domain comprising or consisting of a sequence selected from the group consisting of SEQ ID NO: 98 to 103, optionally further comprising a lysine (K) residue at the C-terminus.

72. The isolated monoclonal antibody of any previous claim, wherein the engineered Fc region comprises: a. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 99; b. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 98; c. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 100 ; d. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 95 and a CH3 domain comprising or consisting of SEQ ID NO: 98 ; e. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 96 and a CH3 domain comprising or consisting of SEQ ID NO: 98 ; f. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 101 ; g. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 97 and a CH3 domain comprising or consisting of SEQ ID NO: 98; h. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 99; i. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 95 and a CH3 domain comprising or consisting of SEQ ID NO: 99; j. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 102; k. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 100;141l. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 94 and a CH3 domain comprising or consisting of SEQ ID NO: 101 ; or m. a CH2 domain comprising or consisting of the sequence of SEQ ID NO: 93 and a CH3 domain comprising or consisting of SEQ ID NO: 103.

73. The isolated monoclonal antibody of any previous claim, wherein the heavy chain further comprises a CH1 domain comprising or consisting of the sequence of SEQ ID NO: 92.

74. The isolated monoclonal antibody of any previous claim, respectively comprising the heavy chain and light chain sequence of: a. SEQ ID NOs: 155 and 624, 191 and 624, 227 and 624, 263 and 624, 299 and 624,335 and 624, 371 and 624, 407 and 624, 443 and 624, 479 and 624, 515 and 624,551 and 624, 587 and 624: b. SEQ ID NOs: 156 and 625, 192 and 625, 228 and 625, 264 and 625, 300 and 625,336 and 625, 372 and 625, 408 and 625, 444 and 625, 480 and 625, 516 and 625,552 and 625, 588 and 625; c. SEQ ID NOs: 157 and 626, 193 and 626, 229 and 626, 265 and 626, 301 and 626,337 and 626, 373 and 626, 409 and 626, 445 and 626, 481 and 626, 517 and 626,553 and 626, 589 and 626; d. SEQ ID NOs: 158 and 627, 194 and 627, 230 and 627, 266 and 627, 302 and 627,338 and 627, 374 and 627, 410 and 627, 446 and 627, 482 and 627, 518 and 627,554 and 627, 590 and 627; e. SEQ ID NOs: 159 and 628, 195 and 628, 231 and 628, 267 and 628, 303 and 628,339 and 628, 375 and 628, 411 and 628, 447 and 628, 483 and 628, 519 and 628,555 and 628, 591 and 628; f. SEQ ID NOs: 160 and 629, 196 and 629, 232 and 629, 268 and 629, 304 and 629,340 and 629, 376 and 629, 412 and 629, 448 and 629, 484 and 629, 520 and 629,556 and 629, 592 and 629; g. SEQ ID NOs: 161 and 630, 197 and 630, 233 and 630, 269 and 630, 305 and 630,341 and 630, 377 and 630, 413 and 630, 449 and 630, 485 and 630, 521 and 630,557 and 630, 593 and 630; h. SEQ ID NOs: 162 and 631, 198 and 631, 234 and 631 , 270 and 631, 306 and 631 ,342 and 631, 378 and 631 , 414 and 631 , 450 and 631, 486 and 631, 522 and 631 ,558 and 631, 594 and 631; i. SEQ ID NOs: 163 and 632, 199 and 632, 235 and 632, 271 and 632, 307 and 632,343 and 632, 379 and 632, 415 and 632, 451 and 632, 487 and 632, 523 and 632,559 and 632, 595 and 632;142j. SEQ ID NOs: 164 and 633, 200 and 633, 236 and 633, 272 and 633, 308 and 633,344 and 633, 380 and 633, 416 and 633, 452 and 633, 488 and 633, 524 and 633,560 and 633, 596 and 633; k. SEQ ID NOs: 165 and 634, 201 and 634, 237 and 634, 273 and 634, 309 and 634,345 and 634, 381 and 634, 417 and 634, 453 and 634, 489 and 634, 525 and 634,561 and 634, 597 and 634; l. SEQ ID NOs: 166 and 635, 202 and 635, 238 and 635, 274 and 635, 310 and 635,346 and 635, 382 and 635, 418 and 635, 454 and 635, 490 and 635, 526 and 635,562 and 635, 598 and 635; m. SEQ ID NOs: 167 and 636, 203 and 636, 239 and 636, 275 and 636, 311 and 636,347 and 636, 383 and 636, 419 and 636, 455 and 636, 491 and 636, 527 and 636,563 and 636, 599 and 636; n. SEQ ID NOs: 168 and 637, 204 and 637, 240 and 637, 276 and 637, 312 and 637,348 and 637, 384 and 637, 420 and 637, 456 and 637, 492 and 637, 528 and 637,564 and 637, 600 and 637; o. SEQ ID NOs: 69 and 638, 205 and 638, 241 and 638, 277 and 638, 313 and 638,349 and 638, 385 and 638, 421 and 638, 457 and 638, 493 and 638, 529 and 638,565 and 638, 601 and 638; p. SEQ ID NOs: 170 and 639, 206 and 639, 242 and 639, 278 and 639, 314 and 639,350 and 639, 386 and 639, 422 and 639, 458 and 639, 494 and 639, 530 and 639,566 