Antibody molecule that specifically binds human cd47 and cynomologue cd47 or an antigen-binding fraction thereof, immunoconjugate, nucleic acid molecule, vector, host cell, pharmaceutical composition, uses thereof, and related methods

Description

1 / 85 Antibody molecule that binds specifically to human CD47 and cynomolgus monkey CD47 or a binding fraction. TO THE SAME ANTIGEN, IMMUNOCONJUGATE, NUCLEIC ACID MOLECULE, VECTOR, HOST CELL, PHARMACEUTICAL COMPOSITION, USES THEREOF AND RELATED METHODS / Split application from BR 11 2020 003306 5) FIELD OF THE INVENTION

[001] The invention relates to antibody molecules that bind specifically to CD47 (Cluster of Differentiation 47, also known as integrin-associated protein [IAP]) and their medical uses. BACKGROUND OF THE INVENTION

[002] CD47 (also known as integrin-associated protein [IAP]) is a transmembrane protein belonging to the immunoglobulin superfamily and binds to several known partners, including: membrane integrins, thrombospondin-1 (TSP-1), and signal-regulating protein alpha (SIRPq). CD47 is associated with a variety of cellular processes, including apoptosis, proliferation, cell adhesion and migration, and most importantly, plays a key role in immune and angiogenic responses. CD47-SIRPq signaling is a critical molecular interaction that inhibits the activation of phagocytosis by macrophages and other myeloid cells. This promotes the survival of tumor cells and therefore acts as a myeloid lineage-specific immune checkpoint.

[003] Preclinical evidence suggests that blocking CD47-SIRPq signaling can increase macrophage phagocytic activity and inhibit xenograft growth in several experimental models of hematologic and solid malignancies. Since macrophage activity is also a recognized factor in the biology of tissue remodeling associated with inflammation, such as tissue fibrosis and atherosclerotic plaque formation, the CD47-SIRPQ signaling axis also possesses considerable potential. Petition 870260064866, dated 01 / 07 / 2026, page 11 / 146 2 / 85 therapeutic in non-cancerous diseases. Therefore, anti-CD47 mAbs have the potential to act as immunotherapeutic agents in cancer and other contexts, in addition to amplifying the effectiveness of currently established therapies.

[004] Most currently approved antibody therapies are derived from immunized rodents. Many of these antibodies have undergone a process known as humanization, through the grafting of murine CDRs into structural sequences of human v genes (see Nelson et al., 2010, Nat Rev Drug Discov 9: 767-774). This process is generally imprecise and leads to a reduction in the binding affinity of the resulting antibody to its target. To return to the binding affinity of the original antibody, murine residues are usually introduced at key positions in the variable domain structures of the grafted v domains (also known as back-mutations).

[005] Although humanized antibodies via CDR grafting and reverse mutations have been shown to induce lower rates of immune response in the clinic compared to those with fully murine v domains, humanized antibodies using this basic grafting method still carry significant risks in clinical development due to physical potential instability and immunogenicity motifs still lodged in the grafted CDR loops. Antibodies such as CD47 inhibitors that target receptors on immune cells and whose pharmacological function is to stimulate immune responses through antigen presentation, are at greater risk of provoking anti-drug antibody responses. These anti-drug antibody responses in the patient can reduce the half-life, potency, and safety of the drug during clinical use.Since testing protein immunogenicity in animals is often not predictive of immune responses in humans, antibody engineering for therapeutic use focuses on minimizing this risk. Petition 870260064866, dated 01 / 07 / 2026, page 12 / 146 3 / 85 predicted epitope content of human T cells, amino acid content of non-human germline protein, and aggregation potential in purified protein.

[006] The ideal humanized anti-CD47 antagonist antibody would therefore have as many identical residues as possible in the v domains as those found in the structures and CDRs of well-characterized human germline sequences. Townsend et al. (2015; PNAS 112: 15354-15359) describe a method for generating antibodies in which CDRs derived from rat, rabbit, and mouse antibodies were grafted onto preferred human structures and then subjected to a human germline alignment approach called Enhanced Binary Substitution. Although the approach has demonstrated fundamental plasticity in the original antibody paratopes, in the absence of highly accurate antibody-antigen co-crystal structural data, it is still not possible to reliably predict which individual residues in the CDR loops of any antibody can be converted to the human germline and in what combination.

[007] The germline alignment of CDRs is therefore a complex multifactorial problem, as several functional properties of the molecule must be preferentially maintained, including in this case: target binding specificity, affinity to CD47 of test species in humans and animals (e.g., cynomolgus macaque, also known as the crab-eating macaque, i.e., Macaca fascicularis), the biophysical stability of the domain and / or IgG expression. Antibody engineering studies have shown that mutation of single residue positions in key CDRs can have dramatic effects on all these desired molecular properties.

[008] Document WO2014 / 093678A2 describes a murine anti-CD47 IgG antagonist molecule called VxP037 and also the preparation of humanized forms of VxP037. These forms Petition 870260064866, dated 01 / 07 / 2026, page 13 / 146 4 / 85 humanized forms of VxP037 were produced using classical humanization techniques, i.e., grafting Kabat-defined murine CDRs onto human heavy and light chain structure sequences, with some of the human structure residues potentially being reverse mutated to correspondingly positioned murine VxP037 residues. For the reasons mentioned above, these humanized forms of VxP037 described in WO2014 / 093678A2 are not ideal.

[009] The present invention provides a series of optimized anti-CD47 antibodies and their medical uses. SUMMARY OF THE INVENTION

[010] According to one aspect of the invention, an antibody molecule is provided that binds specifically to human CD47 and, optionally, also to cynomolgus monkey CD47 and / or mouse CD47, or an antigen-binding fraction thereof, wherein the antibody molecule or antigen-binding fraction comprises a variable heavy chain region with: an HCDR1 with amino acids in sequence in the following order: GYT or any amino acid (e.g., S, N, or R) - FT or a conservative substitution of TN or a conservative substitution of NYYI or a conservative substitution of IF or any amino acid (e.g., V or G) (SEQ ID NO: 1); A HCDR2 with amino acids in sequence in the following order: M or a conservative substitution of MGI or any amino acid (e.g., N, V, or D)-IN or any amino acid (e.g., Y)-PV or any acidic amino acid (e.g., G or F)-D or a conservative substitution of DG or a conservative substitution of GDTN or a conservative substitution of N (e.g., R)-Y or a conservative substitution of YN or a conservative substitution of N (e.g., S)-PSFQG (SEQ ID NO: 2); and a HCDR3 with amino acids in sequence in the following order: GGY or any amino acid (e.g., H, I, Q, or F)-T or Petition 870260064866, dated 01 / 07 / 2026, p. 14 / 146 5 / 85 any amino acid (e.g., V or I)-M or any amino acid (e.g., T, R, P, A, or L)-D or any amino acid (e.g., G)-R or any amino acid (e.g., Q, N, Y, S, W, K, A, E, F, H, I, L, M, T, or V) (SEQ ID NO: 3).

[011] In aspects of the invention, the HCDR1 of the antibody molecule or antigen-binding fraction can exclude the GYTFTNYYVF sequence (SEQ ID NO: 4) (murine / humanized VxP037 antibody HCDR1 disclosed in document WO2014 / 093678A2) and / or the HCDR3 of the antibody molecule or antigen-binding fraction can exclude the GGYTMDY sequence (SEQ ID NO: 5) (murine / humanized VxP037 antibody HCDR3 disclosed in WO2014 / 093678A2).

[012] The antibody molecule or antigen-binding fragment may further comprise a variable region of the light chain with: an LCDR1 with amino acids in sequence in the following order: RSSQ or a conservative substitution of QSL or a conservative substitution of LL or a conservative substitution of LHSN or any amino acid (e.g., Q, S, T, A, or G) or a conservative substitution of N (e.g., Q, S, T, or G)-G or a conservative substitution of G (e.g., A)-Y or any amino acid (e.g., N or S)-T or a conservative substitution of T (e.g., N)-YLH or any amino acid (e.g., D) (SEQ ID NO: 6); An LCDR2 with amino acids in sequence in the following order: K or any amino acid (e.g., L or M)-V or any amino acid (e.g., G)-SN or any amino acid (e.g., Y)-RL or any amino acid (e.g., F, A, or S)S (SEQ ID NO: 7); and an LCDR3 with amino acids in sequence in the following order: F or any amino acid (e.g., L, M, S, T, or V)-QQ or any amino acid (e.g., N, A, T, or S)-T or any Petition 870260064866, dated 01 / 07 / 2026, p. 15 / 146 6 / 85 amino acid (e.g., L, M, or I)-H or a conservative HT substitution or any amino acid (e.g., V, I, A, or F)-P or any amino acid (e.g., L)-R or any amino acid (e.g., W)-T (SEQ ID NO: 8).

[013] In aspects of the invention, LCDR1 of the antibody molecule or antigen-binding fraction can exclude the RSSQSLVHSNGNTYLH sequence (SEQ ID NO: 9) (murine antibody VxP037 / humanized LCDR1 disclosed in WO2014 / 093678A2) and / or LCDR2 of the antibody molecule or antigen-binding fraction can exclude the KVSYRFS sequence (SEQ ID NO: 10) (murine antibody VxP037 / humanized LCDR2 disclosed in WO2014 / 093678A2) and / or LCDR3 of the antibody molecule or antigen-binding fraction can exclude the SQNTHVPRT sequence (SEQ ID NO: 11) (murine antibody VxP037 / humanized LCDR3 disclosed in WO2014 / 093678A2).

[014] The CDR sequences above are defined using the Unified definition, as set out in Table 1 and described below. Alternatively, the CDR sequences in the present invention may be defined using the shorter AHo definition (see Table 1), which is based on structural biology and aims to unify the nomenclature for all immunoglobulin v domains.

[015] Using the shorter definition of CDR AHo, the invention in one aspect provides an antibody molecule that binds specifically to human CD47 and, optionally, also to cynomolgus monkey CD47 and / or mouse CD47, or to an antigen-binding fraction thereof, wherein the antibody molecule or antigen-binding fraction comprises a variable heavy chain region with: an HCDR1 with amino acids in sequence in the following order: GS-GYT or any amino acid (e.g., S, N, or R)-FT or a conservative substitution of TN or a conservative substitution of NYY (SEQ ID NO: 12); Petition 870260064866, dated 01 / 07 / 2026, p. 16 / 146 7 / 85 an HCDR2 with amino acids in sequence in the following order: IN or any amino acid (e.g., Y)-PV or any amino acid (e.g., G or F)-D or a conservative substitution of DG or a conservative substitution of GDTN or a conservative substitution of N (e.g., R)-Y or a conservative substitution of YN or a conservative substitution of N (e.g., S)-PSFQG (SEQ ID NO: 13); and an HCDR3 with amino acids in sequence in the following order: GGY or any amino acid (e.g., H, I, Q, or F)-T or any amino acid (e.g., V or I)-M or any amino acid (e.g., T, R, P, A, or L)-D or any amino acid (e.g., G) (SEQ ID NO: 14).

[016] Using the AHo definition, HCDR1 of the antibody molecule or antigen-binding fragment may exclude the sequence GSGYTFTNYY (SEQ ID NO: 15) (murine antibody VxP037 / humanized HCDR1 disclosed in document WO2014 / 093678A2) and / or HCDR3 of the antibody molecule or antigen-binding fragment may exclude the sequence GGYTMD (SEQ ID NO: 16) (murine antibody VxP037 / humanized HCDR3 disclosed in WO2014 / 093678A2).

[017] The antibody molecule or antigen-binding fragment may further comprise a variable region of the light chain with CDRs defined using the AHo definition as follows: an LCDR1 with amino acids in sequence in the following order: SSQ or a conservative substitution of QSL or a conservative substitution of LL or a conservative substitution of LHSN or any amino acid (e.g., Q, S, T, A, or G) or a conservative substitution of N (e.g., Q, S, T, or G)-G or a conservative substitution of G (e.g., A)-Y or any amino acid (e.g., N or S)-T or a conservative substitution of T (e.g., N)-Y (SEQ ID NO: 17); Petition 870260064866, dated 01 / 07 / 2026, p. 17 / 146 8 / 85 an LCDR2 with amino acids in sequence in the following order: K or any amino acid (e.g., L or M) - V or any amino acid (e.g., G) - SN or any amino acid (e.g., Y) - RL or any amino acid (e.g., F, A, or S) - S (SEQ ID NO: 7); and an LCDR3 with amino acids in sequence in the following order: Q or any amino acid (e.g., N, A, T, or S) - T or any amino acid (e.g., L, M, or I) - H or a conservative substitution of HT or any amino acid (e.g., V, I, A, or F) - P or any amino acid (e.g., L) - R or any amino acid (e.g., W) (SEQ ID NO: 18).

[018] Using AHo's definition, in aspects of the invention, the LCDR1 of the antibody molecule or antigen-binding fraction may exclude the SSQSLVHSNGNTY sequence (SEQ ID NO: 19) (murine antibody VxP037 / humanized LCDR1 disclosed in WO2014 / 093678A2) and / or the LCDR2 of the antibody molecule or antigen-binding fraction may exclude the KVSYRFS sequence (SEQ ID NO: 10) (murine antibody VxP037 / humanized LCDR2 disclosed in WO2014 / 093678A2) and / or the LCDR3 of the antibody molecule or antigen-binding fraction may exclude the NTHVPR sequence (SEQ ID NO: 20) (murine antibody VxP037 / humanized LCDR3 disclosed in WO2014 / 093678A2).

[019] Also provided according to the invention is an immunoconjugate comprising the antibody molecule or its antigen-binding moiety, as defined herein, linked to a therapeutic agent.

[020] In another aspect, the invention provides a nucleic acid molecule that encodes the antibody molecule or its antigen-binding moiety, as defined herein.

[021] A vector comprising the nucleic acid molecule of the invention is also provided. Petition 870260064866, dated 01 / 07 / 2026, page 18 / 146 9 / 85

[022] A host cell comprising the nucleic acid molecule or vector of the invention as defined herein is also provided.

[023] In a further aspect, a method is provided for producing an anti-CD47 antibody and / or an antigen-binding fraction, comprising culturing the host cell of the invention under conditions that result in the expression and / or production of the antibody and / or its antigen-binding fraction and isolating the antibody and / or its antigen-binding fraction from the host cell or culture.

[024] In another aspect of the invention, a pharmaceutical composition is provided comprising the antibody molecule or its antigen-binding moiety of the invention, as defined herein, or the immunoconjugate of the invention, as defined herein, or the nucleic acid molecule of the invention, as defined herein, or the vector of the invention as defined herein.

[025] In addition, a method is provided for improving an immune response in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction of the invention, as defined herein, or the immunoconjugate of the invention, as defined herein, or the nucleic acid molecule of the invention as defined herein, or the vector of the invention as defined herein, or the pharmaceutical composition of the invention as defined herein.

[026] In a further aspect, a method is provided for treating or preventing cancer in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction of the invention, as defined herein, or the immunoconjugate of the invention, as defined herein, or the nucleic acid molecule of the invention as defined herein, or the vector of the invention as defined herein, or the pharmaceutical composition of the invention as defined herein. Petition 870260064866, dated 01 / 07 / 2026, page 19 / 146 10 / 85

[027] The invention also provides an antibody molecule or its antigen-binding fraction of the invention, as defined herein, or the immunoconjugate of the invention, as defined herein, or the nucleic acid molecule of the invention, as defined herein, or the vector of the invention, as defined herein, or the pharmaceutical composition of the invention, as defined herein, for use in the treatment of cancer.

[028] In another aspect, the invention provides the antibody molecule, or its antigen-binding fraction, or the immunoconjugate, or the nucleic acid molecule, or the vector for use, or the treatment method of the invention, as defined herein, for sequential or simultaneous use in a combined combination with a second therapeutic agent, for example, an anticancer agent.

[029] In a further aspect, the use of an antibody molecule or an antigen-binding fraction of the invention, as defined herein, or an immunoconjugate of the invention, as defined herein, or a nucleic acid molecule of the invention, as defined herein, or a vector of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, in the manufacture of a medicament for the treatment of cancer is provided.

[030] The invention also provides a method for treating or preventing an ischemia-reperfusion injury, an autoimmune disease or an inflammatory disease in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the nucleic acid molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein.

[031] Autoimmune disease or inflammatory disease can be selected in all aspects of the group consisting of: Petition 870260064866, dated 01 / 07 / 2026, page 20 / 146 11 / 85 arthritis, multiple sclerosis, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, Graves' disease, Hashimoto's thyroiditis, and ankylosing spondylitis.

[032] Ischemia-reperfusion injury in all aspects can occur in organ transplantation, acute kidney injury, cardiopulmonary bypass surgery, pulmonary hypertension, sickle cell disease, myocardial infarction, stroke, surgical resections and reconstructive surgery, reattachment of an appendix or other body part, skin grafting, or trauma.

[033] Also provided is an antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the nucleic acid molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein, for use in the treatment of an ischemia-reperfusion injury, an autoimmune disease or an inflammatory disease.

[034] Furthermore, the use of an antibody molecule or its antigen-binding fraction, as defined herein, or an immunoconjugate as defined herein, or a nucleic acid molecule as defined herein, or a vector as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of an ischemia-reperfusion injury, an autoimmune disease or an inflammatory disease is provided.

[035] The invention also provides a method for the treatment or prevention of a cardiovascular disease or a fibrotic disease in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the acid core molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein. Petition 870260064866, dated 01 / 07 / 2026, page 21 / 146 12 / 85

[036] Also provided is an antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the nucleic acid molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein, for use in the treatment of a cardiovascular disease or a fibrotic disease.

[037] Furthermore, the use of an antibody molecule or its antigen-binding fraction, as defined herein, or an immunoconjugate as defined herein, or a nucleic acid molecule as defined herein, or a vector as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of an ischemia-reperfusion injury, an autoimmune disease, an inflammatory disease or a fibrotic disease is provided.

[038] Cardiovascular disease in any aspect of the invention may be, for example, coronary heart disease or atherosclerosis.

[039] Fibrotic disease in any aspect of the invention may be selected from the group consisting of myocardial infarction, angina, osteoarthritis, pulmonary fibrosis, cystic fibrosis, bronchitis and asthma.

[040] The invention also provides a method for producing an antibody molecule that binds specifically to human CD47 and, optionally, also to cynomolgus monkey CD47 and / or mouse CD47, or to an antigen-binding fraction, comprising the steps of: (1) grafting anti-CD47 CDRs from a non-human source into a human v-domain structure to produce a humanized anti-CD47 antibody molecule or antigen-binding fragment thereof; (2) generate a phage library of clones of the humanized anti-CD47 antibody molecule or its antigen-binding fraction, comprising one or more mutations in the CDRs; Petition 870260064866, dated 01 / 07 / 2026, p. 22 / 146 13 / 85 (3) screening of the phage library for binding to human CD47 and optionally also to cynomolgus monkey CD47 and / or mouse CD47; (4) select clones from screening step (3) possessing binding specificity to human CD47 and optionally also to cynomolgus monkey CD47 and / or mouse CD47; and (5) production of an antibody molecule that binds specifically to human CD47 and optionally also to cynomolgus monkey CD47 and / or mouse CD47, or to an antigen-binding fraction of the clones selected in step (4).

[041] The method may comprise an additional step of producing additional clones based on the clones selected in step (4), for example, based on additional exploratory mutagenesis at specific positions in the CDRs of the clones selected in step (4), to improve humanization and / or minimize the human T cell epitope content and / or improve the manufacturing properties in the antibody molecule or its antigen-binding fraction produced in step (5).

