Reagents and methods for imaging pdgfralfa-expressing cancers

Description

1 / 139 REAGENTS AND METHODS FOR IMAGING PDGFRALFA-EXPRESSING CANCERS Field of Invention

[001] The invention relates to reagents for in vivo imaging and detection of cancers expressing platelet-derived growth factor receptor alpha (PDGFRalpha) and methods of use, including methods for cancer imaging and methods for selecting patients for treatment. Related Orders

[002] This application claims priority over U.S. Interim Application No. 63 / 494160 filed on April 4, 2023, and over International Application No. PCT / AU2023 / 050263 filed on April 4, 2023, the full content of which is incorporated herein by reference. Fundamentals of the Invention

[003] Medical imaging methods are frequently used to aid in the diagnosis and staging of the progression of various types of cancer. Such methods can be advantageous in eliminating or reducing the need for invasive techniques (such as obtaining a biopsy sample) to confirm the diagnosis, which are not always necessary and can lead to complications.

[004] Not all cancers can be successfully detected using standard medical imaging. Furthermore, many imaging techniques allow the detection of masses, but not Petition 870250087401, dated 09 / 26 / 2025, page 35 / 207 2 out of 139 are able to successfully distinguish between benign and malignant tissue.

[005] Cancer is a heterogeneous disease with large variations in tumor morphology and physiology. Although some conventional histological and clinical features have been correlated with prognosis, the vast heterogeneity among cancer forms, ranging from the cellular to the tissue level, affects the response to therapy and the subsequent benefit to the patient. Therefore, the selective treatment of cancer patients who will benefit from a specific treatment continues to represent a challenge.

[006] There is a need for improved methods and compositions for use in the detection and / or imaging of various types of cancer in vivo. There is a need for improved methods and compositions to determine the likelihood of a patient benefiting from a particular cancer treatment.

[007] Reference to any prior technique in the specification is not an acknowledgment or suggestion that such prior technique is part of the common general knowledge in any jurisdiction or that such prior technique could reasonably be expected to be understood, considered relevant and / or combined with other prior techniques by one skilled in the art. Summary of the Invention Petition 870250087401, dated 09 / 26 / 2025, page 36 / 207 3 / 139

[008] The present invention relates to agents and methods for detecting, imaging and diagnosing cancers that express the platelet-derived growth factor receptor alpha (PDGFRalpha); and methods for identifying individuals for treatment with a PDGFRalpha inhibitor.

[009] In a first aspect, the present invention provides an olaratumab antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment is conjugated to a radioisotope, for: - the detection or imaging of tumors expressing PDGFRalpha in an individual; - for the diagnosis of a cancer that expresses PDGF-alpha in an individual; - to produce an image of a cancer that expresses PDGF-alpha in an individual; - to classify a cancer as responsive to treatment with a PDGF-alpha inhibitor; - to classify or select a patient for eligibility for cancer therapy with a PDGF-alpha inhibitor; or - to monitor the response of a cancer that expresses PDGFRalpha or of an individual with a cancer that expresses PDGFRalpha to treatment.

[0010] It shall be understood that an olaratumab antibody or an antigen-binding fragment, wherein the antibody or Petition 870250087401, dated 09 / 26 / 2025, page 37 / 207 4 / 139 antigen-binding fragment is conjugated to a radioisotope, it may also be referred to here as a radiolabeled olaratumab antibody or an antigen-binding fragment thereof.

[0011] In a second aspect, the present invention provides an olaratumab antibody bioconjugate or olaratumab antibody, suitable for radiolabeling with a diagnostic radioisotope.

[0012] Preferably, the olaratumab bioconjugate comprises an olaratumab antibody conjugated to any chelating group or ligand suitable for further conjugation to a radioisotope. Optionally, the olaratumab bioconjugate is selected from: olaratumab-TMT (6,6bis[N,N,N'-tetra(carboxymethyl)aminomethyl)-4'-(3-amino-4methoxyphenyl)-2,2':6',2-terpyridine), olaratumab-DOTA (1,4,7,10-tetra-azacyclododecane-NN',N(N'-tetraacetic acid), olaratumab-TCMC, olaratumab-DO3A, olaratumabCB-DO2A, olaratumab-NOTA, olaratumab-Diamsar, olaratumab-DTPA, olaratumab-CHX-A-DTPA, olaratumabTETE, olaratumab-Te2A, olaratumab-HBED, olaratumab-DFO, olaratumab-DFOsq, olaratumab-DFO-NCS and olaratumab-HOPO or olaratumab chelated to a chelating agent, as disclosed in document no. WO 2022 / 133537, or to any other chelating agent, as described in this document or known to a person skilled in the art. Petition 870250087401, dated 09 / 26 / 2025, page 38 / 207 5 / 139

[0013] The olaratumab antibody or the antigen-binding fragment thereof preferably comprises an antigen-binding domain that competitively inhibits the binding of an antibody comprising a VH comprising a sequence as set forth in SEQ ID NO: 4 and a VL comprising a sequence as set forth in SEQ ID NO: 12.