and 639, 602 and 639; q. SEQ ID NOs: 171 and 640, 207 and 640, 243 and 640, 279 and 640, 315 and 640,351 and 640, 387 and 640, 423 and 640, 459 and 640, 495 and 640, 531 and 640,567 and 640, 603 and 640; r. SEQ ID NOs: 172 and 641 , 208 and 641 , 244 and 641 , 280 and 641 , 316 and 641 ,352 and 641 , 388 and 641 , 424 and 641 , 460 and 641 , 496 and 641 , 532 and 641 ,568 and 641 , 604 and 641 ; s. SEQ ID NOs: 173 and 642, 209 and 642, 245 and 642, 281 and 642, 317 and 642,353 and 642, 389 and 642, 425 and 642, 461 and 642, 497 and 642, 533 and 642,569 and 642, 605 and 642; t. SEQ ID NOs: 174 and 643, 210 and 643, 246 and 643, 282 and 643, 318 and 643,354 and 643, 390 and 643, 426 and 643, 462 and 643, 498 and 643, 534 and 643,570 and 643, 606 and 643; u. SEQ ID NOs: 175 and 644, 211 and 644, 247 and 644, 283 and 644, 319 and 644,355 and 644, 391 and 644, 427 and 644, 463 and 644, 499 and 644, 535 and 644,571 and 644, 607 and 644;143v. SEQ ID NOs: 176 and 645, 212 and 645, 248 and 645, 284 and 645, 320 and 645,356 and 645, 392 and 645, 428 and 645, 464 and 645, 500 and 645, 536 and 645,572 and 645, 608 and 645; w. SEQ ID NOs: 177 and 646, 213 and 646, 249 and 646, 285 and 646, 321 and 646,357 and 646, 393 and 646, 429 and 646, 465 and 646, 501 and 646, 537 and 646,573 and 646, 609 and 646; x. SEQ ID NOs: 178 and 647, 214 and 647, 250 and 647, 286 and 647, 322 and 647,358 and 647, 394 and 647, 430 and 647, 466 and 647, 502 and 647, 538 and 647,574 and 647, 610 and 647; y. SEQ ID NOs: 179 and 648, 215 and 648, 251 and 648, 287 and 648, 323 and 648,359 and 648, 395 and 648, 431 and 648, 467 and 648, 503 and 648, 539 and 648,575 and 648, 611 and 648; z. SEQ ID NOs: 180 and 649, 216 and 649, 252 and 649, 288 and 649, 324 and 649,360 and 649, 396 and 649, 432 and 649, 468 and 649, 504 and 649, 540 and 649,576 and 649, 612 and 649; aa. SEQ ID NOs: 181 and 650, 217 and 650, 253 and 650, 289 and 650, 325 and 650,361 and 650, 397 and 650, 433 and 650, 469 and 650, 505 and 650, 541 and 650,577 and 650, 613 and 650; bb. SEQ ID NOs: 182 and 651, 218 and 651, 254 and 651 , 290 and 651 , 326 and 651 ,362 and 651, 398 and 651 , 434 and 651 , 470 and 651 , 506 and 651 , 542 and 651 ,578 and 651, 614 and 651; cc. SEQ ID NOs: 183 and 652, 219 and 652, 255 and 652, 291 and 652, 327 and 652,363 and 652, 399 and 652, 435 and 652, 471 and 652, 507 and 652, 543 and 652,579 and 652, 615 and 652; dd. SEQ ID NOs: 184 and 653, 220 and 653, 256 and 653, 292 and 653, 328 and 653,364 and 653, 400 and 653, 436 and 653, 472 and 653, 508 and 653, 544 and 653,580 and 653, 616 and 653; ee. SEQ ID NOs: 185 and 654, 221 and 654, 257 and 654, 293 and 654, 329 and 654,365 and 654, 401 and 654, 437 and 654, 473 and 654, 509 and 654, 545 and 654,581 and 654, 617 and 654; ff. SEQ ID NOs: 186 and 655, 222 and 655, 258 and 655, 294 and 655, 330 and 655,366 and 655, 402 and 655, 438 and 655, 474 and 655, 510 and 655, 546 and 655,582 and 655, 618 and 655; gg. SEQ ID NOs: 187 and 656, 223 and 656, 259 and 656, 295 and 656, 331 and 656,367 and 656, 403 and 656, 439 and 656, 475 and 656, 511 and 656, 547 and 656,583 and 656, 619 and 656;144hh. SEQ ID NOs: 188 and 657, 224 and 657, 260 and 657, 296 and 657, 332 and 657,368 and 657, 404 and 657, 440 and 657, 476 and 657, 512 and 657, 548 and 657,584 and 657, 620 and 657; ii. SEQ ID NOs: 189 and 658, 225 and 658, 261 and 658, 297 and 658, 333 and 658,369 and 658, 405 and 658, 441 and 658, 477 and 658, 513 and 658, 549 and 658,585 and 658, 621 and 658; jj. SEQ ID NOs: 190 and 659, 226 and 659, 262 and 659, 298 and 659, 334 and 659,370 and 659, 406 and 659, 442 and 659, 478 and 659, 514 and 659, 550 and 659,586 and 659, or 622 and 659; kk. SEQ ID NOs: 669 and 666, 670 and 666, 671 and 666, 672 and 666, 673 and 666, 674 and 666, 675 and 666, 676 and 666, 677 and 666, 678 and 666, 679 and 666, 680 and 666, 681 and 666;II. SEQ ID NOs: 682 and 667, 683 and 667, 684 and 667, 685 and 667, 686 and 667, 687 and 667, 688 and 667, 689 and 667, 690 and 667, 691 and 667, 692 and 667, 693 and 667, 694 and 667; mm. SEQ ID NOs: 695 and 668, 696 and 668, 697 and 668, 698 and 668, 699 and 668, 700 and 668, 701 and 668, 702 and 668, 703 and 668, 704 and 668, 705 and 668, 706 and 668, 707 and 668; nn. SEQ ID NOs: 725 and 723, 726 and 723, 727 and 723, 728 and 723, 729 and 723, 730 and 723, 731 and 723, 732 and 723, 733 and 723, 734 and 723, 735 and 723, 736 and 723, 737 and 723; or oo. SEQ I D NOs: 743 and 741 , 744 and 741 , 745 and 741 , 746 and 741 , 747 and 741 , 748 and 741 , 749 and 741 , 750 and 741 , 751 and 741 , 752 and 741 , 753 and 741 , 754 and 741 , 755 and 741.