[042] The method may comprise an additional step of evaluating the immunogenicity of one or more v domains in the clones selected in step (4) or in the antibody molecule produced in step (5) and, optionally, generating one or more additional mutations, for example, in a CDR and region of the structure, to reduce immunogenicity. Immunogenicity may be evaluated by identifying the location of T cell epitopes, for example, using in silico technologies as described herein. BRIEF DESCRIPTION OF THE FIGURES

[043] Figure 1. Direct-binding ELISA of library-derived anti-CD47 scFvs against human and mouse CD47-Fc proteins. Clones were derived from 3 separate phage selection branches (A shows periprep ELISA from branch A; B shows periprep ELISA from branch B; and C shows periprep ELISA from branch C). Petition 870260064866, dated 01 / 07 / 2026, page 23 / 146 14 / 85 where phage populations were selected for biotinylated human, mouse, and / or cynomolgus monkey CD47Fc proteins in each round. After each selection round, library-derived clones (black circles) were screened against human and mouse CD47-Fc. Mean ± SD values ​​in each round are represented by gray bars. In each graph, the X-axis shows the selection circle (R), with H denoting human and mouse, and the Y-axis shows binding signal (OD 450nm).

[044] Figure 2. Analysis of CDR residue tolerance to germline mutation. A graph of murine amino acid retention frequencies in CDRs from the ELISA-positive population of 854 unique scFv clones is shown for the VH (A) and Vl (B) domains, respectively. Only those residues targeted for human / murine residue mutagenesis are plotted, except for HCDR3. In each graph, CDR residues are shown on the X-axis and the Y-axis shows the percentage retention of each murine residue. The CDR residues observed in parentheses on the X-axis were identical to those found in the human germlines used for grafting (IGKV2-28 and IGHV5-51). Residues in HCDR2 that are not in parentheses, but whose values ​​are set to 0, were altered to the human germline during the grafting process.In both plots, the dashed gray line at 75% represents the cutoff point for tolerance to the replacement of murine residues by the human germline.

[045] Figure 3. Direct titration ELISA for IgG binding to human, mouse, and canine CD47-Fc proteins. The chimeric anti-CD47 clones (mVH / mVL), derived from the human IgG1 format library, were titrated (in μg / ml) in a direct binding ELISA against human, mouse, and canine CD47-Fc proteins (AH). mVH / mVL, library-derived clones, and the designer clone MH demonstrated binding activity against all 3 CD47 orthologs. The VH-A1 / VL-B1 clone binds to CD47. Petition 870260064866, dated 01 / 07 / 2026, p. 24 / 146 15 / 85 human and canine, but does not bind to the mouse. The TTP clone has lost almost all binding functions. In each graph, the X-axis shows the IgG concentration in μg / ml and the Y-axis shows the binding signal (OD 450 nm).

[046] Figure 4. CD47-Fc-SIRPa competition assay based on ELISA. The ELISA binding signal for human (A), cine (B), and mouse (C) CD47-Fc proteins to human SIRPa bound to the plaque was examined in the presence of titrated major library derivatives of competitors: A-D5, G-B6, D-H3, and VHA1 / VL-B1 in IgG1null format, IgG1 isotype as a negative control, plus mVH / mVL in IgG1null format as a positive control. All library-derived IgGs and mVH / mVL demonstrated a concentration-dependent reduction in binding to human, murine, and cine CD47-Fc proteins, suggesting the maintenance of a shared epitope. Notably, clone AD5 exhibited significantly increased potency in neutralizing mouse CD47 compared to mVH / mVL, and VH-A1 / VL-B1 did not show the ability to neutralize murine CD47 activity. Neither the designer clone MH nor TTP exhibited any neutralization signal and are not plotted here for clarity.In each graph, the X-axis shows the antibody concentration in nM and the Y-axis shows the binding signal (OD 450 nm). In the figure legends, IC refers to the isotype control.

[047] Figure 5. Binding specificity analyses for prioritized lead clones. Risk of off-target homolog binding for mVH / mVL in IgG1 format (A) and IgG1null (B) and library-derived lead clones A-D5 (C), VHA1 / VL-B1 (D), F-E7 (E), D-H3 (F), and G-B6 (G) in IgG1 format were examined by direct ELISA on CD47-Fc orthologs and a panel of 14 human immunoglobulin superfamily proteins labeled on each X-axis (B refers to blank). Binding to human, canine, and murine CD47Fcs (h / c / mCD47-Fc) was performed in a Petition 870260064866, dated 01 / 07 / 2026, p. 25 / 146 16 / 85 IgG concentration of 1 μg / ml. Binding to all other proteins was performed at an IgG concentration of 10 μg / ml. In each graph, the Y-axis shows binding signal (OD 450 nm). For almost all IgGs, binding was observed only to hCD47Fc, mCD37-Fc, and cCD47-Fc. No binding was observed above the bottom for any other human protein. Notably, the VHA1 / VL-B1 clone again showed no reactivity to murine CD47.

[048] Figure 6. Flow cytometric binding to CD47+ CHO-K1 cino and human cells. The commercial anti-CD47 antibody MS1991, human IgG1 (IgG1) and IgG4 (IgG4) isotype controls, and major library-derived IgGs in IgG1null (IgG1N) and IgG4 (S228P) formats were examined for specific binding to cino-transfected CHO-K1 cells (A), human-transfected CHO-K1 cells (B), and wild-type (by weight, i.e., non-transfected) CHO-K1 cells (C). IgGs were tested at concentrations ranging from 24–100,000 ng / ml. Concentration-dependent binding was observed against human and cino cell lines for all CD47-specific antibodies, but not for the isotype controls. Low-level binding signals above the background against wild-type CHO-K1 cells were observed for most antibodies, with a significantly stronger signal for mVH / mVL-derived IgGs and a particularly weak signal for VH-A1 / VL-B1 IgGs.In each graph, the X-axis shows each IgG tested and its concentration in ng / ml, and the Y-axis shows the mean fluorescence intensity (MFI).

[049] Figure 7. Cytometric flow assay of binding to human HL60 cells. Commercial anti-CD47 antibody MS1991, human IgG1 and IgG4 isotype controls (IgG1 and IgG4, respectively), major library-derived IgGs in both IgG1null (IgG1N) and IgG4 (S228P) formats were examined for specific binding to HL60 cells. IgGs were tested at concentrations ranging from 24-100000 ng / ml. A Petition 870260064866, dated 01 / 07 / 2026, page 26 / 146 17 / 85 concentration-dependent binding was observed for all clones except the isotype controls. In each graph, the X-axis shows each IgG tested and its concentration in ng / ml, and the Y-axis shows the mean fluorescence intensity (MFI).

[050] Figure 8. Development risk ELISAs. This assay showed that antibodies A-D5, G-B6, D-H3, VH-A1 / VL-B1 and mVH / mVL in IgG1null form exhibit little or no binding to negatively charged biomolecules Insulin (A), double-stranded DNA (dsDNA) (B) and single-stranded DNA (ssDNA) (C). In each graph, the X-axis shows the IgG concentration in μg / ml and the Y-axis shows the binding signal (OD 450 nm). Strong off-target binding to these molecules, as observed for Bococizumab and Briakinumab analogs, has been shown to be a high-risk indicator of poor clinical performance of therapeutic antibodies.

[051] Figure 9. Direct titration ELISA for binding of designer IgGs to human, mouse, and canine CD47-Fc proteins. Chimeric anti-CD47 clones (mVH / mVL), designer clones derived from A-D5 in human IgG1null format, were titrated (in μg / ml) in a direct binding ELISA against human (A), canine (B), and mouse (C) CD47Fc proteins. In each graph, the X-axis shows the IgG concentration in μg / ml and the Y-axis shows the binding signal (OD 450 nm). Most clones demonstrated binding activity against all 3 CD47 orthologs, although clone A-D5.7 showed only weak binding to canine CD47 and clone A-D5.10 lost almost all mouse CD47 binding function. In the figure legend, IgG1NI refers to the null isotype of IgG1.

[052] Figure 10. CD47-Fc-SIRP« competition test based on ELISA for designer IgGs. The ELISA binding signal for human (A), canine (B) and mouse (C) CD47-Fc proteins to human SIRPa bound to the plate was examined in the presence of competing designer IgGs titrated in the IgG1null format, plus the IgG1 isotype as a negative control (represented by IgG1NI). Petition 870260064866, dated 01 / 07 / 2026, p. 27 / 146 18 / 85 and mVH / mVL in IgGlnull format as a positive control. In each graph, the X-axis shows the IgG concentration in nM and the Y-axis shows the binding signal (OD 450 nm). Notably, several clones derived from A-D5 again exhibited significantly increased potency in neutralizing mouse CD47 compared to mVH / mVL. Neither the designer clone AD5.7 nor A-D5.10 exhibited any neutralization signal in the orthologs for which they showed weak binding signal on ELISA and are not plotted here for clarity.

[053] Figure 11. Direct titration ELISA for designer IgGs derived from A-D5.4 that bind to human, mouse, and canine CD47-Fc proteins. Chimeric anti-CD47 clones (mVH / mVL), clones derived from designer A-D5.4, in human IgGlnull format, were titrated (in μg / ml) in a direct binding ELISA against human (A), canine (B), and mouse (C) CD47-Fc proteins. In each graph, the X-axis shows the IgG concentration in μg / ml and the Y-axis shows the binding signal (OD 450 nm). All clones demonstrated binding activity against all 3 CD47 orthologs. In the figure legends, IgGlNI refers to the IgG1null isotype.

[054] Figure 12. CD47-Fc-SIRP« competition assay based on ELISA for designer IgGs. The ELISA binding signal for human (A), cine (B), and mouse (C) CD47-Fc proteins to human SIRPa bound to the plate was examined in the presence of competing designer IgGs titrated in IgG1null format, plus the IgG1 isotype as a negative control (represented by “IgGlNI”) and mVH / mVL in IgG1null format as a positive control. In each graph, the X-axis shows the IgG concentration in nM and the Y-axis shows the binding signal (OD 450 nm). Notably, several clones derived from A-D5.4 again exhibited significantly increased potency in neutralizing mouse CD47 compared to mVH / mVL. Petition 870260064866, dated 01 / 07 / 2026, p. 28 / 146 19 / 85

[055] Figure 13. Binding specificity analyses for designer clones A-D5.4 and A-D5.16. The risk of off-target homolog binding for A-D5.4 (A) and A-D5.16 (B) in IgG1null format was examined by direct ELISA on CD47-Fc orthologs and a panel of 14 human immunoglobulin superfamily proteins (as indicated on each X-axis; B refers to white). Binding to all proteins was performed at an IgG concentration of 10 μg / ml. In each graph, the Y-axis shows binding signal (OD 450 nm). For both IgGs, binding was observed only to hCD47-Fc, mCD37-Fc, and cCD47-Fc. No binding was observed above the background for any other human protein.

[056] Figure 14. Development risk ELISAs for designer clones A-D5.4 and A-D5.16. This assay showed that A-D5.4 and A-D5.16 antibodies in the IgG1null form exhibit low binding (below the negative control, Ustekinumab) to negatively charged biomolecules Insulin (A), double-stranded DNA (dsDNA) (B), and single-stranded DNA (ssDNA) (C). In each graph, the X-axis shows the IgG concentration in μg / ml and the Y-axis shows the binding signal (OD 450 nm). Strong off-target binding to these molecules, as observed for Bococizumab and Briakinumab analogs, has been shown to be a high-risk indicator of poor clinical performance of therapeutic antibodies.

[057] Figure 15. Flow cytometric binding of library-derived designer IgGs to CHO-K1 cells. Commercial anti-CD47 antibody MS1991, human IgG1 and IgG4 isotype controls (represented by I IgG1 and I IgG4, respectively), and major IgGs A-D5, A-D5.4, and A-D5.16, in both IgG1null and IgG4 formats, were examined for specific binding to wild-type (i.e., non-transfected) CHO-K1 cells. IgGs were tested at concentrations ranging from 24 to 25,000 ng / ml. Concentration-dependent binding was observed for the mVH / mVL parental antibody in both IgG1null and IgG4 formats, but only weak or no binding was observed. Petition 870260064866, dated 01 / 07 / 2026, p. 29 / 146 20 / 85 observed in the Isotype, MS1991 and IgGs A-D5, A-D5.4 and AD5.16 controls in both IgG formats. In each graph, the X-axis shows the IgG concentration in ng / ml, and the Y-axis shows the MFI.

[058] Figure 16. Cytometric flow assay of binding to human HL60 cells. Commercial anti-CD47 antibody MS1991, human IgG1 and IgG4 isotype controls (represented by I IgG1 and I IgG4, respectively), major IgGs in IgGlnull and IgG4 (S228P) formats were examined for specific binding to HL60 cells. IgGs were tested at concentrations ranging from 24-100000 ng / ml. Concentration-dependent binding was observed for all clones except the Isotype controls. In each graph, the X-axis shows the IgG concentration in ng / ml, and the Y-axis shows MFI.

[059] Figure 17. T cell epitope peptide content in the v domains of the main antibody. The v domains of mVH / mVL, A-D5, A-D5.4, A-D5.16, and A-D5.16-DI antibodies were examined for the presence of germline (GE), high external affinity (HAF), low external affinity (LAF), and TCED+ T cell receptor epitopes. The VH and VL domains of mVH / mVL were found to contain multiple high-risk human T cell epitopes and few germline epitopes. In all main clones, the high-risk epitope content was significantly reduced, and the germline epitope content significantly improved.

[060] Figure 18. Direct titration ELISA for designer IgGs A-D5.16 and A-D5.16-DI that bind to human, mouse, and canine CD47-Fc proteins. The chimeric anti-CD47 clones (mVH / mVL), designer A-D5.16 and A-D5.16-DI in human IgG1null format were titrated (in μg / ml) in a direct binding ELISA against human (A), canine (B), and mouse (C) CD47-Fc proteins. All clones demonstrated binding activity against all 3 CD47 orthologs. In each graph, the X-axis shows Petition 870260064866, dated 01 / 07 / 2026, p. 30 / 146 21 / 85 is the IgG concentration in μg / ml, and the Y-axis shows the binding signal (OD 450 nm).

[061] Figure 19. CD47-Fc-SIRPa S competition assay based on ELISA for designer IgGs. The ELISA binding signal for human (A), cino (B), and mouse (C) CD47-Fc proteins to human SIRPa bound to the plate was examined in the presence of competitor-titrated IgGs titrated in IgG1 format, plus the IgG1 isotype as a negative control and mVH / mVL in IgG1null format as a positive control. In each graph, the X-axis shows the antibody concentration in nM and the Y-axis shows the binding signal (OD 450 nm).

[062] Figure 20. Phagocytosis analyses by flow cytometry. (A) Flow cytometry analysis of phagocytosis of CSFE-labeled HL60 cells by human CD14+ macrophages was performed at multiple concentrations (as shown on the X-axis) for clones A-D5, A-D5.4, A-D5.16 and mVH / mVL in IgG4 format (S228P) and additionally A-D5 in IgG1null format (represented by IgG1 A-D5N). The X-axis shows the antibody concentration (μg / ml) and the Y-axis shows the % of cells that are CSFE+ and CD14+. (B) The analysis was then repeated in several human macrophage donors for A-D5 and mVH / mVL in IgG4 format, at a standard concentration of 10 μg / ml. The X-axis shows the donor number and the Y-axis shows the percentage of cells that are CFSE+ and CD14+. V indicates vehicle. DETAILED DESCRIPTION OF THE INVENTION

[063] According to a first aspect of the invention, an antibody molecule is provided that binds specifically to human CD47 and, optionally, also to cynomolgus monkey CD47 and / or mouse CD47, or an antigen-binding fragment thereof, wherein the antibody molecule or antigen-binding fragment comprises a variable heavy chain region with: Petition 870260064866, dated 01 / 07 / 2026, p. 31 / 146 22 / 85 an HCDR1 with amino acids in sequence in the following order: GY-T or any amino acid (e.g., S, N, or R)-FT or a conservative substitution of TN or a conservative substitution of NYYI or a conservative substitution of IF or any amino acid (e.g., V or G) (SEQ ID NO: 1); an HCDR2 with amino acids in sequence in the following order: M or a conservative substitution of MGI or any amino acid (e.g., N, V, or D)-IN or any amino acid (e.g., Y)-PV or any acidic amino acid (e.g., G or F)-D or a conservative substitution of DG or a conservative substitution of GDTN or a conservative substitution of N (e.g., R)-Y or a conservative substitution of YN or a conservative substitution of N (e.g., S)-PSFQG (SEQ ID NO: 2); and an HCDR3 with amino acids in sequence in the following order: GG-Y or any amino acid (e.g., H, I, Q, or F)-T or any amino acid (e.g., V or I)-M or any amino acid (e.g., T, R, P, A, or L)-D or any amino acid (e.g., G)-R or any amino acid (e.g., Q, N, Y, S, W, K, A, E, F, H, I, L, M, T, or V) (SEQ ID NO: 3).

[064] In aspects of the invention, the HCDR1 of the antibody molecule or antigen-binding fraction can exclude the GYTFTNYYVF sequence (SEQ ID NO: 4) (murine antibody VxP037 / humanized HCDR1 disclosed in WO2014 / 093678A2) and / or the HCDR3 of the antibody molecule or antigen-binding fraction can exclude the GGYTMDY sequence (SEQ ID NO: 5) (murine antibody VxP037 / humanized HCDR3 disclosed in WO2014 / 093678A2).

[065] The antibody molecule or its antigen-binding fragment according to the invention may further comprise a variable region of the light chain with: an LCDR1 with amino acids in sequence in the following order: RS-SQ or a conservative substitution of QSL or a Petition 870260064866, dated 01 / 07 / 2026, p. 32 / 146 23 / 85 conservative substitution of LL or a conservative substitution of LHSN or any amino acid (e.g., Q, S, T, A, or G) or a conservative substitution of N (e.g., Q, S, T, or G)-G or a conservative substitution of G (e.g., A)-Y or any amino acid (e.g., N or S)-T or a conservative substitution of T (e.g., N)-YLH or any amino acid (e.g., D) (SEQ ID NO: 6); An LCDR2 with amino acids in sequence in the following order: K or any amino acid (e.g., L or M) - V or any amino acid (e.g., G) - SN or any amino acid (e.g., Y) - RL or any amino acid (e.g., F, A, or S) - S (SEQ ID NO: 7); and an LCDR3 with amino acids in sequence in the following order: F or any amino acid (e.g., L, M, S, T, or V) - QQ or any amino acid (e.g., N, A, T, or S) - T or any amino acid (e.g., L, M, or I) - H or a conservative substitution of HT or any amino acid (e.g., V, I, A, or F) - P or any amino acid (e.g., L) - R or any amino acid (e.g., W) - T (SEQ ID NO: 8).

[066] In aspects of the invention, LCDR1 of the antibody molecule or antigen-binding fraction can exclude the RSSQSLVHSNGNTYLH sequence (SEQ ID NO: 9) (murine antibody VxP037 / humanized LCDR1 disclosed in WO2014 / 093678A2) and / or LCDR2 of the antibody molecule or antigen-binding fraction can exclude the KVSYRFS sequence (SEQ ID NO: 10) (murine antibody VxP037 / humanized LCDR2 disclosed in WO2014 / 093678A2) and / or LCDR3 of the antibody molecule or antigen-binding fraction can exclude the SQNTHVPRT sequence (SEQ ID NO: 11) (murine antibody VxP037 / humanized LCDR3 disclosed in WO2014 / 093678A2).