[0014] In any aspect or embodiment contained herein, the olaratumab antibody or antigen-binding fragment comprises an HCDR1, an HCDR2, and an HCDR3 of an antigen-binding domain with a variable heavy chain, as defined in SEQ ID NO: 4, and an LCDR1, LCDR2, and LCDR3 of an antigen-binding domain with a VL defined in SEQ ID NO: 12.

[0015] As used herein, the sequences of complementarity-determining regions (CDRs) of an antigen-binding protein of the invention may be defined in accordance with the IMGT, Chothia or Kabat numbering systems, or any other CDR numbering system known to those skilled in the art.

[0016] In any aspect or embodiment of the invention, the olaratumab antibody or antigen-binding fragment comprises an antigen-binding domain comprising: i) a VH that includes a complementarity-determining region (CDR) 1 comprising a sequence of, Petition 870250087401, dated 09 / 26 / 2025, page 39 / 207 6 / 139 at least, approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 1, a CDR2 comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence defined in SEQ ID NO: 2, and a CDR3 comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%,at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 3;, ii) a VH comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, by Petition 870250087401, dated 09 / 26 / 2025, page 40 / 207 7 / 139 less 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 4; iii) a VL that includes a CDR1 that includes a sequence of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 9, a CDR2 comprising a sequence of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, by at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence established in SEQ ID NO: 10 and a CDR3 comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%,at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, Petition 870250087401, dated 09 / 26 / 2025, page 41 / 207 8 / 139 at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 11; iv) a VL comprising a sequence that is at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence established in SEQ ID NO: 12; (v) a VH comprising a CDR1 comprising a sequence set out in SEQ ID NO: 1, a CDR2 comprising a sequence set out in SEQ ID NO: 2 and a CDR3 comprising a sequence set out in SEQ ID NO: 3; (vi) a VH comprising a sequence set out in SEQ ID NO: 4; (vii) a VL comprising a CDR1 comprising a sequence set out in SEQ ID NO: 9, a CDR2 comprising a sequence set out in SEQ ID NO: 10 and a CDR3 comprising a sequence set out in SEQ ID NO: 11; (viii) a VL comprising a sequence set out in SEQ ID NO: 12; (ix) a VH comprising a CDR1 comprising a sequence set out in SEQ ID NO: 1, a CDR2 comprising a sequence set out in SEQ ID NO: 2, and a CDR3 Petition 870250087401, dated 09 / 26 / 2025, page 42 / 207 9 / 139 comprising a sequence established in SEQ ID NO: 3; and a VL comprising a CDR1 comprising a set of sequences SEQ ID NO: 9, a CDR2 comprising a sequence established in SEQ ID NO: 10, and a CDR3 comprising a sequence established in SEQ ID NO: 11; or (x) a VH comprising a sequence established in SEQ ID NO: 4, and a VL comprising a sequence established in SEQ ID NO: 12. [001 7] The olaratumab antibody or its antigen-binding fragment may also include: (i) a VH that includes a framework region (FR) 1 comprising or consisting of a sequence that is at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and at least 99% identical to a sequence as set out in SEQ ID NO: 5; an FR2 that includes or is composed of a sequence of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% Petition 870250087401, dated 09 / 26 / 2025, page 43 / 207 10 / 139 99% identical to a sequence as set forth in SEQ ID NO: 6; an FR3 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set forth in SEQ ID NO: 7; an FR4 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 8;and (ii) a VL that includes a framework region (FR) 1 comprising or consisting of a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% and at least 99% identical to a sequence; Petition 870250087401, dated 09 / 26 / 2025, page 44 / 207 11 / 139 as set out in SEQ ID NO: 13; an FR2 that includes or is made up of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 14; an FR3 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 15;an FR4 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 16.

[0018] In another form, the antibody olaratumab or Petition 870250087401, dated 09 / 26 / 2025, page 45 / 207 12 / 139 antigen-binding fragment comprises: (i) a VH comprising a framework region (FR) 1 comprising or consisting of a sequence, as set forth in SEQ ID NO: 5; an FR2 comprising or consisting of a sequence as set forth in SEQ ID NO: 6; an FR3 comprising or consisting of a sequence as set forth in SEQ ID NO: 7; an FR4 comprising or consisting of a sequence as set forth in SEQ ID NO: 8, and (ii) a VL comprising a framework region (FR) 1 comprising or consisting of a sequence, as set forth in SEQ ID NO: 13; an FR2 comprising or consisting of a sequence as set forth in SEQ ID NO: 14; an FR3 comprising or consisting of a sequence as set forth in SEQ ID NO: 15; an FR4 comprising or consisting of a sequence as set forth in SEQ ID NO: 16.

[0019] In any embodiment, the olaratumab antibody or its antigen-binding fragment comprises an HV comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or by Petition 870250087401, dated 09 / 26 / 2025, page 46 / 207 13 / 139 less than 99% identical to a sequence established in SEQ ID NO: 4; and / or a VL comprising a sequence that is at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence established in SEQ ID NO: 12; wherein the sequence variation between VH and VL and the sequence of SEQ ID NO: 4 and 12 are not in the CDRs and wherein the antigen-binding protein retains the ability to bind to PDGFRalpha.