75. A humanised monoclonal antibody which specifically binds to amyloid fibrils, wherein: a. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 72 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 73; b. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 74 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 75; c. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 76 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 77;145d. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 78 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 79; e. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 80 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 81; f. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 660 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 661; g. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 662 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 663; h. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 664 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 665; i. h. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 56 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 57; j. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 58 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 59; k. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 60 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 61; l. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 62 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 63; m. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 64 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 65; n. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 721 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 722; or o. the VL domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 739 and the VH domain comprises or consists of a sequence having at least 90% sequence identity with SEQ ID No. 740.14676. The humanised monoclonal antibody of claim 75, wherein: a. wherein the VL domain comprises or consists of the sequence of SEQ ID No. 72 and the VH domain comprises or consists of the sequence of SEQ ID No. 73; b. the VL domain comprises or consists of the sequence of SEQ ID No. 74 and the VH domain comprises or consists of the sequence of SEQ ID No. 75; or c. the VL domain comprises or consists of the sequence of SEQ ID No. 76 and the VH domain comprises or consists of the sequence of SEQ ID No. 77; d. wherein the VL domain comprises or consists of the sequence of SEQ ID No. 78 and the VH domain comprises or consists of the sequence of SEQ ID No. 79; e. wherein the VL domain comprises or consists of the sequence of SEQ ID No. 80 and the VH domain comprises or consists of the sequence of SEQ ID No. 81; f. the VL domain comprises or consists of the sequence of SEQ ID No. 660 and the VH domain comprises or consists of the sequence of SEQ ID No. 661; g. the VL domain comprises or consists of the sequence of SEQ ID No. 662 and the VH domain comprises or consists of the sequence of SEQ ID No. 663; h. the VL domain comprises or consists of the sequence of SEQ ID No. 664 and the VH domain comprises or consists of the sequence of SEQ ID No. 665; i. h. the VL domain comprises or consists of the sequence of SEQ ID No. 56 and the VH domain comprises or consists of the sequence of SEQ ID No. 57; j. the VL domain comprises or consists of the sequence of SEQ ID No. 58 and the VH domain comprises or consists of the sequence of SEQ ID No. 59; k. the VL domain comprises or consists of the sequence of SEQ ID No. 60 and the VH domain comprises or consists of the sequence of SEQ ID No. 61; l. the VL domain comprises or consists of the sequence of SEQ ID No. 62 and the VH domain comprises or consists of the sequence of SEQ ID No. 63; m. the VL domain comprises or consists of the sequence of SEQ ID No. 64 and the VH domain comprises or consists of the sequence of SEQ ID No. 65; n. the VL domain comprises or consists of the sequence of SEQ ID No. 721 and the VH domain comprises or consists of the sequence of SEQ ID No. 722; or o. the VL domain comprises or consists of the sequence of SEQ ID No. 739 and the VH domain comprises or consists of the sequence of SEQ ID No. 740.