[067] The CDR sequences above are defined using the Unified definition, as set out in Table 1. Alternatively, the CDR sequences in the present invention may be defined using the shorter AHo definition (see the Petition 870260064866, dated 01 / 07 / 2026, p. 33 / 146 24 / 85 Table 1), which is based on structural biology and aims to unify the nomenclature for all V domains of immunoglobulin.

[068] Using the shorter definition of AHo, the invention, in one aspect, provides an antibody molecule that binds specifically to human CD47 and, optionally, also to cynomolgus monkey CD47 and / or mouse CD47, or to an antigen-binding fragment, wherein the antibody molecule or antigen-binding fragment comprises a variable region of the heavy chain with: an HCDR1 with amino acids in sequence in the following order: GS-GYT or any amino acid (e.g., S, N, or R)-FT or a conservative substitution of TN or a conservative substitution of NYY (SEQ ID NO: 12); A HCDR2 with amino acids in sequence in the following order: IN or any amino acid (e.g., Y)-PV or any amino acid (e.g., G or F)-D or a conservative substitution of DG or a conservative substitution of GDTN or a conservative substitution of N (e.g., R)-Y or a conservative substitution of YN or a conservative substitution of N (e.g., S)-PSFQG (SEQ ID NO: 13); and a HCDR3 with amino acids in sequence in the following order: GG-Y or any amino acid (e.g., H, I, Q, or F)-T or any amino acid (e.g., V or I)-M or any amino acid (e.g., T, R, P, A, or L)-D or any amino acid (e.g., G) (SEQ ID NO: 14).

[069] Using the AHo definition, HCDR1 of the antibody molecule or antigen-binding fragment may exclude the sequence GSGYTFTNYY (SEQ ID NO: 15) (murine antibody VxP037 / humanized HCDR1 disclosed in document WO2014 / 093678A2) and / or HCDR3 of the antibody molecule or antigen-binding fragment may exclude the sequence GGYTMD (SEQ ID NO: 16) (murine antibody VxP037 / humanized HCDR3 disclosed in WO2014 / 093678A2). Petition 870260064866, dated 01 / 07 / 2026, p. 34 / 146 25 / 85

[070] The antibody molecule or antigen-binding fragment may further comprise a variable region of the light chain with: an LCDR1 with amino acids in sequence in the following order: SS-Q or a conservative substitution of QSL or a conservative substitution of LL or a conservative substitution of LHSN or any amino acid (e.g., Q, S, T, A, or G) or a conservative substitution of N (e.g., Q, S, T, or G)-G or a conservative substitution of G (e.g., A)-Y or any amino acid (e.g., N or S)-T or a conservative substitution of T (e.g., N)-Y (SEQ ID NO: 17); An LCDR2 with amino acids in sequence in the following order: K or any amino acid (e.g., L or M) - V or any amino acid (e.g., G) - SN or any amino acid (e.g., Y) - RL or any amino acid (e.g., F, A, or S) - S (SEQ ID NO: 7); and an LCDR3 with amino acids in sequence in the following order: Q or any amino acid (e.g., N, A, T, or S) - T or any amino acid (e.g., L, M, or I) - H or a conservative substitution of HT or any amino acid (e.g., V, I, A, or F) - P or any amino acid (e.g., L) - R or any amino acid (e.g., W) (SEQ ID NO: 18).

[071] Using AHo's definition, in aspects of the invention, the LCDR1 of the antibody molecule or antigen-binding fraction may exclude the SSQSLVHSNGNTY sequence (SEQ ID NO: 19) (murine antibody VxP037 / humanized LCDR1 disclosed in WO2014 / 093678A2) and / or the LCDR2 of the antibody molecule or antigen-binding fraction may exclude the KVSYRFS sequence (SEQ ID NO: 10) (murine antibody VxP037 / humanized LCDR2 disclosed in WO2014 / 093678A2) and / or the LCDR3 of the antibody molecule or antigen-binding fraction may exclude the NTHVPR sequence (SEQ ID NO: 20) (murine antibody VxP037 / humanized LCDR3 disclosed in WO2014 / 093678A2). Petition 870260064866, dated 01 / 07 / 2026, p. 35 / 146 26 / 85

[072] As elaborated herein, the present inventors have for the first time succeeded in generating a number of optimized anti-CD47 antibody molecules using CDR sequences derived from the murine anti-CD47 antibody VxP037 disclosed in WO2014 / 093678A2. In embodiments of the present invention, these antibody molecules were selected to have binding specificity to both human CD47 and cynomolgus monkey CD47 and, for some clones, also to mouse CD47 (to facilitate studies in animal test species). Further refinement of the optimized antibody molecules, as described herein, provided improved binding to the mouse CD47 ortholog, improved potency in neutralizing mouse CD47-SIRPq signaling, improved variable domain stability, high expression yields and / or reduced immunogenicity.For example, we demonstrate here that the murine anti-CD47 antibody progenitor molecule VxP037 carries two main immunogenicity risks in LCDR1 and LCDR2 that will be performed with classical humanization techniques (as used in document WO2014 / 093678A2), but which are improved in the optimization of antibody molecules as described here.

[073] The antibody molecule or antigen-binding fragment of the present invention may have improved in silico immunogenicity compared with an antibody molecule comprising the CDR sequences of the SEQ ID NOs: 4 (HCDR1), 123 (HCDR2), 5 (HCDR3), 9 (LCDR1), 10 (LCDR2) and 11 (LCDR3).

[074] The antibody molecule or antigen-binding fragment of the present invention may not exhibit binding to hamster CD47 or may exhibit reduced binding to hamster CD47 compared to an antibody molecule comprising the CDR sequences of SEQ ID NOS: 4 (HCDR1), 123 (HCDR2), 5 (HCDR3), 9 (LCDR1), 10 (LCDR2), and 11 (LCDR3). For example, the molecule of Petition 870260064866, dated 01 / 07 / 2026, p. 36 / 146 The antibody or antigen-binding fraction of the present invention may exhibit no binding to CHO cells as measured by flow cytometry, or reduced binding to CHO cells as measured by flow cytometry, compared to an antibody comprising the CDR sequences of SEQ ID NOs: 4 (HCDR1), 123 (HCDR2), 5 (HCDR3), 9 (LCDR1), 10 (LCDR2), and 11 (LCDR3). As shown in Fig. 15, the representative antibody molecules of the present invention have little or no cross-reactivity with CHO cells, while the original murine v domains of the mVH / mVL clone in IgG1null or IgG4 format conduct strong, concentration-dependent binding to CHO cells.

[075] The preferred optimized anti-CD47 antibody molecules of the present invention do not necessarily have the maximum number of human germline substitutions at the corresponding murine CDRs or at other amino acid positions (as a structure). As elaborated in the experimental section below, we found that maximally humanized antibody molecules are not necessarily maximally optimized in terms of anti-CD47 binding characteristics and / or other desirable characteristics.

[076] The present invention encompasses modifications to the amino acid sequence of the antibody molecule or its antigen-binding moiety, as defined herein. For example, the invention includes antibody molecules and their corresponding antigen-binding moieties comprising functionally equivalent variable regions and CDRs that do not significantly affect their properties, as well as variants possessing enhanced or diminished activity or affinity. For example, the amino acid sequence can be mutated to obtain an antibody with the desired binding affinity to CD47. Insertions are provided that include amino- and / or carboxyl-terminal fusions with lengths ranging from one residue to polypeptides containing one hundred or more residues, as well as intrasequent insertions. Petition 870260064866, dated 01 / 07 / 2026, page 37 / 146 28 / 85 of single or multiple amino acid residues. Examples of terminal insertions include an antibody molecule with an N-terminal methionyl residue or the antibody molecule fused with an epitope tag. Other variants of antibody molecule insertion include the fusion to the N- or C-terminal of the antibody of an enzyme or polypeptide that increases the antibody's half-life in the bloodstream.

[077] The antibody molecule or antigen-binding fragment of the invention may include glycosylated and non-glycosylated polypeptides, as well as polypeptides with other post-translational modifications, such as, for example, glycosylation with different sugars, acetylation and phosphorylation. The antibody molecule or antigen-binding fragment of the invention may be mutated to alter these post-translational modifications, for example, by adding, removing or replacing one or more amino acid residues to form or remove a glycosylation site.

[078] The antibody molecule or antigen-binding fragment of the invention can be modified, for example, by amino acid substitution to remove potential proteolytic sites in the antibody.

[079] In the antibody molecule or in its antigen-binding fragment, HCDR1 may have the amino acid sequence: G-YT / S / N / RFT / NN / SYYI / VF / V / G (SEQ ID NO: 21); HCDR2 may have the amino acid sequence: M / IGV / N / I / DIN / YPV / G / FN / DG / SDTN / R / KF / YN / SPSFQG (SEQ ID NO: 22); and HCDR3 may have the amino acid sequence: GGF / H / I / Q / YT / V / IM / T / R / P / A / LD / GY / Q / N / R / S / W / K / A / E / F / H / I / L / M / T / V (SEQ ID NO: 23). Alternatively, using the definition of AHo, in the antibody molecule or its antigen-binding fragment, HCDR1 may have the amino acid sequence: GSGYT / S / N / RFT / NN / SYY (SEQ ID NO: 24); HCDR2 may have the amino acid sequence: IN / YPV / G / FN / DG / SDTN / R / KF / YN / SPSFQG (SEQ ID NO: Petition 870260064866, dated 01 / 07 / 2026, p. 38 / 146 29 / 85 25); and HCDR3 may have the amino acid sequence: G-GF / H / I / Q / YT / V / IM / T / R / P / A / LD / G (SEQ ID NO: 26).

[080] For example, HCDR1 may have the amino acid sequence: GYT / SFTNYYIF (SEQ ID NO: 27); HCDR2 may have the amino acid sequence: M / IGI / DINPVN / DGDTN / RF / YN / SPSFQG (SEQ ID NO: 28); and HCDR3 may have the amino acid sequence: GGF / YTM / PDY / R / K / I (SEQ ID NO: 29). Alternatively, using the AHo definition, HCDR1 may have the amino acid sequence: GSGYT / SFTNYY (SEQ ID NO: 30); HCDR2 may have the amino acid sequence: INPVN / DGD-TN / RF / YN / SPSFQG (SEQ ID NO: 31); and HCDR3 may have the amino acid sequence: GGF / YTM / PD (SEQ ID NO: 32).

[081] In the antibody molecule or its antigen-binding fragment, LCDR1 may have the amino acid sequence: R-SS-Q / HSF / LL / VHSN / Q / AG / AY / N / SN / TYLH / D (SEQ ID NO: 33); LCDR2 may have the amino acid sequence: L / K / MV / G-SN / YRA / F / L / SS (SEQ ID NO: 34); and LCDR3 may have the amino acid sequence: F / L / M / S / T / VQQ / N / A / T / ST / L / M / IQ / HT / V / I / A / FP / LR / WT (SEQ ID NO: 35). Alternatively, using the AHo definition, in the antibody molecule or its antigen-binding fragment, LCDR1 may have the amino acid sequence: SSQ / HS-F / LL / VHSN / Q / AG / AY / N / SN / TY (SEQ ID NO: 36); LCDR2 may have the amino acid sequence: L / K / MV / GSN / YRA / F / L / SS (SEQ ID NO: 34); and LCDR3 may have the amino acid sequence: Q / N / A / T / ST / L / M / IQ / HT / V / I / A / FP / LR / W (SEQ ID NO: 37).

[082] For example, LCDR1 may have the amino acid sequence: RSSQSLL / VHSN / Q / AGY / NN / TYLH / D (SEQ ID NO: 38); LCDR2 may have the amino acid sequence: L / KV / GSN / YRA / F / LS (SEQ ID NO: 39); and LCDR3 may have the amino acid sequence: F / SQQ / N / AT / LQ / HT / VPRT (SEQ ID NO: 40). Alternatively, using the AHo definition, LCDR1 may have the amino acid sequence: SSQSLL / VHSN / Q / A-GY / NN / TY (SEQ ID NO: 41); LCDR2 may have the sequence of Petition 870260064866, dated 01 / 07 / 2026, p. 39 / 146 30 / 85 amino acids: L / KV / GSN / YRA / F / LS (SEQ ID NO: 39); and LCDR3 may have the amino acid sequence: Q / N / AT / LQ / HT / VPR (SEQ ID NO: 42).

[083] In specific embodiments of the invention, as defined using the unified CDR definition, the antibody molecule or antigen-binding fraction may comprise: (a) as amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGDINPVNGDTNYSPSFQG (SEQ ID NO: 44) (HCDR2), GGYTPDY (SEQ ID NO: 45) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 44)) (LCDR1), KGSNRFS (SEQ ID NO: 47) (LCDR2) e SQNLHVPRT (SEQ ID NO: 48) (LCDR3) [Clone D-H3]; or (b) as sequences of amino acids GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYTYLH (SEQ ID NO: 50) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) e FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5]; or (c) as sequences of amino acids GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), IGDINPVNGDTNFSPSFQG (SEQ ID NO: 55) (HCDR2), GGYTMDK (SEQ ID NO: 56) (HCDR3), RSSQSLVHSNGYTYLH (SEQ ID NO: 55) (LCDR1), KGSYRAS (SEQ ID NO: 58) (LCDR2) e SQNTQTPRT (SEQ ID NO: 59) (LCDR3) [Clone G-B6];or (d) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVNGDTNYNPSFQG (SEQ ID NO: 60) (HCDR2), GGYTMGK (SEQ ID NO: 61) (HCDR3), RSSQSLVHSNGNTYLD 62 (SEQ ID NO: 43)) (LCDR1), KGSYRFS (SEQ ID NO: 63) (LCDR2) and SQATHTPRT (SEQ ID NO: 64) (LCDR3) [Clone F-E7]; or (e) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGFTMDY (SEQ ID NO: 66) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 65)) (LCDR1), KGSNRAS (SEQ ID NO: 67) (LCDR2) and SQNTHTPRT (SEQ ID NO: 68) (LCDR3) [Clone VH-A1 / VL-B1]; or (f) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), IGIINPVDGDTRYSPSFQG (SEQ ID NO: 69) (HCDR2), GGYTMDI; Petition 870260064866, dated 01 / 07 / 2026, p. 40 / 146 31 / 85 (SEQ ID NO: 70) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO)) (LCDR1), LGSNRFS (SEQ ID NO: 71) (LCDR2) e SQNTQTPRT (SEQ ID NO: 59) (LCDR3) [Clone MH]; ou (g) ​​as sequências de aminoácidos GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDI (SEQ ID NO: 70) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO)) (LCDR1), LGSNRAS (SEQ ID NO: 72) (LCDR2) e SQATQTPRT (SEQ ID NO: 73) (LCDR3) [Clone TTP]; or (h) as amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYTYLH (SEQ ID NO: 50) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) e FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.1]; or (i) as sequences of amino acids GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYNPSFQG (SEQ ID NO: 74) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYTYLH (SEQ ID NO52) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) e FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.2]; or (j) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYTYLH (SEQ ID NO:) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.3]; or (k) the amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 50)) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5. 4]; or (l) the amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 50)) (LCDR1), KGSNRLS (SEQ ID NO: 75) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5. 5]; or. Petition 870260064866, dated 01 / 07 / 2026, p. 41 / 146 32 / 85 (m) amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 50)) (LCDR1), KGSNRLS (SEQ ID NO: 75) (LCDR2) and FQNTQTPRT (SEQ ID NO: 76) (LCDR3) [Clone A-D5.6]; or (n) the amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 50)) (LCDR1), LGSNRLS (SEQ ID NO: 77) (LCDR2) and FQNTQTPRT (SEQ ID NO: 76) (LCDR3) [Clone A-D5.7]; or (o) the amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSQQYYLH (SEQ ID NO: 50)) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.8]; or (p) the amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYTYLH (SEQ ID NO: 50)) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQQTHTPRT (SEQ ID NO: 79) (LCDR3) [Clone A-D5.9]; or (q) the amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSQQYYLH (SEQ ID NO: 50)) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQQTHTPRT (SEQ ID NO: 79) (LCDR3) [Clone A-D5. 10]; or (r) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 50)) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.11]; or (s) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYNPSFQG (SEQ ID NO: 74) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYNYLH (SEQ ID NO: 43)). Petition 870260064866, dated 01 / 07 / 2026, p. 42 / 146 33 / 85 (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.12]; or (t) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNGYNYLSSE (SEQ ID NO: 43), KVQSNR ID NO: ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.13]; or (u) as amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSSGYNYLHSE (SEQ ID NO: 43), KVQSNR ID NO: ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.14]; or (v) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSGYNYLH (SEQ ID NO: 43), KVQSNR ID NO: (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.15]; or (w) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSAGYNYLH (SEQ ID NO:) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5. 16]; or (x) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSTGYNYLH (SEQ ID NO)) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5. 17]; or (y) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNAYNYLH (SEQ ID NO:) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5.18]; or. Petition 870260064866, dated 01 / 07 / 2026, p. 43 / 146 34 / 85 (z) the amino acid sequences GYSFTNYYIF (SEQ ID NO: 43) (HCDR1), MGIINPVDGDTRYSPSFQG (SEQ ID NO: 65) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSAGYNYLH (SEQ ID NO:) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5. 16-DI]; or (z. 1) the amino acid sequences GYTFTNYYIF (SEQ ID NO: 49) (HCDR1), MGIINPVDGDTNYNPSFQG (SEQ ID NO: 50) (HCDR2), GGYTMDR (SEQ ID NO: 51) (HCDR3), RSSQSLLHSNQYTYLH (SE): 52) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2) and FQNTHTPRT (SEQ ID NO: 54) (LCDR3) [Clone A-D5-DI].

[084] In the specific embodiments of the invention described above, CDRs may alternatively be defined using the definition of AHo CDR, such that the antibody molecule or antigen-binding fraction comprises: (a) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVNGDTNYSPSFQG (SEQ ID NO: 87) (HCDR2), GGYTPD (SEQ ID NO: 88) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KGSNRFS (SEQ ID NO: 47) (LCDR2) and NLHVPR (SEQ ID NO: 90) (LCDR3) [Clone D-H3]; or (b) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5]; or (c) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVNGDTNFSPSFQG (SEQ ID NO: 94) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLVHSNGYTY (SEQ ID NO: 95)) (LCDR1), KGSYRAS (SEQ ID NO: 58) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone G-B6]; or (d) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVNGDTNYNPSFQG (SEQ ID NO: 97) (HCDR2), GGYTMG (SEQ ID NO: 98) (HCDR3), SSQSLVHSNGNTY (SEQ ID NO:) (LCDR1), KGSYRFS Petition 870260064866, dated 01 / 07 / 2026, p. 44 / 146 35 / 85 (SEQ ID NO: 63) (LCDR2) and ATHTPR (SEQ ID NO: 99) (LCDR3) [Clone F-E7]; or (e) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGFTMD (SEQ ID NO: 101) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KGSNRAS (SEQ ID NO: 67) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone VH-A1 / VL-B1]; or (f) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), LGSNRFS (SEQ ID NO: 71) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone MH]; or (g) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), LGSNRAS (SEQ ID NO: 72) (LCDR2) and ATQTPR (SEQ ID NO: 102) (LCDR3) [TTP clone];or (h) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.1]; or (i) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYNPSFQG (SEQ ID NO: 103) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.2]; or (j) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.3]; or; Petition 870260064866, dated 01 / 07 / 2026, p. 45 / 146 36 / 85 (k) amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89)) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 4]; or (l) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KGSNRLS (SEQ ID NO: 75) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.5]; or (m) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KGSNRLS (SEQ ID NO: 75) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone A-D5.6]; or (n) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), LGSNRLS (SEQ ID NO: 77) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone A-D5.7]; or (o) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSQGYTY (SEQ ID NO: 104) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.8]; or (p) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and QTHTPR (SEQ ID NO: 105) (LCDR3) [Clone A-D5.9]; or (q) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSQGYTY (SEQ ID NO: 104) (LCDR1),. Petition 870260064866, dated 01 / 07 / 2026, p. 46 / 146 37 / 85 KVSNRLS (SEQ ID NO: 53) (LCDR2) and QTHTPR (SEQ ID NO: 105) (LCDR3) [Clone A-D5.10]; or (r) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.11]; or (s) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYNPSFQG (SEQ ID NO: 103) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 12]; or (t) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.13]; or (u) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSSGYNY (SEQ ID NO: 106) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 14]; or (v) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSGGYNY (SEQ ID NO: 107) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 15]; or (w) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSAGYNY (SEQ ID NO: 108) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 16]; or. Petition 870260064866, dated 01 / 07 / 2026, p. 47 / 146 38 / 85 (x) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSTGYNY (SEQ ID NO: 109) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 17]; or (y) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNAYNY (SEQ ID NO: 110) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 18]; or (z) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSAGYNY (SEQ ID NO: 108) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 16-DI]; or (z.1) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2) and NTHTPR (SEQ ID NO: 93) LCDR3) [Clone A-D5-DI].

[085] The antibody molecule or antigen-binding fraction of the invention (defined using AHo's definition) may comprise: an HCDR1 with the amino acid sequence GSGYTFTNYY (SEQ ID NO: 15) or GSGYSFTNYY (SEQ ID NO: 86); an HCDR2 with the amino acid sequence INPVDGDTNYNPSFQG (SEQ ID NO: 91) or INPVDGDTRYSPSFQG (SEQ ID NO: 100); and an HCDR3 with the amino acid sequence GGYTMD (SEQ ID NO: 16) and, optionally, further comprising: an LCDR1 with the amino acid sequence SSQSLLHSNGYNY (SEQ ID NO: 89) or SSQSLLHSNGYTY (SEQ ID NO: 92) or SSQSLLHSAGYNY (SEQ ID NO: 108); Petition 870260064866, dated 01 / 07 / 2026, p. 48 / 146 39 / 85 an LCDR2 with the amino acid sequence KVSNRLS (SEQ ID NO: 53) or KVSNRFS (SEQ ID NO: 85); and an LCDR3 with the amino acid sequence NTHTPR (SEQ ID NO: 93).

[086] The antibody molecule above or the antigen-binding fraction may alternatively be defined using the equivalent Unified CDR definitions as disclosed here.

[087] In particular embodiments of the invention, the antibody molecule or antigen-binding fragment may comprise the six CDR sequences of Clone A-D5, Clone A-D5.4 or Clone A-D5.16 or Clone A-D5.16-DI or Clone A-D5-DI as defined above, or a suitable combination of the CDR sequences of each of these clones.

[088] For example, in the antibody molecule or antigen-binding fraction, as defined using the unified CDR definition, HCDR1 may have the amino acid sequence: GYT / SF-TNYYIF (SEQ ID NO: 27); HCDR2 may have the amino acid sequence: MGIINPVDGDTN / RYN / SPSFQG (SEQ ID NO: 111); HCDR3 may have the amino acid sequence: GGY-TM-DR (SEQ ID NO: 51); LCDR1 may have the amino acid sequence: RSSQSLHSN / AGYN / TYLH (SEQ ID NO: 112); LCDR2 may have the amino acid sequence: KVSNRL / FS (SEQ ID NO: 113); and LCDR3 may have the amino acid sequence: FQNTHTPRT (SEQ ID NO: 54).

[089] Alternatively, in the antibody molecule or antigen-binding fragment, as defined using the AHo definition, HCDR1 may have the amino acid sequence: GSGYT / SF-TNYY (SEQ ID NO: 30); HCDR2 may have the amino acid sequence: INPVDGDTN / RYN / SPSFQG (SEQ ID NO: 114); HCDR3 may have the amino acid sequence: GGYTMD (SEQ ID NO: 16); LCDR1 may have the amino acid sequence: SS-QSLLHSN / AGYN / TY (SEQ ID NO: 115); LCDR2 may have the amino acid sequence: KVSNRL / FS (SEQ ID NO: 113); and Petition 870260064866, dated 01 / 07 / 2026, p. 49 / 146 40 / 85 LCDR3 may have the amino acid sequence: NTHTPR (SEQ ID NO: 93).

[090] The antibody molecule or antigen-binding fragment, as defined herein, may comprise one or more substitutions, deletions and / or insertions that remove a post-translational modification (PTM) site, for example, a glycosylation site (N-linked or O-linked), a deamination site, a phosphorylation site or an isomerization / fragmentation site.

[091] More than 350 types of PTMs are known. The main forms of PTMs include phosphorylation, glycosylation (N- and O-linked), soilation, palmitoylation, acetylation, sulfation, myristoylation, pre-alkylation, and methylation (of K- and R residues). Statistical methods for identifying putative amino acid sites responsible for specific PTMs are well known in the art (see Zhou et al., 2016, Nature Protocols 1: 1318-1321). Removal of such a site, for example, by substitution, deletion, and / or insertion, and then optional testing (experimentally and / or theoretically) for (a) binding activity and / or (b) loss of the PTM is contemplated.

[092] For example, murine LCDR1 VxP037 (as defined herein, i.e., the amino acid sequence RSSQSLVHSNGNTYLH (SEQ ID NO: 9)) has been identified as having a putative deamidation site at residue 10(N) and / or 12(N). Removal of either of these two sites at equivalent positions in an LCDR1 of the invention, for example by conservative substitution (such as S, A, Q or D), is provided for (as for example in clone A-D5.8, clone A-D5 and other clones in Tables 3 and 4, or clones A-D5.11 to A-D5.18 in Table 5).

[093] Similarly, murine LCDR3 VxP037 (as defined herein, i.e., amino acid sequence SQNTHVPRT (SEQ ID NO: 11)) was identified as having a putative deamidation site at residue 3(N). Removal of this site at a position Petition 870260064866, dated 01 / 07 / 2026, p. 50 / 146 41 / 85 equivalent in an LCDR3 of the invention, for example, by conservative or non-conservative substitution (such as A, S, H, D, T, K, G, E, Q or R), is provided (as for example in clone F-E7 and other clones in Tables 3 and 4).

[094] Similarly, murine HCDR3 VxP037 (as defined herein, i.e., amino acid sequence GGYTMDY (SEQ ID NO: 5)) was identified as having a putative oxidation site at residue 5 (M). Removal of this site at an equivalent position in an HCDR3 of the invention, for example, by conservative or non-conservative substitution (such as P, A, T, S, L, F, W, V, I, Y or R), is provided for (as for example in clone D-H3 and other clones in Tables 3 and 4). [09 5] The antibody molecule or its antigen-binding fragment may be human, humanized, or chimeric. [09 6] The antibody molecule or its antigen-binding moiety may comprise one or more human variable domain structure carriers into which CDRs have been inserted. [09 7] The antibody molecule or its antigen-binding fragment may comprise a human germline IGHV5-51 scaffold into which the corresponding HCDR sequences have been inserted. [09 8] The antibody molecule or its antigen-binding fragment may comprise a human germline IGKV2-28 scaffold into which the corresponding LCDR sequences have been inserted. [09 9] The antibody molecule or its antigen-binding fragment may comprise an immunologically inert constant region.

[100] The antibody molecule or its antigen-binding fragment may be a Fab fragment, an F(ab)2 fragment, an Fv fragment, a tetrameric antibody, a tetravalent antibody, a multispecific antibody (e.g., a bivalent antibody), a single antibody domain (e.g., Petition 870260064866, dated 01 / 07 / 2026, page 51 / 146 42 / 85 a shark antibody [VNAR antibody], or a fragment thereof, or a camelid antibody [VHH antibody], or a fragment thereof), a monoclonal antibody or a fusion protein. Antibody molecules and methods for their construction and use are described, for example, Holliger & Hudson (2005, Nature Biotechnol. 23 (9): 1126-1136).

[101] In another aspect of the invention, an immunoconjugate is provided comprising the antibody molecule or its antigen-binding moiety of the invention, as defined herein, linked to a therapeutic agent.

[102] Examples of suitable therapeutic agents include cytotoxins, radioisotopes, chemotherapeutic agents, immunomodulatory agents, antiangiogenic agents, antiproliferative agents, pro-apoptotic agents, and cytostatic and cytolytic enzymes (e.g., RNAs). Other therapeutic agents include a therapeutic nucleic acid, such as a gene encoding an immunomodulatory agent, an antiangiogenic agent, an antiproliferative agent, or a pro-apoptotic agent. These drug descriptors are not mutually exclusive, and therefore a therapeutic agent may be described using one or more of the above terms.

[103] Examples of therapeutic agents suitable for use in immunoconjugates include taxanes, maytansines, CC-1065 and duocarmycins, calicheamicins and other enedines, and auristatins. Other examples include antifolates, vinca alkaloids, and anthracyclines. Plant toxins, other bioactive proteins, enzymes (i.e., ADEPT), radioisotopes, and photosensitizers can also be used in immunoconjugates. In addition, conjugates can be made using secondary vehicles as cytotoxic agents, such as liposomes or polymers. Suitable cytotoxins include an agent that inhibits or prevents cell function and / or results in cell destruction. Representative cytotoxins include Petition 870260064866, dated 01 / 07 / 2026, page 52 / 146 43 / 85 antibiotics, tubulin polymerization inhibitors, alkylating agents that bind to and disrupt DNA, and agents that disrupt protein synthesis or the function of essential cellular proteins, such as protein kinases, phosphatases, topoisomerases, enzymes, and cyclins.

[104] Representative cytotoxins include, but are not limited to, doxorubicin, daunorubicin, idarubicin, aclarubicin, zorubicin, mitoxantrone, epirubicin, carubicin, nogalamycin, menogaril, pitarubicin, valrubicin, cytarabine, gemcitabine, trifluridine, ancitabine, enocitabine, azacitidine, doxyfluhdine, pentostatin, broxuhdine, capecitabine, cladhbine, decitabine, floxuhdine, fludarabine, gougerotin, puromycin, tegafur, thiazofur, adamycin, cisplatin, carboplatin, cyclophosphamide, dacarbazine, vinblastine, vinctristine, mitoxantrone, bleomycin, mechlorethamine, prednisone, procarbazine, methotrexate, fluorouracil, etoposide, taxol, taxol analogues, platinums such as cis-platinum and carbo-platinum, mitomycin, thiotepa, taxanes, vincristine, daunorubicin, epirubicin, actinomycin, authramycin, azaserines, bleomycins, tamoxifen, idarubicin, dolastatins / auristatins, hemiasterins, esperamycins and maytansinoids.

[105] Suitable immunomodulatory agents include antihormones that block hormonal action in tumors and immunosuppressive agents that suppress cytokine production, downregulate autoantigen expression, or mask MHC antigens.

[106] Also provided is a nucleic acid molecule that encodes the antibody molecule or its antigen-binding moiety of the invention, as defined herein.

[107] A vector comprising the nucleic acid molecule of the invention, as defined herein, is also provided. Petition 870260064866, dated 01 / 07 / 2026, page 53 / 146 44 / 85

[108] A host cell comprising the nucleic acid molecule or vector of the invention as defined herein is also provided.

[109] In a further aspect, a method is provided for producing an anti-CD47 antibody and / or an antigen-binding fraction, comprising culturing the host cell of the invention under conditions resulting in the expression and / or production of the antibody and / or its antigen-binding fraction and isolating the antibody and / or its antigen-binding fraction from the host cell or culture.

[110] In another aspect of the invention, a pharmaceutical composition is provided comprising the antibody molecule or its antigen-binding moiety of the invention, as defined herein, or the nucleic acid molecule of the invention, as defined herein, or the vector of the invention, as defined herein.

[111] In addition, a method is provided for improving an immune response in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction of the invention, as defined herein, or the immunoconjugate of the invention, as defined herein, or the nucleic acid molecule of the invention as defined herein, or the vector of the invention as defined herein, or the pharmaceutical composition of the invention as defined herein.

[112] In a further aspect, a method is provided for treating or preventing cancer in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction of the invention, as defined herein, or the immunoconjugate of the invention, as defined herein, or the nucleic acid molecule of the invention as defined herein, or the vector of the invention as defined herein, or the pharmaceutical composition of the invention as defined herein.

[113] Cancer can, for example, be selected from the group consisting of: pancreatic cancer, melanoma, breast cancer, Petition 870260064866, dated 01 / 07 / 2026, page 54 / 146 45 / 85 lung cancer, bronchial cancer, colorectal cancer, prostate cancer, stomach cancer, ovarian cancer, bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical or endometrial cancer, oral cavity or pharynx cancer, liver cancer, kidney cancer, testicular cancer, bile duct cancer, small intestine or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, and hematologic tissue cancer.

[114] The invention also provides an antibody molecule or its antigen-binding moiety as defined herein, or the immunoconjugate as defined herein, or the nucleic acid molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein, for use in the treatment of cancer.

[115] In another aspect, the invention provides the antibody molecule, or its antigen-binding fraction, or the immunoconjugate, or the nucleic acid molecule, or the vector for use, or the treatment method of the invention, as defined herein, for sequential or simultaneous use in a combined combination with a second therapeutic agent, for example, an anticancer agent.

[116] In a further aspect, the use of an antibody molecule or an antigen-binding fraction of the invention, as defined herein, or an immunoconjugate of the invention, as defined herein, or a nucleic acid molecule of the invention, as defined herein, or a vector of the invention as defined herein, or a pharmaceutical composition of the invention as defined herein, in the manufacture of a medicament for the treatment of cancer is provided. Petition 870260064866, dated 01 / 07 / 2026, page 55 / 146 46 / 85

[117] The invention also provides a method for treating or preventing an ischemia-reperfusion injury, an autoimmune disease or an inflammatory disease in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the nucleic acid molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein.

[118] Ischemia-reperfusion injury in all aspects can occur in organ transplantation, acute kidney injury, cardiopulmonary bypass surgery, pulmonary hypertension, sickle cell disease, myocardial infarction, stroke, surgical resections and reconstructive surgery, reattachment of an appendix or other body part, skin grafting or trauma.

[119] Autoimmune or inflammatory disease may be selected from the group consisting of: arthritis, multiple sclerosis, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, Graves' disease, Hashimoto's thyroiditis and ankylosing spondylitis.

[120] Also provided is an antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the nucleic acid molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein, for use in the treatment of an ischemia-reperfusion injury, an autoimmune disease or an inflammatory disease.

[121] In addition, provision is made for the use of an antibody molecule or its antigen-binding fraction as defined herein, or an immunoconjugate as defined herein, or a nucleic acid molecule as defined herein, or a vector as defined herein, or a pharmaceutical composition as defined herein Petition 870260064866, dated 01 / 07 / 2026, page 56 / 146 47 / 85 defined, in the manufacture of a medicament for the treatment of an ischemia-reperfusion injury, an autoimmune disease or an inflammatory disease.

[122] The invention also provides a method for the treatment or prevention of a cardiovascular disease or a fibrotic disease in an individual, comprising administering an effective amount of the antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the acid core molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein.

[123] Also provided is an antibody molecule or its antigen-binding fraction, as defined herein, or the immunoconjugate as defined herein, or the nucleic acid molecule as defined herein, or the vector as defined herein, or the pharmaceutical composition as defined herein, for use in the treatment of a cardiovascular disease or a fibrotic disease.

[124] Furthermore, the use of an antibody molecule or its antigen-binding moiety, as defined herein, or an immunoconjugate as defined herein, or a nucleic acid molecule as defined herein, or a vector as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of a cardiovascular disease or a fibrotic disease is provided.

[125] Cardiovascular disease in any aspect of the invention may be, for example, coronary heart disease or atherosclerosis.

[126] Fibrotic disease in any aspect of the invention may be selected from the group consisting of myocardial infarction, angina, osteoarthritis, pulmonary fibrosis, asthma, cystic fibrosis and bronchitis.

[127] The pharmaceutical composition of the invention may comprise a pharmaceutically acceptable excipient. An excipient Petition 870260064866, dated 01 / 07 / 2026, page 57 / 146 A pharmaceutically acceptable 48 / 85 vehicle may be a compound or a combination of compounds that are part of a pharmaceutical composition that does not cause side effects and that allows, for example, easier administration of the anti-CD47 antibody molecule, an increase in its shelf life and / or its effectiveness in the body, or an increase in its solubility in solution. These pharmaceutically acceptable vehicles are well known and will be adapted by the person skilled in the art according to the method of administration of the anti-CD47 antibody molecule.

[128] In some embodiments, the antiCD47 antibody molecule may be supplied in a lyophilized form for reconstitution prior to administration. For example, lyophilized antibody molecules may be reconstituted in sterile water and mixed with saline solution prior to administration to an individual.

[129] Anti-CD47 antibody molecules will normally be administered in the form of a pharmaceutical composition, which may comprise at least one component in addition to the antibody molecule. Thus, pharmaceutical compositions may comprise, in addition to the anti-CD47 antibody molecule, an excipient, carrier, buffer, stabilizer, or other pharmaceutically acceptable materials well known to those skilled in the art. These materials must be non-toxic and must not interfere with the efficacy of the anti-CD47 antibody molecule. The precise nature of the carrier or other material will depend on the route of administration, which may be bolus, infusion, injection, or any other suitable route, as discussed below.

[130] For parenteral administration, for example, subcutaneous or intravenous administration, for example, by injection, the pharmaceutical composition comprising the anti-CD47 antibody molecule may be in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has adequate pH, isotonicity and stability. Those skilled in Petition 870260064866, dated 01 / 07 / 2026, page 58 / 146 49 / 85 techniques are capable of preparing suitable solutions using, for example, isotonic vehicles such as sodium chloride injection, Ringe's solution, lactated Ringe's solution. Preservatives, stabilizers, buffers, antioxidants and / or other additives may be employed as needed, including buffers such as phosphate, citrate and other organic acids; antioxidants such as ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; paraben alcohol, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3'-pentanol; and m-cresol); low molecular weight polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine;Monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions, such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[131] A pharmaceutical composition comprising an anti-CD47 antibody molecule may be administered alone or in combination with other treatments, depending simultaneously or sequentially on the condition to be treated.

[132] An anti-CD47 antibody molecule, as described herein, may be used in a method of treating the human or animal body, including prophylactic or preventive treatment (e.g., treatment before the onset of a condition in an individual to reduce the risk of the condition occurring in the individual; delaying its onset or reducing its severity after onset). The treatment method may comprise the administration Petition 870260064866, dated 01 / 07 / 2026, page 59 / 146 50 / 85 of the anti-CD47 antibody molecule to an individual in need of it.