77. The humanised monoclonal antibody of claim 75 or 76 wherein the antibody binds to at least 3, 4, 5, 6, 7, 8, 9, 10 or 11 different types of amyloid fibrils, selected from ALK, ALA, ATTR wild type, ATTR variant, AA, AApoAl, ALys, AP2m, AGel, AIAPP and AFib amyloid fibrils.14778. The humanised monoclonal antibody of claim 75 or 76, wherein the antibody binds to at least ATTRwt, ATTRv, ALK, ALA, AA, AApoAl, Ap2m, AFib, AGel and AIAPP amyloid fibrils.

79. The humanised monoclonal antibody of claim 75 to 78, respectively comprising the heavy and light chain sequence of: SEQ ID NOs: 119 and 624, 120 and 625, 121 and 626, 122 and 627, 123 and 628, 124 and 629, 125 and 630, 126 and 631, 127 and 632, 128 and 633, 129 and 634, 130 and 635, 131 and 636, 132 and 637, 133 and 638, 134 and 639, 135 and 640, 136 and 641 , 137 and 642, 138 and 643, 139 and 644, 140 and 645, 141 and 646, 142 and 647, 143 and 648, 144 and 649, 145 and 650, 146 and 651 , 147 and 652, 148 and 653, 149 and 654, 150 and 655, 151 and 656, 152 and 657, 708 and 666, 709 and 667, 710 and 668, 724 and 723, 140 and 645, 141 and 646, 142 and 647, 143 and 648, 144 and 649, 742 and 741.

80. An antibody of any previous claim, wherein the amyloid fibrils are endogenous amyloid fibrils.

81. An isolated monoclonal antibody or a humanised antibody or antigen binding portion thereof according to any preceding claim, which also effectively promotes regression of systemic murine AA amyloid deposits when administered parenterally to mice with experimentally induced systemic AA amyloidosis.

82. An isolated monoclonal antibody or a humanised antibody or antigen binding portion according to any preceding claim, the in vivo efficacy of which is complement dependent.

83. An isolated monoclonal antibody or a humanised antibody or antigen binding portion thereof according to any preceding claim, the in vivo efficacy of which is Fey receptor binding dependent.

84. An isolated monoclonal antibody or a humanised antibody according to any preceding claim, for use in the treatment of disease.

85. An isolated monoclonal antibody or a humanised antibody for use according to claim 85, wherein the disease is amyloidosis, optionally systemic amyloidosis.14886. A method for removing amyloid deposits from the tissues in a subject suffering from systemic amyloidosis, comprising administering at least one isolated monoclonal antibody or a humanised antibody according to any one of claims 1 to 83.

87. A pharmaceutical composition comprising an isolated monoclonal antibody or a humanised antibody according to any one of claims 1 to 83, and optionally further comprising one or more pharmaceutically acceptable excipients.

88. The pharmaceutical composition of claim 87, for use in medicine.

89. The pharmaceutical composition of claim 87, for use in the treatment of systemic amyloidosis.149

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