[133] Administration is normally in a therapeutically effective amount, sufficient to show benefit to a patient. This benefit may be at least the improvement of at least one symptom. The actual amount administered, the rate and timing of administration will depend on the nature and severity of what is being treated, the specific mammal being treated, the clinical condition of each patient, the cause of the disorder, the site of treatment, delivery of the composition, the method of administration, the schedule of administration, and other factors known to physicians. Treatment prescription, for example, decisions about dosage, etc., is the responsibility of general practitioners and other physicians and may depend on the severity of symptoms and / or progression of a disease being treated. Appropriate doses of antibody molecules are well known in the art (Ledermann JA et al., 1991, Int. J. Cancer 47: 659-664; Bagshawe KD et al.(1991, Antibody, Immunoconjugates and Radiopharmaceuticals 4: 915922). Specific dosages may be indicated here or in the Physician's Desk Reference (2003), as appropriate for the type of medication to be administered. A therapeutically effective amount or appropriate dose of an antibody molecule can be determined by comparing its in vitro activity and in vivo activity in an animal model. Methods are known for extrapolating effective dosages from mice and other test animals to humans. The precise dose will depend on several factors, including whether the antibody is for prevention or treatment, the size and location of the area to be treated, the precise nature of the antibody (e.g., whole antibody, fragment), and the nature of any detectable tag or other molecule attached to the antibody. Petition 870260064866, dated 01 / 07 / 2026, page 60 / 146 51 / 85

[134] A typical antibody dose will be in the range of 100 μg to 1 g for systemic applications and 1 μg to 1 mg for topical applications. A higher initial dose may be administered, followed by one or more lower doses. Typically, the antibody will be a complete antibody, for example, the IgG1 or IgG4 isotype. This is a dose for a single treatment of an adult patient, which may be adjusted proportionally for children and infants, and also adjusted for other antibody formats in proportion to molecular weight. Treatments may be repeated daily, twice weekly, weekly, or monthly, at the physician's discretion. The treatment regimen for an individual may depend on the pharmacokinetic and pharmacodynamic properties of the antibody composition, the route of administration, and the nature of the condition being treated.

[135] Treatment may be periodic and the period between administrations may be about two weeks or more, for example, about three weeks or more, about four weeks or more, about once a month or more, about five weeks or more, or about six weeks or more. For example, treatment may be every two to four weeks or every four to eight weeks. Treatment may be administered before and / or after surgery and / or may be administered or applied directly to the anatomical site of the surgical treatment or invasive procedure. Suitable formulations and routes of administration are described above.

[136] In some embodiments, anti-CD47 antibody molecules, as described herein, may be administered as subcutaneous injections. Subcutaneous injections may be administered using an autoinjector, for example, for long-term prophylaxis / treatment.

[137] In some preferred embodiments, the therapeutic effect of the anti-CD47 antibody molecule may persist for several half-lives, depending on the dose. For example, the effect Petition 870260064866, dated 01 / 07 / 2026, p. 61 / 146 The therapeutic effect of a single dose of the anti-CD47 antibody molecule (52 / 85) may persist in an individual for 1 month or more, 2 months or more, 3 months or more, 4 months or more, 5 months or more, or 6 months or more.

[138] The invention also provides a method for producing an antibody molecule that binds specifically to human CD47 and, optionally, also to cynomolgus monkey CD47 and / or mouse CD47, or to an antigen-binding fraction, comprising the steps of: (1) grafting anti-CD47 CDRs from a non-human source into a human v-domain structure to produce a humanized anti-CD47 antibody molecule or an antigen-binding fragment thereof; (2) generate a phage library of clones of the humanized anti-CD47 antibody molecule or its antigen-binding fraction, comprising one or more mutations in the CDRs; (3) screening of the phage library for binding to human CD47 and optionally also to cynomolgus monkey CD47 and / or mouse CD47; (4) select clones from screening step (3) possessing binding specificity to human CD47 and optionally also to cynomolgus monkey CD47 and / or mouse CD47; and (5) production of an antibody molecule that binds specifically to human CD47 and optionally also to cynomolgus monkey CD47 and / or mouse CD47, or to an antigen-binding fraction of the clones selected in step (4).

[139] The method may comprise an additional step of producing additional clones based on the clones selected in step (4), for example, based on additional exploratory mutagenesis at specific positions in the CDRs of the clones selected in step (4), to improve humanization, minimize human T cell epitope content and / or improve Petition 870260064866, dated 01 / 07 / 2026, page 62 / 146 53 / 85 the manufacturing properties in the antibody molecule or its antigen-binding fraction produced in step (5).

[140] The method may comprise an additional step of evaluating the immunogenicity of one or more v domains in the clones selected in step (4) or in the antibody molecule produced in step (5) and, optionally, generating one or more additional mutations, for example, in a CDR and region of the structure, to reduce immunogenicity. Immunogenicity may be evaluated by identifying the location of T cell epitopes, for example, using in silico technologies as described herein.

[141] The refinements applicable to the above method are described in Example 1 below.

[142] As used herein, the term CD47 refers to Integrin-Associated Protein (IAP) and its variants that retain at least some of the biological activity of CD47. As used herein, CD47 includes all mammalian species of the native CD47 sequence, including humans, rats, mice, and chickens. The term CD47 is used to include variants, isoforms, and species homologs of human CD47. The antibodies of the invention can cross-react with CD47 from other non-human species, in particular CD47 from cynomolgus macaques (Macaca fascicularis). In certain embodiments, the antibodies can be completely specific for human CD47 and cannot exhibit non-human cross-reactivity.

[143] As used herein, an antagonist as used in the context of the antibody of the invention or an anti-CD47 antagonist antibody (referred to as an anti-CD47 antibody) refers to an antibody capable of binding to CD47 and inhibiting the biological activity of CD47 and / or downstream pathways mediated by CD47 signaling. An anti-CD47 antagonist antibody encompasses antibodies that can block, antagonize, suppress, or reduce (including significantly) the biological activity of CD47, including Petition 870260064866, dated 01 / 07 / 2026, p. 63 / 146 54 / 85 downstream pathways mediated by CD47 signaling, such as receptor binding and / or obtaining a cellular response to CD47. For the purposes of the present invention, it will be explicitly understood that the term anti-CD47 antagonist antibody encompasses all terms, titers, functional states, and characteristics by which the biological activity of CD47 itself (including, but not limited to, its ability to enhance phagocytosis activation by myeloid lineage cells), or the consequences of that activity or biological activity, are substantially abolished, diminished, or neutralized to any significant degree.

[144] CD47 binds specifically, interacts specifically, binds preferentially, binds or interacts with CD47 if it binds with greater affinity, avidity, more readily and / or for a longer duration than it binds to other receptors.

[145] An antibody molecule is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.As used herein, the term antibody molecule encompasses not only intact polyclonal or monoclonal antibodies, but also any antigen-binding fragment (e.g., an antigen-binding fraction) or single chain thereof, fusion proteins comprising an antibody, and any other modified configuration of the immunoglobulin molecule comprising an antigen recognition site, including, for example, but not limited to, scFv, single-domain antibodies (e.g., shark antibodies [VNAR antibodies] or a fragment thereof and camelid antibodies [VHH antibodies] or fragments thereof), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, and bis-scFv. Petition 870260064866, dated 01 / 07 / 2026, page 64 / 146 55 / 85

[146] An antibody molecule encompasses an antibody of any class, such as IgG, IgA, or IgM (or its subclass), and the antibody does not need to be of any specific class. Depending on the amino acid sequence of the antibody's constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be divided into subclasses (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The constant regions of the heavy chain that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[147] The term antigen-binding fraction of an antibody molecule, as used herein, refers to one or more fragments of an intact antibody that retain the ability to bind specifically to CD47. The antigen-binding functions of an antibody molecule can be performed by fragments of an intact antibody. Examples of binding fragments included in the term antigen-binding fraction of an antibody molecule include Fab; Fab'; F(ab')2; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a single-domain antibody fragment (dAb) and an isolated complementarity-determining region (CDR).

[148] The term Fc region is used to define a C-terminal region of an immunoglobulin heavy chain. The “Fc region” can be a native sequence Fc region or a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the Fc region of the human IgG heavy chain is generally defined to extend from an amino acid residue at the Cys226 position, or from Pro230, to its terminus. Petition 870260064866, dated 01 / 07 / 2026, page 65 / 146 56 / 85 carboxyl. The numbering of residues in the Fc region is that of the EU index, as in Kabat. The Fc region of an immunoglobulin generally comprises two constant domains, CH2 and CH3. As is known in the art, an Fc region may be present in dimer or monomer form.

[149] An antibody “variable region” refers to the antibody light chain variable region or the antibody heavy chain variable region, alone or in combination. As known in the art, heavy and light chain variable regions consist of four structural regions (FRs) connected by three complementarity-determining regions (CDRs), also known as hypervariable regions, contributing to the formation of the antibody antigen-binding site. When choosing FRs to flank CDRs, for example, when humanizing or optimizing an antibody, antibody FRs containing CDR sequences in the same canonical class are preferred.

[150] The CDR definitions used in this application combine the domains used in the many disparate and often conflicting schemes that have been created in the field, based on the combination of immunoglobulin repertoire analyses and structural analyses of antibodies in isolation and in their crystals with antigens (see review by Swindells et al., 2016, abYsis: Integrated antibody sequence and structure management, analysis and prediction. J Mol Biol. [PMID: 27561707; Epub August 22, 2016]). The CDR definition used here (a Unified definition) incorporates the lessons from all of this previous information and includes all the appropriate loop positions needed to sample the entire residue landscape that potentially mediates target binding complementarity.

[151] Table 1 shows the amino acid sequences of the murine anti-CD47 antibody CDRs VxP037, as defined here (a Unified Scheme), compared with well-known alternative systems for defining the same CDRs. Petition 870260064866, dated 01 / 07 / 2026, p. 66 / 146 57 / 85

[152] As used herein, the term conservative substitution refers to the substitution of one amino acid for another amino acid that does not significantly alter functional activity. A preferred example of a conservative substitution is the substitution of one amino acid for another amino acid that has a ^0 value in the following BLOSUM 62 substitution matrix (see Henikoff and Henikoff, 1992, PNAS 89: 10915-10919): ARNDCQEGHILKMFPSTWYV A 4 -1 -2 -2 0 -1 -1 0 -2 -1 -1 -1 -1 -2 -1 1 0 -3 -20 R -1 5 0 -2 -3 1 0 -2 0 -3 -2 2 -1 -3 -2 -1 -1 -3 -2-3 N -2 0 6 1 -3 0 0 0 1 -3 -3 0 -2 -3 -2 1 0 -4 -2-3 D -2 -2 1 6 -3 0 2 -1 -1 -3 -4 -1 -3 -3 -1 0 -1 -4 -3-3 C 0 -3 -3 -3 9 -3 -4 -3 -3 -1 -1 -3 -1 -2 -3 -1 -1 -2 -2-1 Q -1 1 0 0 -3 5 2 -2 0 -3 -2 1 0 -3 -1 0 -1 -2 -1-2 E -1 0 0 2 -4 2 5 -2 0 -3 -3 1 -2 -3 -1 0 -1 -3 -2-2 G 0 -2 0 -1 -3 -2 -2 6 -2 -4 -4 -2 -3 -3 -2 0 -2 -2 -3-3 H -2 0 1 -1 -3 0 0 -2 8 -3 -3 -1 -2 -1 -2 -1 -2 -2 2-3 I -1 -3 -3 -3 -1 -3 -3 -4 -3 4 2 -3 1 0 -3 -2 -1 -3 -13 L -1 -2 -3 -4 -1 -2 -3 -4 -3 2 4 -2 2 0 -3 -2 -1 -2 -11 K -1 2 0 -1 -3 1 1 -2 -1 -3 -2 5 -1 -3 -1 0 -1 -3 -2-2 M -1 -1 -2 -3 -1 0 -2 -3 -2 1 2 -1 5 0 -2 -1 -1 -1 -11 F -2 -3 -3 -3 -2 -3 -3 -3 -1 0 0 -3 0 6 -4 -2 -2 1 3-1 P -1 -2 -2 -1 -3 -1 -1 -2 -2 -3 -3 -1 -2 -4 7 -1 -1 -4 -3-2 S 1 -1 1 0 -1 0 0 0 -1 -2 -2 0 -1 -2 -1 4 1 -3 -2-2 T 0 -1 0 -1 -1 -1 -1 -2 -2 -1 -1 -1 -1 -2 -1 1 5 -2 -20 W -3 -3 -4 -4 -2 -2 -3 -2 -2 -3 -2 -3 -1 1 -4 -3 -2 11 2-3 Y -2 -2 -2 -3 -2 -1 -2 -3 2 -1 -1 -2 -1 3 -3 -2 -2 2 7-1 V 0 -3 -3 -3 -1 -2 -2 -3 -3 3 1 -2 1 -1 -2 -2 0 -3 -14.

[153] The term monoclonal antibody (Mab) refers to an antibody, or its antigen-binding fraction, that is derived from a single copy or clone, including, for example, any eukaryotic, prokaryotic or phage clone, and not the method by which it is produced. Preferably, a monoclonal antibody of the invention exists in a homogeneous or substantially homogeneous population. Petition 870260064866, dated 01 / 07 / 2026, p. 67 / 146 58 / 85

[154] A humanized antibody molecule refers to a form of non-human antibody molecules (e.g., murine), or their antigen-binding moiety, which are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding antibody subsequences) that contain a minimal sequence derived from non-human immunoglobulin. Humanized antibodies may be human immunoglobulins (receptor antibody) in which residues of a CDR of the recipient are replaced by residues of a CDR of a non-human species (donor antibody), such as mouse, rat or rabbit with the desired specificity, affinity and capacity.

[155] Human antibody or fully human antibody refers to an antibody molecule, or its antigen-binding fraction, derived from transgenic mice carrying human antibody genes or from human cells.

[156] The term chimeric antibody is intended to refer to an antibody molecule, or its antigen-binding moiety, in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody molecule in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.

[157] Antibody-drug conjugate and immunoconjugate refer to an antibody molecule, or its antigen-binding moiety, including antibody derivatives that bind to CD47 and are conjugated to cytotoxic, cytostatic and / or therapeutic agents.

[158] The antibody molecules of the invention, or their antigen-binding fraction, can be produced using techniques well known in the art, for example, recombinant technologies, phage display technologies, synthetic technologies or Petition 870260064866, dated 01 / 07 / 2026, page 68 / 146 59 / 85 combinations of such technologies or other technologies readily known in the art.

[159] The term epitope refers to the portion of a molecule capable of being recognized and bound by an antibody molecule or its antigen-binding moiety, in one or more of the antigen-binding regions of the antibody molecule. Epitopes may consist of defined regions of the primary secondary or tertiary protein structure and include combinations of secondary structural units or target structural domains recognized by the antigen-binding regions of the antibody or its antigen-binding moiety. Epitopes may also consist of a defined chemically active surface cluster of molecules such as amino acids or sugar side chains and have specific three-dimensional structural features as well as specific charge features.The term antigenic epitope, as used herein, is defined as a portion of a polypeptide to which an antibody molecule can bind specifically, as determined by any method well known in the art, for example, by conventional immunoassays, competitive antibody binding assays, or by X-ray crystallography or related structural determination methods (e.g., NMR).

[160] The term binding affinity or KD refers to the rate of dissociation of a given antigen-antibody interaction. KD is the ratio of the dissociation rate, also called the “off-rate” (kOff), to the association rate or “on-rate” (kon). Thus, KD equals kOff / kOn and is expressed as a molar concentration (M). It follows that the lower the KD, the greater the binding affinity. Therefore, a KD of 1 μM indicates weak binding affinity compared to a KD of 1 nM. KD values ​​for antibodies can be determined using well-established methods in the art. One method for determining the KD of an antibody is using surface plasmon resonance (SPR). Petition 870260064866, dated 01 / 07 / 2026, page 69 / 146 60 / 85 typically using a biosensor system, such as the Biacore® system.

[161] The term potency is a measure of biological activity and may be designated as IC50, or the effective concentration of an antibody or antibody conjugated to CD47 antigen to inhibit 50% of the activity measured in a CD47 activity assay as described herein.

[162] The phrase effective amount or therapeutically effective amount, as used herein, refers to an amount necessary (in dosages and for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount is at least the minimum amount, but less than a toxic amount, of an active agent that is necessary to confer therapeutic benefit to an individual.

[163] The term inhibit or neutralize, as used herein in relation to the bioactivity of an antibody molecule of the invention, means the ability of the antibody to antagonize, prohibit, prevent, restrict, retard, substantially slow down, decelerate, interrupt, substantially slow down, eliminate, stop, reduce or reverse, for example, the progression or severity of that which is being inhibited, including, but not limited to, a biological activity or binding interaction of the antibody molecule to CD47.

[164] A host cell includes an individual cell or cell culture that may be or has been a recipient of vectors for incorporation of polynucleotide inserts. Host cells include the progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in the complement of genomic DNA) to the original cell, due to natural, accidental, or deliberate mutation. A host cell includes cells transfected in vivo with a polynucleotide(s) of this invention. Petition 870260064866, dated 01 / 07 / 2026, page 70 / 146 61 / 85

[165] As used herein, vector means a construct that is capable of delivering and preferably expressing one or more gene(s) or sequence(s) of interest in a host cell. Examples of vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid or phage vectors, DNA or RNA expression vectors associated with cationic condensation agents, DNA or RNA expression vectors encapsulated in liposomes, and certain eukaryotic cells, such as producer cells.

[166] The term treatment, as used herein, unless otherwise indicated, means to reverse, alleviate, inhibit the progress of, delay the progression of, delay the onset of, or prevent the disorder or condition to which that term applies, or one or more symptoms of such disorder or condition. The term treatment, as used herein, unless otherwise indicated, refers to the act of treating as defined above. The term treatment also includes adjunctive and neoadjunctive treatment of an individual. For the avoidance of doubt, reference herein to treatment includes reference to curative, palliative, and prophylactic treatment. For the avoidance of doubt, references herein to treatment also include references to curative, palliative, and prophylactic treatment.

[167] It is understood that, whenever embodiments are described here using the idiom “comprising”, otherwise analogous embodiments described in terms of “consisting of” and / or “consisting essentially of” are also provided.

[168] Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group is absent from one or Petition 870260064866, dated 01 / 07 / 2026, page 71 / 146 62 / 85 more members of the group. The present invention also provides for the explicit exclusion of one or more of any of the members of the group in the claimed invention.

[169] Unless defined otherwise, all technical and scientific terms used herein have the same meaning that is commonly understood by one skilled in the art to which this invention pertains. In case of conflict, this specification, including definitions, shall prevail. Throughout this specification and claims, the word "comprises" or variations such as "comprises" or "comprises" shall be understood as implying the inclusion of an integer or group of integers, but not the exclusion of any other integer or group of integers. Unless otherwise provided by the context, singular terms shall include plurals and plural terms shall include the singular. Any example(s) following the term "for example" or "such as" are not intended to be exhaustive or limiting.

[170] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the knowledge of the art.

[171] Particular, non-limiting embodiments of the present invention will now be described with reference to the accompanying drawings. EXAMPLE 1. Generation and characterization of optimized anti-CD47 therapeutic antibodies Introduction

[172] In this example, we successfully generated a panel of optimized and antagonistic anti-CD47 antibodies. These anti-CD47 antibodies are well expressed, biophysically stable, highly soluble, and of maximized identity to preferred human germlines. Petition 870260064866, dated 01 / 07 / 2026, page 72 / 146 63 / 85 Materials and methods IgG cloning, transient expression, purification

[173] The DNA sequences encoding the v domain of the antibody were cloned via restriction-linkage cloning into separate heavy and light chain IgG expression cassettes in separate plasmid vectors. Antibodies were expressed in two forms of manipulated human IgG: IgG4 with the S228P mutation to stabilize the IgG4 hinge and IgG1null - IgG1 with the L234A / L235A / G237A lower hinge mutations, which minimize the effector functions triggered by the Fcy receptor. IgGs were expressed in HEK-293pi cells after transient transfection with endotoxin-free IgG expression plasmid preparations, according to the manufacturer's protocols. IgGs were purified using a single-step protocol: The conditioned medium was loaded (pure) onto a 1 ml ProA sepharose column, pre-equilibrated in PBS pH7.4.The column was washed with 5 volumes of PBS pH 7.4 before the protein was eluted with 100 mM glycine, pH 2.7, and subjected to dialysis in PBS pH 7.4 using a 30 kDa dialysis membrane. ELISAs for binding to IgG titration

[174] To coat Greiner Bio-One High-binding ELISA plates, target proteins were diluted to 1 μg / ml in carbonate buffer and added at 100 μl per well, at 4 °C, o / n. Coated plates were washed 3x with PBS pH 7.4, blocked with 1% BSA in PBS (380 μl / well) for 1 hour at room temperature, then washed 3x with PBS-Tween 20 (PBST). CD47 antibodies (100 μl / well; diluted in PBST) were then added and incubated for 1 hour at room temperature. Plates were then washed 3x with PBST and goat anti-human kappa chain HRP (100 μl / well) was added at room temperature for 1 hour. The plates were then washed 3 times with PBST and twice with PBS before the addition of 100 μL of TMB per well. The reactions Petition 870260064866, dated 01 / 07 / 2026, page 73 / 146 64 / 85 were interrupted by adding 100 μL of 2M H2SO4 / cavity and the OD was read on a plate reader at 450 nm.

[175] Anti-CD47 antibodies were tested for polyreactivity by ELISA. Purified, recombinant, target and non-target antigens were coated onto 96-well Nunc maxisorp plates at 100 ng per well in carbonate buffer at 4 °C overnight. The plates were then washed 3x with PBS, blocked with 1% BSA in PBS, then washed 3x with PBS-Tween20. A series of primary antibody dilutions was then applied, the plates were washed 3x with PBS-Tween20 followed by application of human anti-cabra kappa chain secondary antibody-HRP 1:4,000. The wells were then washed 3x with PBSTween20 and 2x with PBS, 100 μl of TMB peroxidase substrate was added per well, the reaction was stopped by the addition of 100 μl of 2M H2SO4, and the absorbances were read at 450 nm. Analysis of IgG binding via ELISA on negatively charged biomolecular surfaces was performed as previously described (see Mouquet et al., 2010, Nature 467: 591-595). Generation and selection of CD47 libraries

[176] The CD47 scFv repertoire was assembled by bulk oligo synthesis and PCR. The amplified scFv repertoire was then cloned via restriction ligation into a phagoid vector, transformed into E.coli TG-1 cells, and the phage repertoire rescued essentially as previously described in detail (Finlay et al., 2011, Methods Mol Biol 681: 383-401).

[177] Phage selections were performed by coating streptavidin magnetic microspheres with CD47Fc protein (human or cine), washing the spheres three times with PBS and resuspending them in PBS pH 7.4 plus 5% skim milk protein (SMP). These spheres were coated with a 200 nM target protein in round 1 of selection, followed by 100, 50 and 10 nM in subsequent rounds. Binding competition trial CD47-SIRPq Petition 870260064866, dated 01 / 07 / 2026, page 74 / 146 65 / 85

[178] A competitive ELISA assay was established to examine the ability of optimized derivats to block the binding interaction of CD47 with SIRPa. To coat Greiner Bio-One High bind ELISA plates, 10 μg / ml of human SIRPa-Fc in carbonate coating buffer was added at 100 μl per well, at 4 °C, o / n. Coated plates were washed 3x with PBS pH 7.4, blocked with 1% BSA in PBS (380 μl / well) for 1 hour at room temperature, then washed 3x with PBSTween 20 (PBST). Biotinylated human, mouse, or cino CD47-Fc was then added at 0.2 μg / ml in PBS, 100 μl per well, at room temperature for 60 minutes with or without the addition of competing IgGs. The plates were then washed 3 times with PBST and Streptavidin-HRP (100 μL / well) added at room temperature for 1 hour. The plates were then washed 3 times with PBST and twice with PBS before the addition of 100 μL of TMB per well.The reactions were stopped by adding 100 μL of 2M H2SO4 per cavity, and the OD was read on a plate reader at 450 nm. T cell epitope content of the v domain of the antibody: in silico analyses

[179] In silico technologies (Abzena, Ltd.), which are based on identifying the location of T-cell epitopes in antibodies and therapeutic proteins, were used to assess the potential immunogenicity in the v domains of the antibody. iTope™ was used to analyze the VL and VH sequences of key leads for peptides with high-affinity promiscuous binding to human MHC class II. Promising peptides with high affinity for MHC class II are thought to correlate with the presence of T-cell epitopes that are high-risk indicators for clinical immunogenicity of drug proteins. The iTope™ software predicts favorable interactions between amino acid side chains of a peptide and specific binding pockets (in particular pocket positions; p1, p4, p6, p7 and Petition 870260064866, dated 01 / 07 / 2026, page 75 / 146 66 / 85 p9) within the open binding grooves of 34 human MHC class II alleles. These alleles represent the most common HLA-DR alleles found worldwide, without weighting assigned to those found with higher prevalence in any particular ethnic population. Twenty of the alleles contain the 'open' p1 configuration and 14 contain the 'closed' configuration, where the glycine at position 83 is replaced by a valine. The location of the key binding residues is achieved by in silico generation of 9-mer peptides that overlap by eight amino acids spanning the test protein sequence. This process successfully discriminates with high precision between peptides that bind and those that do not bind to MHC class II molecules.

[180] In addition, the sequences were analyzed using the TCED™ (T Cell Epitope Database™) search to find matches with T cell epitopes previously identified by in vitro analyses of human T cell epitope mapping from other protein sequences. TCED™ is used to search any test sequence in a large database (> 10,000 peptides) of unrelated protein-derived peptides and antibody sequences. Phagocytosis analysis of cancer cells

[181] Human peripheral blood mononuclear cells (PBMCs) were isolated from whole blood by density gradient centrifugation. CD14+ PBMCs were subsequently isolated by magnetic cell isolation using CD14 microspheres. In parallel, HL-60 cells were labeled using a green cell tracer dye CFSE (carboxyfluorescein diacetate, succinimidyl ester). A total of 1.25 x 10⁶ labeled HL-60 cells were pre-incubated in the presence of anti-CD47 antibodies in 24-well plates for 1 hour at 37 °C in a humidified atmosphere containing 5% CO₂. After incubation, 5 x 10⁵ CD14-positive cells were added to each well and incubated for a further hour in the Petition 870260064866, dated 01 / 07 / 2026, page 76 / 146 67 / 85 same culture conditions. Cells were harvested by vigorous pipetting, fixed using ice-cold 4% paraformaldehyde for 10 minutes, and then blocked with an Fc receptor binding inhibitor monoclonal antibody for 10 minutes. After the blocking step, cells were incubated with an Alexa Fluor 647-conjugated anti-human CD14 antibody (AF647) at room temperature for 30 minutes and fixed for an additional 5 minutes in 4% paraformaldehyde.

[182] Cells were analyzed on a BD Fortessa flow cytometer, recording side scatter and forward scatter properties, along with CFSE and AF647 fluorescence intensity data. Data were captured until at least 1 x 10⁴ AF647 positive events were recorded. Data were analyzed post-acquisition using FlowJo software (version 10.4.2). Briefly, cellular debris was eliminated by scatter properties (SSC Area by FSC Area). Single cells were also blocked by SSC-Area by SSC-Height and then by FSC-Area by FSC-Height. From the remaining population of single cells, CFSE and double-positive CD14 cells were blocked using a quadrant gate placed based on the CD14-positive cell population in the vehicle-treated assay. The percentage of CFSE-positive cells from the CD14-positive population was calculated and plotted using GraphPad Prism software (version 7.0a). Results and discussion CDR grafting into preferred v genes of the human germline

[183] ​​CDRs of a murine antagonistic anti-CD47 IgG VP037 (Mvh / MVL; see WO2014 / 093678 and Table 2) were initially introduced into human germline immunoglobulin structural V-domain sequence scaffolds using CDR grafting. To focus our engineering efforts on definitively advantageous therapeutic IgG compounds with Petition 870260064866, dated 01 / 07 / 2026, page 77 / 146 68 / 85 optimal drug-like properties, it was decided to graft CDRs of the parental antibody onto preferred germline scaffolds IGHV5-51 and IGKV2-28, which are known to have good solubility and are frequently used in the expressed human antibody repertoire.

[184] These grafted CDR structures and definitions are described in Table 2. Heavy and light chain sequences for murine anti-CD47 antibody are also shown in Table 2. Although this CDR grafting process is well known, it is still problematic to predict whether a given set of human v-domain sequences will act as suitable acceptor structures for non-human CDR grafting. The use of unsuitable structures can lead to loss of target binding function, protein stability problems, or even impaired expression of the final IgG. The IGHV5-51 / IGKV2-28 graft was therefore pursued as a model for CDR mutagenesis and selection of improved clones. Library generation and sorting

[185] The IGHV5-51 / IGKV2-28 v-domain sequences grafted onto CDRs were combined into a VL-VH scFv format, and a mutagenesis library cassette was generated by bulk oligo synthesis and assembly. The final scFv library was ligated to a phage display vector and transformed into E. coli by electroporation to generate 1.3 x 109 independent clones. The build quality of the library was verified by sequencing 96 clones. These sequencing data showed that the positions encoding the murine or human germline residue at each variation position were effectively sampled at a frequency of approximately 50%. The libraries were rescued using the helper phage M13, and selections were performed on biotinylated CD47-Fc proteins from humans, mice, and cynomolgus monkeys in three separate branches A, B, and C. Petition 870260064866, dated 01 / 07 / 2026, page 78 / 146 69 / 85

[186] Post-selection screening (Fig. 1) and DNA sequencing revealed the presence of 854 unique scFv clones, binding to both human and mouse CD47, with significantly increased human content in the CDRs, while the structural sequences remained entirely germline. Among these 854 clones, germline coat mutations were observed in all CDRs (Table 3). The top clones were ranked based on the level of germline coat CDR versus ELISA signal for binding to both human and mouse CD47-Fc (Fig. 1). The v domains of the top four clones in this ranking, plus a fifth clone ('VHA1 / VL-B1') that combined the two heaviest and lightest v domains of the humanized light chain observed, were subcloned into IgG vector expression for further testing as shown below (Table 4).

[187] Although germline coat mutations were observed in all CDRs for the main clones derived directly from library selections, it remained possible that sequence analyses would allow other clones to be designed to have maximum humanization. The 854 unique sequence hits with binding signals against human and mouse protein were therefore used to analyze the frequency of murine amino acid retention in CDRs from this functionally characterized population. Positional amino acid retention frequency was expressed as a percentage found in the VH and VL domains (Fig. 2A and B). Murine residues with RF < 75% were considered positions that are possibly not essential for target binding paratope and are likely open to germline alignment, in a series of combinatorial designs.

[188] A project containing only murine waste with RF>75% was designated MH (MH = Maximally Humanized). Another designer clone ('TTP' = Totally Theoretically Possible) was also Petition 870260064866, dated 01 / 07 / 2026, page 79 / 146 70 / 85 was created, combining the 5 most humanized CDRs observed in the population. The MH and TTP clones were generated by gene synthesis and (along with the 4 library-derived clones described above and the positive control mVH / mVL v domains and CD47 non-reactive v domains) cloned into human expression vectors for production as IgG1null and IgG4 (S228P). All IgGs were readily expressed and purified from transient transfections of HEK-293 cells. Specificity of primary IgG and potency characteristics

[189] The purified IgGs described above were then tested for binding to human, mouse, and cine CD47-Fc using direct titration ELISA (Fig. 3). Surprisingly, this analysis demonstrated that while clones MH, A-D5, and D-H3 maintained binding affinity for all 3 CD47 orthologs, two clones showed reduced binding to mouse CD47 (G-B6 and F-E7), one clone (VHA 1 / VL-B1) maintained comparable binding to human and mouse CD47 but had lost cross-reactivity to mouse CD47, and one clone (TTP) had lost almost all binding function.

[190] In a CD47-SIRPq blocking assay (Fig. 4), A-D5, G-B6, F-E7, and D-H3 all exhibited concentration-dependent blocking of the interaction between human, mouse, and canine CD47 with SIRPn-Fc. The concentration varies as does the mVH / mVL IgG1 antibody. Notably, VH-A1 / VL-B1 IgG1 exhibited potent blocking of human and canine CD47, but no blocking of mouse CD47. Interestingly, the MH clone, despite demonstrating binding to all 3 CD47 orthologs in the ELISA, showed no blocking signal in any assay. The TTP clone was also negative in all blocking assays.

[191] To ensure that the main clones have not suffered any loss of target specificity during the process of Petition 870260064866, dated 01 / 07 / 2026, page 80 / 146 71 / 85 mutation and new selection; the main and control IgG1 clones were tested for binding to a panel of 14 purified human immunoglobulin superfamily proteins (Fig. 5). All five IgGs exhibited binding signals at 1 μg / ml to CD47-Fc (OD450 nm human > 2.0, mouse > 2.0, mouse > 1.25) and no detectable binding (OD450 nm < 0.1) against any other protein. A notable exception was the VH-A1 / Vl-B1 clone, which again showed strong binding to human and cytoplasmic CD47, but no signal against mouse CD47. Cytometric flow analyses of the binding specificity of major IgG on the cell membrane.

[192] Antibodies to CD47 were analyzed for concentration-dependent binding on the cell surface using flow cytometry. CHO-K1 cells were stably transfected with human, mouse, or full-length cDNAs from CD47. Anti-CD47 mVH / mVL, VH-A1 / VL-B1, AD5, G-B6, F-E7, and D-H3 IgG and an IgG1 isotype control were all tested in IgG1null and IgG4 (S228P) formats, alongside a human anti-CD47 anti-human MS47 monoclonal CD1, over a concentration range of 100,000-24 ng / ml for binding to human, cyne, or wild-type ('wt', i.e., non-transferred) CHO-K1. All IgGs, except the isotype control, showed concentration-dependent binding to human CD47+ cells and cytokines, with a maximum MFI in each case > 10 times greater than the signals observed for binding to non-transferred CHO-K1 (Fig. 6).Measurable binding to CHO-K1 cells by weight was observed for all clones except VH-A1 / VLB1, but only at high antibody concentrations. mVH / mVL IgGs, however, showed the strongest reactivity with a signal > 10 times greater than the negative control without antibody at concentrations as low as 24 ng / ml. This background binding may be indicative of the original mouse antibody VxP037 having not only cross-reactivity to mouse CD47, but also... Petition 870260064866, dated 01 / 07 / 2026, page 81 / 146 72 / 85 also hamster. Minimizing this cross-reactivity to hamster CD47 is preferable for a therapeutic protein, as antibodies will typically be produced in CHO cell culture for clinical use. The high binding affinity of IgG to hamster CD47 protein can potentially lead to a significant increase in the undesirable protein content of co-purified host cell CD47 in production runs, which must be removed from the drug to avoid immunogenicity in patients.

[193] To examine the binding of major IgGs to human CD47+ cancer cells, HL60 cells (derived from human acute myeloid leukemia) were also used in flow cytometry analyses, as above. All antibodies, except the isotype control IgGs, showed strong concentration-dependent binding to HL60 cells (Fig. 7). Analysis of primary IgG in developmental ELISA assays

[194] It is known in the art that the binding of IgGs intended for therapeutic use to various indicative biological substrates is a high-risk indicator of poor performance in patients due to low bioavailability and short half-life in vivo. Three such biological substrates are insulin, dsDNA, and ssDNA. These three substrates were therefore used to coat ELISA plates and examine the binding of IgG1null versions of the optimized lead antibodies. The binding signals for these human IgG-based antibodies were compared with human IgG 'positive control' antibodies that were found to have reduced reactivity and poor performance, which halted their progress in clinical trials (human IgG1 analogs of Bococizumab and Briakinumab). For a human IgG1 negative control antibody, an IgG1 analog of Ustekinumab was used, which reacts with the same therapeutic target as Briakinumab but has a higher pK and has been successfully approved. Petition 870260064866, dated 01 / 07 / 2026, page 82 / 146 73 / 85 as a therapeutic product. In the ELISA analyses shown in Fig. 8, the positive control antibodies exhibited the expected strong reactivity for all 3 substrates, while the negative control showed low reactivity. Importantly, all tested IgG1null key proteins showed binding to the negative control against all 3 substrates. This finding underscored the maintenance of highly specific, target-oriented binding in the optimized AD5, G-B6, D-H3, and VH-A1 / VL-B1 clones. Designer IgG analyses based on the main clone A-D5

[195] As described above, clone A-D5 proved to have highly specific binding to human, mouse, and cinerex CD47, low off-target binding potential, enhanced neutralization of mouse CD47, reduced background binding to CHO cells, and multiple human germline mutations in CDRs. As a library-derived clone, however, sequence A-D5 still retained a number of non-germline (mouse-derived) residues that were suggested as potentially superfluous by the data found in Figs. 2A and 2B. Sequence A-D5 and all other library-derived clones also retained an 'NG' motif in CDR-L1 that presented a high risk of deamidation, as it was found to exhibit high solvent exposure at the apex of the long, flexible IGKV2 -28 loop germline model CDR-L1.In an attempt to simultaneously maximize the human germline sequence in the variable domains of A-D5 and minimize the high-risk deamidation motif content in the protein, a series of designer clones was created. This effort was carried out in two phases, with the first-phase clones A-D5.1 to A-D5.10 containing the CDR sequences described in Table 4. These clones were expressed and purified in IgG1null format and examined for target binding by ELISA on all CD47 orthologs (Fig. 9A, B, C) and neutralization of the CD47- interaction. Petition 870260064866, dated 01 / 07 / 2026, p. 83 / 146 74 / 85 SIRPα for all orthologs (Fig. 10A, B, C). At this stage, it was found that the human germline and these enhancements could be combined with a moderate loss of potency. Furthermore, the initial mutations that attempted to remove the 'NG' motif in CDR-L1 (via conservative N to Q substitution) were successful, although with associated reductions in potency in target-binding ELISAs and in neutralization of CD47-SIRPα interaction (Fig. 10A, B, C).

[196] In the second phase, a series of other mutants were engineered onto the best-performing mutant from phase 1: A-D5.4 (Table 5). These 9 mutants sampled the additional humanization of CDR-H2 from AD.4, with or without also replacing the 'N' in the deamidation hazard motif 'NG' by conservative and non-conservative mutations such as S, G, A, and T, or replacing the 'G' residue with A. These clones were re-expressed and purified in IgG1null format and examined for target binding by ELISA in all CD47 orthologs (Fig. 11A, B, C) and neutralization of the CD47-SIRPa interaction for all orthologs (Fig. 12A, B, C). In this phase, it was found that the human germline content of CDR-H2 could be increased by 2 more residues without loss of potency compared to clone A-D5. Furthermore, mutations attempting to remove the 'NG' motif in CDR-L1 via N substitution were successful, leading to the identification of clone A-D5.16, which contained the non-conservative N to A mutation, in addition to the maximum humanized CDR-H2, showed only small reductions (approximately 3-fold) in target-binding or CD47-SIRPa neutralization ELISA potency compared to A-D5 and mVL / mVH. The CDR-L1 sequence of AD.16 'RSSQSLLHSAGYNYLH' (SEQ ID NO: 82) (and clones A-D5.14, A-D5.15, A-D5.17, and A-D5.28) contained non-germline residues at only two positions (underlined) and achieved an optimized balance between maximum human germline content and maximum stability characteristics. Petition 870260064866, dated 01 / 07 / 2026, p. 84 / 146 75 / 85

[197] The A-D5 derivatives A-D5.4 and A-D5.16 were subsequently also tested in IgGlnull format for maintenance of binding specificity to ensure that there was no loss of target specificity during the mutation and re-selection process; both clones were tested for binding to a panel of 14 purified human proteins from the immunoglobulin superfamily (Fig. 13). Both IgGs exhibited binding signals at 10 μg / ml on CD47-Fc (human, canine and mouse > 2.0 OD450 nm) and no detectable binding (OD450 nm < 0.1) against any other protein. In the 'Developability' ELISA analyses shown in Fig. 14, the positive control antibodies exhibited the expected strong reactivity for all 3 substrates, while the negative control showed low reactivity. It is important to highlight that the key proteins IgG1null A-D5.4 and A-D5.16 showed negative binding against all 3 substrates.This discovery highlighted the maintenance of highly specific, target-oriented binding in the optimized clones A-D5, A-D5.4, and A-D5.16.

[198] Finally, the A-D5 derivative mutants A-D5.4 and A-D5.16 were examined for binding to wild-type (Fig. 15) and HL60 (Fig. 16) CHO cells by flow cytometry. These analyses confirmed that the original murine v domains of the mVH / mVL clone in IgG1null or IgG4 format drive strong concentration-dependent binding to CHO cells, while the A-D5, A-D5.4 and A-D5.16 clones mediated little or no binding signal in either IgG format (Fig. 15). On the other hand, the mVH / mVL, A-D5, A-D5.4 and A-D5.16 clones demonstrated strong binding to human CD47+ HL60 cells (Fig. 16), demonstrating that binding to human CD47 on the cell membrane had indeed been retained in our optimized clones, but hamster CD47 reactivity was improved. T-cell epitope analyses of antibody V-domain Petition 870260064866, dated 01 / 07 / 2026, p. 85 / 146 76 / 85

[199] In silico technologies (Abzena, Ltd.), which are based on identifying the location of T cell epitopes in antibodies and therapeutic proteins, were used to evaluate the immunogenicity of the v mVH / mVL domains and the lead antibody. Analysis of the v domain sequences was performed with overlapping 9mer peptides (each overlapping the last peptide by 8 residues) that were tested against each of the 34 MHC class II allotypes. Each 9mer was scored based on its potential 'fit' and interactions with MHC class II molecules. The peptide scores calculated by the software ranged from 0 to 1.Peptides that produced a high average binding score (> 0.55 on the iTope™ scoring function) were highlighted, and if > 50% of the MHC class II binding peptides (i.e., 17 of the 34 alleles) had a high binding affinity (score > 0.6), these peptides were defined as 'high-affinity' MHC class II binding peptides, which are considered high-risk for containing CD4+ T cell epitopes. Low-affinity MHC class II binding peptides bind a high number of alleles (> 50%) with a binding score > 0.55 (but without a majority > 0.6). Further sequence analyses were performed using TCED™.The sequences were used to interrogate TCED™ by BLAST search in order to identify any high sequence homology between peptides (T cell epitopes) of unrelated proteins / antibodies that stimulated T cell responses in previous T cell epitope mapping studies conducted at Abzena Ltd.

[200] The peptides were grouped into four classes: High Foreign Affinity ('HAF' - high risk of immunogenicity), Low Foreign Affinity ('LAF' - lower risk of immunogenicity), TCED+ (epitope previously identified in the TCED™ database) and Germline Epitope ('GE' - human germline peptide sequence with high Petition 870260064866, dated 01 / 07 / 2026, page 86 / 146 77 / 85 MHC Class II binding affinity). It is unlikely that germline epitope 9mer peptides have immunogenic potential due to T cell tolerance (i.e., these peptides are recognized as 'self' in the host), as validated by previous studies with a wide range of germline peptides. Importantly, these germline v domain epitopes (further aided by similar sequences in the constant regions of human antibodies) also compete for MHC Class II occupancy on the membrane of antigen-presenting cells, reducing the risk of foreign peptide presentation being sufficient to achieve the 'threshold' activation necessary for T cell stimulation. High GE content is therefore a beneficial quality in the clinical development of a therapeutic antibody.

[201] As shown in Figure 17, the main v domains exhibited significant beneficial changes in peptide epitope content compared to mVH / mVL. Because the v domain engineering process performed here successfully selected antibodies that maintained anti-CD47 potency without the need to include murine residues in the structures (Table 2), several HAF and LAF epitopes found in the structures of both the mVH / mVL light chain v domains were absent in all library-derived and designer-derived derivations (Fig. 17). It was also found that GE epitope content increased significantly (from 3 to ±14 in all derivations), particularly in the VH regions of the main clones, where GE content increased from 0 to 9 in all derivations, and TCED+ epitopes were reduced from 3 to 2 in all derivations (Table 8).It is important to note, however, that multiple foreign epitopes were also eliminated by germline mutations found in the CDRs of the main clones. For example, a TCED+ peptide 'LVHSNGNTY' (SEQ ID. Petition 870260064866, dated 01 / 07 / 2026, page 87 / 146 78 / 85 The sequence NO: 116) found in mVH / mVL LCDR-1 (and therefore in any form of VxP037 previously humanized by CDR grafting) was eliminated in most major clones by the V > L mutation at position 2 and the N > Y mutation at position 7 (Tables 4 and 5). Similarly, the mVH / mVL LCDR2 sequence encoded for three foreign epitope peptides spanning the VL-2LCDR2-3 structure. These included two HAF peptides ('LLIYKVSYR' (SEQ ID NO: 117) and 'YRFSGVPDR' (SEQ ID NO: 118)) and one LAF peptide ('LIYKVSYRF' (SEQ ID NO: 119)). The insertion of LCDR2 into the structure of the human germline IGKV2-28 did not completely remove this problem, as the total sequence 'LLIYKVSYRFSGVPDR' (SEQ ID NO: 120) of mVH / mVL maintains 100% identity in the grafted IGKV2-28 sequence (Table 2). One HAF peptide and two LAF peptides were still found in this region for clones A-D5, A-D5.4, and A-D5.16, while the HAF sequence 'YRFSGVPDR' (SEQ ID NO: 118) was deleted by the Y > N mutation at position 1.Surprisingly, the LCDR2 KVSNRFS sequence (SEQ ID NO: 85), which was identified in the functional linkage population during library screening (Table 3) and contained the single human germline Y>N mutation at position 4, was found to completely enhance all predicted foreign epitopes in that region (no HAF, LAF, or TCED+ peptides were predicted), while also generating two more GE sequences (Fig. 18). It was also observed that the main clones A-D5 and all their design derivatives (Tables 4 and 5) retained the HAF peptide 'VGVYYCFQN' (SEQ ID NO: 121), which was also TCED+, spanning the VL regions of structure 3 and LCDR3. The V mutation at position 1 of this peptide was found to disrupt the predicted epitope structure and remove the immunogenicity risk of this peptide.

[202] The above findings allowed the design of a maximally deimmunized light chain sequence that was paired with the A-D5.16 VH sequence (Table 4) to form the Petition 870260064866, dated 01 / 07 / 2026, p. 88 / 146 79 / 85 clone 'A-D5.16-DI'. A-D5.16-DI contained the LCDR sequence 'RSSQSLLHSAGYNYLH' (SEQ ID NO: 82), the LCDR2 sequence 'KVSNRFS' (SEQ ID NO: 85), and the 2-LCDR3 structure sequence 'AGVYYCFQNTHTPRT' (SEQ ID NO: 122) (residues in Table 2 underlined). This clone was readily expressed in the IgG1null format and was found to retain target binding affinity against human, canine, and mouse CD47 (Fig. 18.AC) comparable to mVH / mVL IgG (reduced in mouse Fig. 18C). A-D5.16-DI was also found to exhibit enhanced CD47-SIRP blockade compared to A-D5. 16 and a blockade comparable to mVH / mVL against human and canine CD47, slightly reduced in the mouse (Fig. 19). These findings, therefore, led to a deimmunized A-D5 clone.4-DI with a lightweight chain design containing the sequence LCDR RSSQSLLHSNGYTYLH (SEQ ID NO: 52) (or SSQSLLHSNGYTY [SEQ ID NO: 92]) using the AHo definition), the sequence LCDR2 KVSNRFS (SEQ ID NO: 85) and the structure sequence 2-LCDR3 AGVYYCFQNTHTPRT (SEQ ID NO: 12s2) (structure residues 2 underlined). Phagocytosis of cancer cells

[203] Studies were conducted to examine the relative potency of CD47 blockade in driving phagocytosis of human HL60 cancer cells by human primary macrophages. As shown in Fig. 20A, in the IgG4 (S228P) format - mVH / mVL, AD5, A-D5.4 and A-D5.16, all drove significant phagocytosis at all concentrations tested. A-D5 in the IgG1null format did not show significant potency at 20 μg / ml, demonstrating the need for binding affinity to Fc gamma 1 receptor 1 to induce phagocytosis. Unexpectedly, IgG4 A-D5, A-D5.4 and A-D5.16 drove significantly more potent phagocytosis at 1 and 10 μg / ml when compared with mVH / mVL. This phenomenon was then examined for IgG4 A-D5 and mVH / mVL using 4 separate human macrophage donors (Fig. 20B). This analysis showed that the highest potency shown in Fig. 20A was correct. Petition 870260064866, dated 01 / 07 / 2026, page 89 / 146 80 / 85 with A-D5 being significantly more potent in all donors (Fig. 20B).

[204] Although the present invention has been described with reference to preferred or exemplary embodiments, those skilled in the art will recognize that various modifications and variations thereof may be made without departing from the spirit and scope of the present invention and that such modifications are clearly contemplated herein. No limitation with respect to the specific embodiments disclosed in this document and set forth in the appended claims is intended or should be inferred.

[205] All documents cited herein are incorporated by reference in their entirety. Table 1. Murine anti-CD47 CDR amino acid sequences, as defined here (Unified Scheme) compared with alternative definitions. SEQ ID NOs are shown in parentheses. Esquema HCDR1 HCDR2 HCDR3 LCDR1 LCDR2 LCDR3 Unificado GYTFTNYYVF (4) IGDINPVNGDT NFNEKFKN (123) GGYTMDY (5) RSSQSLVHSNGNTY LHW (9) YY LIYKVSYRFS (10) SQNTHVPRT (11) Kabat GYTFTNYYVF (124) IGDINPVNGDT NFNEKFKN (125) TRGGYTMDY (5) RSSQSLVHSNGNTY LHW (9)Y LIYKVSYRFS (10) SQNTHVPRT (11) Chotia GYTFTNYYVF (126) IGDINPVNGDT NFNEKFKN (127) TRGGYTMDY (5) RSSQSLVHSNGNTY LHW (9)Y LIYKVSYRFS (10) SQNTHVPRT (11) IMGT GYTFTNYYVF (128) IGDINPVNGDT NFNEKFKN (129) TRGGYTMDY (130) RSSQSLVHSNGNTY LHWY (131) LIYKVSYRFS SQNTHVPRT (11) AHo GSGYTFTNYY (15) IGDINPVNGDT NFNEKFKN (132) TRGGYTMDY (16) RSSQSLVHSNGNTY LHW (19) LIYKVSYRFS (10) SQNTHVPRT (20) AbM GYTFTNYYVF (4) IGDINPVNGDT NFNEKFKN (133) TRGGYTMDY (5) RSSQSLVHSNGNTY LHWY (9)W LIYKVSYRFS (10) SQNTHVPRT (11) Contato GYTFTNYYVF (134) IGDINPVNGDT NFNEKFKN (135) TRGGYTMDY (136) RSSQSLVHSNGNTY LHWY (137) LLIYKVSYRFS (138) SQNTHVPRT (139) Table 2. Amino acid sequence of murine VXP037 antiCD47 v domains (mVH / mVL) and CDR grafts from the cell line. Petition 870260064866, dated 01 / 07 / 2026, pp. 90 / 146 81 / 85 human germline (VH1 / VL1). The SEQ ID NOs are shown in parentheses. 1Human germline definitions used for grafting, based on the IMGT system. 2CDR residues are in bold and underlined. As noted above, the unified CDR definitions used in this manuscript are an expanded definition compared to the classic Kabat definition. Table 3. Amino acid sequences of unique CDRs (using unified definition) from 854 unique anti-CD47 v domains. SEQ ID NOs are shown in parentheses. DOMINIO V Linhagem germinativa humana1 Sequência de aminoácidos2 CD47mVH n / a EVQLQQFGAELVKPGASMKLSCKASGYTFTNYYVFWVKQRPGQGLEWIGDINPVNGDT NFNEKFKNKATLTVDKSSSTTTYLQLSSLTSEDSAVYYCTRGGYTMDYWGQGTLVTVSS (140) CD47- VH1 IGHV5-51 EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYYVFWVRQMPGKGLEWIGDINPVNGDT NFNESFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGYTMDYWGQGTLVTVSS (141) CD47mVL n / a DVVMTQTPLSLSVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSY RFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPRTFGQGTKVEIK (142) CD47- VL1 IGKV2-28 DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGNTYLHWYLQKPGQSPQLLIYKVSY RFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQNTHVPRTFGQGTKVEIK (143) LCDR1 LCDR2 LCDR3 HCDR1 HCDR2 HCDR3 RSSHSLVHSNGN TYLH (144) KGSNRAS (67) FQNTHTTPRT (54) GYNFTNY YIF (145) MGDINPFNGDTNFNPSFQG (146) GGFTMDY (66) RSSQSFLHSNGN NYLH (147) KGSNRFS (47) LQNTHTPRT (148) GYRFTNY YIF (149) MGDINPGDGDTNFNPSFQG (150) GGHTMDY (151) RSSQSLLHSNGN NYLD (152) KGSNRSS (153) MQALHTPWT (154) GYRFTNY YVF (155) MGDINPGNGDTNFNPSFQG (156) GGITMDY (157) RSSQSLLHSNGN NYLH(158) KGSYRAS (58) MQALHVPRT (159) GYSFNNY YIF (160) MGDINPGNGDTNYNPSFQG (161) GGQTMDQ (162) RSSQSLLHSNGN TYLD (163) KGSYRFS (63) MQALQVPWT (164) GYSFTNY YIF (43) MGDINPGNGDTNYSPSFQG (165) GGYIMDY (166) RSSQSLLHSNGN TYLH (167) KGSYRLS (168) MQATHVPWT (169) GYSFTSY YIF (170) MGDINPGNGDTRFNPSFQG (171) GGYTADY (172) Petition: 870260064866, on 01 / 07 / 2026, page. 91 / 146 82 / 85 RSSQSLLHSNGS NYLH (173) KVSNRAS (174) MQATQVPWT (175) GYSFTSY YIV (176) MGDINPGNGDTRFSPSFQG (177) GGYTLDY (178) RSSQSLLHSNGY NYLH (46) KVSNRFS (85) MQNLQTPRT (179) GYSFTSY YVF (180) MGDINPGNGDTRYNPSFQG (181) GGYTMDA (182) RSSQSLLHSNGY TYLD (183) KVSNRLS (53) MQNTHIPRT (184) GYSFTSY YVG (185) MGDINPGNGDTRYSPSFQG (186) GGYTMDE (187) RSSQSLLHSNGY TYLH (52) KVSYRAS (188) MQNTHTLRT (189) GYTFTNY YIF (49) MGDINPGNSDTNFNPSFQG (190) GGYTMDF (191) RSSQSLVHSNGN NYLD (192) KVSYRLS (193) MQNTHTPRT (194) GYTFTSY YIF (195) MGDINPGNSDTNYNPSFQG (196) GGYTMDH (197) RSSQSLVHSNGN NYLH (201) LGSNRAS (72) MQNTHVPRT (198) GYTFTSY YVF (199) MGDINPVDGDTKYNPSFQG (200) GGYTMDI (70) RSSQSLVHSNGN TYLD (62) LGSNRFS(71)MQNTQTPRT (202) MGDINPVDGDTNFNPSFQG (203) GGYTMDK (56) RSSQSLVHSNGY NYLH (207) LGSNRLS (77) MQTTHTPRT (204) MGDINPVDGDTNFSPSFQG (205) GGYTMDL (206) RSSQSLVHSNGY TYLD (212) LGSYRAS (208) MQTTQIPRT (209) MGDINPVDDGDTNYNPSFQG (210) GGYTMDM (211) RSSQSLVHSNGY TYLH (57) LGSYRFS (213) SQATHFPRT (214)MGDINPVDGDTNYSPSFQG (215) GGYTMDN (216) LGSYRLS (217) SQATQTPRT (73) MGDINPVDGDTRFNPSFQG (218) GGYTMDQ (219) LVSNRAS (220) SQNIQTPRT (221) MGDINPVDGDTRYNPSFQG (222) GGYTMDR (51) LVSNRFS (223) SQNLHTPRT (224) MGDINPVDGDTRYSPSFQG (225) GGYTMDT (226) LVSNRLS (227) SQNLQTPRT (228) MGDINPVDSDTKFNPSFQG (229) GGYTMDV (230) LVSYRAS (231) SQNMHTPRT (232) MGDINPVDSDTNFNPSFQG (233) GGYTMDW (234) MGSNRFS (235) SQNTHFPRT (236) MGDINPVDSDTNYNPSFQG (237) GGYTMGK (61) MGSYRLS (238) SQNTHVPWT (239) MGDINPVDSDTNYSPSFQG (240) GGYTPDY (45) MVSNRFS (241) SQNTQAPRT (242) MGDINPVDSDTRFNPSFQG (243) GGYTRDY (244) SQNTQTPRT (59) MGDINPVDSDTRYNPSFQG (245) GGYTTDS (246) SQNTQTPWT (247) MGDINPVDSDTRYSPSFQG (248) GGYTTDW (249) SQNTQVPRT (250) MGDINPVNGDTKYNPSFQG (251) GGYTTDY (252) SQSTHVPRT (253) MGDINPVNGDTNFSPSFQG (254) GGYVMDY (255) SQTTHIPRT (256) MGDINPVNGDTNYNPSFQG (257) SQTTHVPRT (258) MGDINPVNGDTNYSPSFQG (44) SQTTQTPRT (259) MGDINPVNGDTRFNPSFQG (260) TQNTHTPRT (261) MGDINPVNGDTRFSPSFQG (262) VQNTQVPRT(263) MGDINPVNGDTRYNPSFQG (264) Petition 870260064866, dated 01 / 07 / 2026, page 92 / 146 83 / 85 MGDINPVNGDTRYSPSFQG (265) MGDINPVNSDTKYNPSFQG (266) MGDINPVNSDTNFNPSFQG (267) MGDINPVNSDTNYSPSFQG (268) MGDINPVNSDTRFNPSFQG (269) MGDINPVNSDTRFSPSFQG (270) MGDINPVNSDTRYNPSFQG (271)MGDINPVNSDTRYSPSFQG (272)MGDIYPGNSDTKYNPSFQG (273)MGDIYPVNGDTRYNPSFQG (274)MGIINPGNGDTRYNPSFQG (275)MGIINPVDGDTKYNPSFQG (276)MGIINPVDGDTNYSPSFQG (277)MGIINPVDGDTRFNPSFQG (278) MGIINPVDGDTRFSPSFQG (279) MGIINPVDGDTRYNPSFQG (74) MGIINPVDGDTRYSPSFQG (65) MGIINPVDSDTNYNPSFQG (280) MGIINPVDSDTRFNPSFQG (281) MGIINPVDSDTRYNPSFQG (282) MGIINPVDSDTRYSPSFQG (283) MGIINPVNGDTKFNPSFQG (284) MGIINPVNGDTKYNPSFQG (285) MGIINPVNGDTKYSPSFQG (286) MGIINPVNGDTNFNPSFQG (287) MGIINPVNGDTNFSPSFQG (288) MGIINPVNGDTNYNPSFQG (60) MGIINPVNGDTNYSPSFQG (289) MGIINPVNGDTRFNPSFQG (290) MGIINPVNGDTRFSPSFQG (291) MGIINPVNGDTRYNPSFQG (292) MGIINPVNGDTRYSPSFQG (293) Petition 870260064866, dated 01 / 07 / 2026, p. 93 / 146 84 / 85 mgiinpvnsdtkynpsfqg (294) mgiinpvnsdtnfnpsfqg (295) mgiinpvnsdtnyspsfqg (296) mgiinpvnsdtrfspsfqg (297) mgiinpvnsdtrynpsfqg (298) mgiinpvnsdtryspsfqg (299) mgninpvdgdtrynpsfqg (300) mgvinpvnsdtnynpsfqg (301) Table 4. Amino acid sequences of CDRs (using unified definition) of interaction-blocking anti-CD47 IgGs CD47-SIRPq unique, library-derived and designer-derived. As SEQ IDs are shown in parentheses. Nome do clone LCDR1 LCDR2 LCDR3 HCDR1 HCDR2 HCDR3 D-H3 RSSQSLLHSNGYNY LH (46) KGSNRFS (47) sqnlhvp RT (48) GYSFTNYY IF (43) mgdinpvngdtny spsfqg (44) ggytpdy (45) A-D5 RSSQSLLHSNGYTY LH (52) KVSNRLS (53) fqnthtp RT (54) GYTFTNYY IF (49) mgiinpvdgdtny npsfqg (50) GGYTMDR (51) G-B6 RSSQSLVHSNGYTY LH (57) KGSYRAS (58) sqntqtp RT (59) GYSFTNYY IF (43) igdinpvngdtnf spsfqg (55) GGYTMDK (56) F-E7 RSSQSLVHSNGNTY LD (62) KGSYRFS (63) sqathtp RT (64) GYSFTNYY IF (43) mgiinpvngdtny npsfqg (60) GGYTMGK (61) VH-A1 / VL- B1 RSSQSLLHSNGYNY LH (46) KGSNRAS (67) sqnthtp RT (68) GYSFTNYY IF (43) mgiinpvdgdtry spsfqg (65) GGFTMDY (66) MH RSSQSLLHSNGYNY LH (46) LGSNRFS (71) sqntqtp RT (59) GYSFTNYY IF (43) igiinpvdgdtry spsfqg (69) GGYTMDI (70) ttp RSSQSLLHSNGYNY LH (46) LGSNRAS (72) sqatqtp RT (73) GYSFTNYY IF (43) mgiinpvdgdtry spsfqg (65) GGYTMDI (70) A-D5.1 RSSQSLLHSNGYTY LH (52) KVSNRLS (53) fqnthtp RT (54) GYSFTNYY IF (43) mgiinpvdgdtny npsfqg (50) GGYTMDR (51) A-D5.2 RSSQSLLHSNGYTY LH (52) KVSNRLS (53) fqnthtp RT (54) GYSFTNYY IF (43) mgiinpvdgdtry npsfqg (74) GGYTMDR (51) A-D5.3 RSSQSLLHSNGYTY LH (52) KVSNRLS (53) fqnthtp RT (54) GYSFTNYY IF (43) mgiinpvdgdtry spsfqg (65) GGYTMDR (51) A-D5.4 RSSQSLLHSNGYNY LH (46) KVSNRLS (53) fqnthtp RT (54) GYTFTNYY IF (49) mgiinpvdgdtny npsfqg (50) GGYTMDR (51) A-D5.5 RSSQSLLHSNGYNY LH (46) KGSNRLS (75) fqnthtp RT (54) GYTFTNYY IF (49) mgiinpvdgdtny npsfqg (50) GGYTMDR (51) A-D5.6 RSSQSLLHSNGYNY LH (46) KGSNRLS (75) fqntqtp RT (76) GYTFTNYY IF (49) mgiinpvdgdtny npsfqg (50) GGYTMDR (51). Petição 870260064866, de 01 / 07 / 2026, pág. 94 / 146 85 / 85 A-D5.7 RSSQSLLHSNGYNY LH (46) LGSNRLS (77) fqntqtp RT (76) GYTFTNYY IF (49) mgiinpvdgdtny npsfqg (50) GGYTMDR (51) A-D5.8 RSSQSLLHSQGYTY LH (78) KVSNRLS (53) fqnthtp RT (54) GYTFTNYY IF (49) MGIINPVDGDTNY npsfqg (50) GGYTMDR (51) A-D5.9 RSSQSLLHSNGYTY LH (52) KVSNRLS (53) fqqthtp RT (79) GYTFTNYY IF (49) MGIINPVDGDTNY npsfqg (50) GGYTMDR (51) A-D5.10 RSSQSLLHSQGYTY LH (78) KVSNRLS (53) fqqthtp RT (79) GYTFTNYY IF (49) MGIINPVDGDTNY npsfqg (50) GGYTMDR (51) Table 5. Amino acid sequences of CDRs (using unified definition) of designer anti-CD47 IgGs, CD47-SIRPq interaction blockers, derived from A-D5. SEQ ID NOs are shown in parentheses. Nome_____do clone LCDR1 LCDR2 LCDR3 HCDR1 HCDR2 HCDR3 A-D5.11 RSSQSLLHSNGYN YLH (46) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTNYNPS FQG (50) GGYTMD R (51) A-D5.12 RSSQSLLHSNGYN YLH (46) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTRYNPS FQG (74) GGYTMD R (51) A-D5.13 RSSQSLLHSNGYN YLH (46) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTRYSPS FQG (65) GGYTMD R (51) A-D5.14 RSSQSLLHSSGYN YLH (80) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTRYSPS FQG (65) GGYTMD R (51) A-D5.15 RSSQSLLHSGGYN YLH (81) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTRYSPS FQG (65) GGYTMD R (51) A-D5.16 RSSQSLLHSAGYN YLH (82) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTRYSPS FQG (65) GGYTMD R (51) A-D5.17 RSSQSLLHSTGYN YLH (83) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTRYSPS FQG (65) GGYTMD R (51) A-D5.18 RSSQSLLHSNAYN YLH (84) KVSNRL S (53) fqnthtp RT (54) GYSFTNYY IF (43) MGIINPVDGDTRYSPS FQG (65) GGYTMD R (51) Petition 870260064866, dated 01 / 07 / 2026, p. 95 / 146

Claims

1 / 12 CLAIMS 1. An antibody molecule that binds specifically to human CD47 and cynomolgus monkey CD47, and optionally also binds to mouse CD47, or an antigen-binding fragment thereof, characterized in that the antibody molecule or the antigen-binding fragment comprises a variable region of the heavy chain with: an HCDR1 having amino acids in the following sequence order: GSGYT / SFTNYY (SEQ ID NO: 30); an HCDR2 having amino acids in the following sequence order: INPVN / DGDTN / RF / YN / SPSFQG (SEQ ID NO: 31); and an HCDR3 having amino acids in the following sequence order: GGF / YTM / PD (SEQ ID NO: 32).

2. An antibody molecule or antigen-binding fragment according to claim 1,characterized by the fact that it comprises a variable region of the light chain with: an LCDR1 possessing amino acids in the following sequence order: SSQSLL / VHSN / Q / AGY / NN / TY (SEQ ID NO: 41); an LCDR2 possessing amino acids in the following sequence order: L / KV / GSN / YRA / F / LS (SEQ ID NO: 39); and an LCDR3 possessing amino acids in the following sequence order: Q / N / AT / LQ / HT / VPR (SEQ ID NO: 42).

3. Antibody molecule or antigen-binding fragment according to claim 2, characterized in that it comprises: (a) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVNGDTNYSPSFQG (SEQ ID NO: 87) (HCDR2), GGYTPD (SEQ ID NO: 88) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KGSNRFS (SEQ ID NO: 47) (LCDR2) and NLHVPR (SEQ ID NO: 90) (LCDR3) [Clone D-H3]; or (b) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD Petition 870260064866, dated 01 / 07 / 2026,p. 96 / 146 2 / 12 (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5]; or (c) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVNGDTNFSPSFQG (SEQ ID NO: 94) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLVHSNGYTY (SEQ ID NO: 95) (LCDR1), KGSYRAS (SEQ ID NO: 58) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone G-B6]; or (d) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVNGDTNYNPSFQG (SEQ ID NO: 97) (HCDR2), GGYTMG (SEQ ID NO: 98) (HCDR3), SSQSLVHSNGNTY (SEQ ID NO: 19) (LCDR1), KGSYRFS (SEQ ID NO: 63) (LCDR2) and ATHTPR (SEQ ID NO: 99) (LCDR3) [Clone F-E7]; or (e) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGFTMD (SEQ ID NO: 101) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1),KGSNRAS (SEQ ID NO: 67) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone VH-A1 / VL-B1]; or (f) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), LGSNRFS (SEQ ID NO: 71) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone MH]; or (g) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), LGSNRAS (SEQ ID NO: 72) (LCDR2) and ATQTPR (SEQ ID NO: 102) (LCDR3) [TTP clone]; or (h) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.1]; or Petition 870260064866, dated 01 / 07 / 2026,pg. 97 / 146 3 / 12 (i) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYNPSFQG (SEQ ID NO: 103) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.2]; or (j) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.3]; or (k) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.4]; or (l) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1),KGSNRLS (SEQ ID NO: 75) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.5]; or (m) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KGSNRLS (SEQ ID NO: 75) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone A-D5.6]; or (n) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), LGSNRLS (SEQ ID NO: 77) (LCDR2) and NTQTPR (SEQ ID NO: 96) (LCDR3) [Clone A-D5.7]; or (o) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSQGYTY (SEQ ID NO: 104) (LCDR1), Petition 870260064866, dated 01 / 07 / 2026,pg. 98 / 146 4 / 12 KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.8]; or (p) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and QTHTPR (SEQ ID NO: 105) (LCDR3) [Clone A-D5.9]; or (q) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSQGYTY (SEQ ID NO: 104) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and QTHTPR (SEQ ID NO: 105) (LCDR3) [Clone A-D5. 10]; or (r) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.11]; or (s) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1),INPVDGDTRYNPSFQG (SEQ ID NO: 103) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.12]; or (t) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 13]; or (u) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSSGYNY (SEQ ID NO: 106) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 14]; or Petition 870260064866, dated 01 / 07 / 2026, p. 99 / 146 5 / 12 (v) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSGGYNY (SEQ ID NO: 107) (LCDR1),KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 15]; or (w) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSAGYNY (SEQ ID NO: 108) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 16]; or (x) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSTGYNY (SEQ ID NO: 109) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 17]; or (y) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNAYNY (SEQ ID NO: 110) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.18]; or (z) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1),INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSAGYNY (SEQ ID NO: 108) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.16-DI]; or (z. 1) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5-DI].

4. Antibody molecule or antigen-binding fragment according to claim 1, characterized in that it comprises: Petition 870260064866, dated 01 / 07 / 2026, p. 100 / 146 6 / 12 one HCDR1 having the amino acid sequence GSGYTFTNYY (SEQ ID NO: 15) or GSGYSFTNYY (SEQ ID NO: 86); one HCDR2 having the amino acid sequence INPVDGDTNYNPSFQG (SEQ ID NO: 91) or INPVDGDTRYSPSFQG (SEQ ID NO: 100); and one HCDR3 having the amino acid sequence GGYTMD (SEQ ID NO: 16) and, optionally,further comprising: an LCDR1 having the amino acid sequence SSQSLLHSNGYNY (SEQ ID NO: 89) or SSQSLLHSNGYTY (SEQ ID NO: 92) or SSQSLLHSAGYNY (SEQ ID NO: 108); an LCDR2 having the amino acid sequence KVSNRLS (SEQ ID NO: 53) or KVSNRFS (SEQ ID NO: 85); and an LCDR3 with the amino acid sequence NTHTPR (SEQ ID NO: 93).

5. Antibody molecule or antigen-binding fragment thereof, according to claim 3 or 4, characterized in that it comprises: (a) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2), and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5]; or (b) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYNY (SEQ ID NO: 89) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2),and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.4]; or (c) the amino acid sequences GSGYSFTNYY (SEQ ID NO: 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSAGYNY (SEQ ID NO: 108) (LCDR1), KVSNRLS (SEQ ID NO: 53) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5.16]; or (d) the amino acid sequences GSGYSFTNYY (SEQ ID NO: Petition 870260064866, 01 / 07 / 2026, p. 101 / 146 7 / 12 86) (HCDR1), INPVDGDTRYSPSFQG (SEQ ID NO: 100) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSAGYNY (SEQ ID NO: 108) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2) and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5. 16-DI]; or (e) the amino acid sequences GSGYTFTNYY (SEQ ID NO: 15) (HCDR1), INPVDGDTNYNPSFQG (SEQ ID NO: 91) (HCDR2), GGYTMD (SEQ ID NO: 16) (HCDR3), SSQSLLHSNGYTY (SEQ ID NO: 92) (LCDR1), KVSNRFS (SEQ ID NO: 85) (LCDR2), and NTHTPR (SEQ ID NO: 93) (LCDR3) [Clone A-D5-DI].

6. Antibody molecule or antigen-binding fragment,according to any one of the preceding claims 1 to 5, characterized in that it comprises one or more substitutions, deletions, or insertions that remove a post-translational modification site, for example, a glycosylation site, a deamination site, a phosphorylation site, or an isomerization / fragmentation site.

7. Antibody molecule or antigen-binding fragment, according to any one of claims 1 to 6, characterized in that it is human, humanized, or chimeric.

8. Antibody molecule or antigen-binding fragment, according to any one of claims 1 to 7, characterized in that it comprises one or more human variable-domain structural backbones into which CDRs have been inserted.

9. Antibody molecule or antigen-binding fragment, according to any one of claims 1 to 8,characterized in that it comprises a human germline structure IGHV5-51 into which the corresponding HCDR sequences have been inserted.

10. Antibody molecule or antigen-binding fragment, according to any one of claims 2 to 9, characterized in that it comprises a human germline structure IGKV2-28 into which the corresponding LCDR sequences have been inserted.

11. Antibody molecule or antigen-binding fragment, according to any one of claims 1 to 10, characterized in that it comprises an immunologically inert constant region.

12. Antibody molecule or antigen-binding fragment, according to any one of claims 1 to 11, characterized in that it is a Fab fragment, an F(ab)2 fragment, an Fv fragment, a tetrameric antibody, a tetravalent antibody, a multispecific antibody (e.g.,12. A bivalent antibody, characterized in that it comprises a single-domain antibody (e.g., VhH or Vnar, or a fragment of either), a monoclonal antibody, or a fusion protein.

13. An immunoconjugate, characterized in that it comprises the antibody molecule or an antigen-binding fraction thereof, as defined in any one of claims 1 to 12, linked to a therapeutic agent.

14. A nucleic acid molecule, characterized in that it encodes the antibody molecule or an antigen-binding fraction thereof, as defined in any one of claims 1 to 12.

15. A vector characterized in that it comprises the nucleic acid molecule as defined in claim 14.

16. A host cell characterized in that it comprises the nucleic acid molecule, as defined in claim 14, or the vector.as defined in claim 15.

17. Method for producing an anti-CD47 antibody and / or an antigen-binding fraction characterized in that it comprises culturing the host cell, as defined in claim 16, under conditions that result in the expression and / or production of the antibody and / or the antigen-binding fraction and isolating the antibody and / or an antigen-binding fraction thereof from the host cell or culture.

18. Pharmaceutical composition, characterized in that it comprises the antibody molecule or antigen-binding fraction thereof, as defined in any one of claims 1 to 12, or the immunoconjugate, as defined in claim 13, or the nucleic acid molecule as defined in claim 14, or the vector as defined in claim 15.

19. Use of the antibody molecule or antigen-binding fraction thereof,as defined in any one of claims 1 to 12, or of the immunoconjugate as defined in claim 13, or of the nucleic acid molecule as defined in claim 14, or of the vector as defined in claim 15, or of the pharmaceutical composition as defined in claim 18, characterized in that it is for the manufacture of a medicament to enhance an immune response in an individual.

20. Use of the antibody molecule or antigen-binding fraction thereof, as defined in any one of claims 1 to 12, or of the immunoconjugate as defined in claim 13, or of the nucleic acid molecule as defined in claim 14, or of the vector as defined in claim 15, or of the pharmaceutical composition as defined in claim 18, characterized in that it is for the manufacture of a medicament for the treatment of cancer.

21. Use according to claim 20,characterized by the fact that the cancer is selected from the group consisting of: pancreatic cancer, melanoma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, stomach cancer, ovarian cancer, bladder cancer, brain or central nervous system cancer, peripheral nervous system cancer, esophageal cancer, cervical or endometrial cancer, oral cavity or pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, bile duct cancer, small intestine or appendix cancer, salivary gland cancer, thyroid gland cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, and hematological tissue cancer.

22. Use, according to any of claims 20 or 21, characterized in that the medicament is for use in a combined application with a second therapeutic agent, for example,an anticancer agent.

23. Use of an antibody molecule or antigen-binding fraction thereof, as defined in any one of claims 1 to 12, or of an immunoconjugate, as defined in claim 13, or of a nucleic acid molecule as defined in claim 14, or of a vector as defined in claim 15, or of a pharmaceutical composition, as defined in claim 18, characterized in that it is for the manufacture of a medicament for the treatment of an ischemia-reperfusion injury, an autoimmune disease or an inflammatory disease.

24. Use according to claim 23, characterized in that the autoimmune disease or inflammatory disease is selected from the group consisting of: arthritis, multiple sclerosis, psoriasis, Crohn's disease, inflammatory bowel disease, lupus, Graves' disease,Hashimoto's thyroiditis and ankylosing spondylitis.

25. Use of an antibody molecule or an antigen-binding fraction thereof, as defined in any of claims 1 to 12, or of an immunoconjugate, as defined in claim 13, or of a nucleic acid molecule, as defined in claim 14, or of a vector as defined in claim 15, or of a pharmaceutical composition, as defined in claim 18, characterized in that it is for the manufacture of a medicament for the treatment of a cardiovascular disease, such as coronary heart disease or atherosclerosis or a fibrotic disease.

26. Use according to claim 25, characterized in that the fibrotic disease is selected from the group consisting of myocardial infarction, angina, osteoarthritis, pulmonary fibrosis, cystic fibrosis, bronchitis,and asthma.

27. Method for producing an antibody molecule that binds specifically to human CD47 and cynomolgus monkey CD47 and optionally also to mouse CD47, or an antigen-binding fraction thereof, characterized in that it comprises the steps of: (1) grafting anti-CD47 CDRs from a non-human source onto a human v-domain structure to produce a humanized anti-CD47 antibody molecule or an antigen-binding fraction thereof; (2) generate a phage library of clones of the humanized anti-CD47 antibody molecule or an antigen-binding fraction thereof, comprising one or more mutations in the CDRs; (3) screen the phage library for binding to human CD47 and cynomolgus monkey CD47, and optionally also to mouse CD47; (4) select clones from screening step (3) possessing binding specificity to human CD47 and cynomolgus monkey CD47, and optionally also to mouse CD47; and (5) produce an antibody molecule that binds specifically to human CD47 and cynomolgus monkey CD47, and optionally also to mouse CD47, or an antigen-binding fraction of the clones selected in step (4).

28. Method according to claim 27, characterized in that it comprises an additional step of Petition 870260064866, dated 01 / 07 / 2026, p. 106 / 146 12 / 12 production of additional clones based on the clones selected in step (4), for example, based on additional exploratory mutagenesis at specific positions in the CDRs of the clones selected in step (4), to improve humanization and / or minimize the human T cell epitope content and / or improve the manufacturing properties in the antibody molecule or antigen-binding fraction thereof produced in step (5).Petition 870260064866, dated 01 / 07 / 2026, pp. 107 / 146.

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