[0020] In any embodiment, the olaratumab antibody or its antigen-binding fragment comprises a VH and / or a VL comprising no more than 1, no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, no more than 7, no more than 8, no more than 9, no more than 10, no more than 11, no more than 12, no more than 13, no more than 14, no more than 15, no more than 16, no more than 17, no more than 18, no more than 19 or no more than 20 amino acid substitutions, deletions or additions, compared to the amino acid sequences established in SEQ ID NO: 4 or 12, respectively; wherein amino acid substitutions, deletions or additions do not Petition 870250087401, dated 09 / 26 / 2025, p. 47 / 207 14 / 139 are in the CDRs and the antigen-binding protein retains the ability to bind to PDGFRalpha.

[0021] As used herein, the terms HCDR1, HCDR2 and HCDR3 will be understood as referring to the variable heavy chain CDRs; the terms LCDR1, LCDR2 and LCDR3 will be understood as referring to the variable light chain CDRs; and the terms HFR1, HFR2, HFR3, HFR4, LFR1, LFR2, LFR3 and LFR4 will be understood as referring to the heavy and light chain structure regions, respectively.

[0022] As described in this document, the olaratumab antibody or antigen-binding fragment may be in the form of: (i) a single-domain antibody (sdAb); (ii) a single-stranded Fv fragment (scFv); (iii) a dimeric scFv (di-scFv); or (iv) one of ii) or iii) linked to a constant region of an antibody, Fc, or a constant domain of heavy chain (CH) 2 and / or CH3.

[0023] In addition, as described in this document, olaratumab or the antigen-binding fragment may be in the form of: i) a diacorporeal; ii) a triacorpo; iii) a tetrabody; (iv) a Fab; Petition 870250087401, dated 09 / 26 / 2025, page 48 / 207 15 / 139 ( v) one F(ab')2; ( vi) a Fv; (vii) a bispecific antibody or other form of multispecific antibody; or (viii) one of i) to vii) linked to a constant region of an antibody, Fc or to a constant domain of heavy chain (CH) 2 and / or CH3.

[0024] Optionally, the variable heavy and light regions of the antigen-binding domain are joined by means of a linker.

[0025] In any embodiment, the antigen-binding domain may include: FR1 - CDR1 - FR2 - CDR2 - FR3 — CDR3 — FR4 - ligand FR1a - CDRla - FR2a - CDR2a - FR3a - CDR3a - FR4a.

[0026] As defined in this document, the linker may be a chemical, one or more amino acids, or a disulfide bond formed between two cysteine ​​residues.

[0027] In any aspect or embodiment of the present invention, the radiolabeled olaratumab or antigen-binding fragment may comprise a human constant region, for example, an IgG constant region, such as an IgGi, IgG2, IgGs or IgG4 constant region or mixtures thereof. In the case of an antibody or protein comprising a Vh and a Vl, the Vh may be linked to a heavy chain constant region and the Vl may be linked to a constant region. Petition 870250087401, dated 09 / 26 / 2025, page 49 / 207 16 / 139 light chain.

[0028] In one example, the olaratumab or antigen-binding fragment comprises a constant region of an IgG4 antibody or a stabilized constant region of an IgG4 antibody. In one example, the olaratumab or antigen-binding fragment comprises a constant region of IgG4 with a proline at position 241 (according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, Washington DC, United States Department of Health and Human Services, 1987 and / or 1991)).

[0029] In one example, olaratumab or antigen-binding fragment comprises a constant heavy chain region, comprising a stabilized constant heavy chain region, comprising a mixture of sequences wholly or partially with or without the C-terminal lysine residue.

[0030] In other embodiments of any aspect herein, olaratumab or the antigen-binding fragment comprises an Fc region wherein the Fc region is designed to have enhanced ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Preferably, the enhanced ability to induce ADCC is conferred by mutation, deletion, or modification of amino acids in the Fc region that interact with an Fc receptor.

[0031] In another embodiment, the olaratumab or antigen-binding fragment comprises a projected Fc region. Petition 870250087401, dated 09 / 26 / 2025, page 50 / 207 17 / 139 to: - to have increased the half-life in vitro or in vivo; - have an increased capacity to induce antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity; and / or - to have a reduced effector function.

[0032] Preferably, the olaratumab antibody is in the form of an antibody (i.e., comprising a variable light chain and a variable heavy chain, linked to a constant region of an antibody including a CH2 and / or CH3 heavy chain).

[0033] In other embodiments, olaratumab may comprise a heavy chain constant region as defined in SEQ ID NO: 17 and / or a light chain constant region as defined in SEQ ID NO: 18.

[0034] In particularly preferred embodiments, olaratumab may comprise a heavy chain as set forth in SEQ ID NO: 19 and / or a light chain as set forth in SEQ ID NO: 20.

[0035] In other embodiments, olaratumab is in the form of an antibody and may include one or more amino acid substitutions in the constant regions, so as to reduce the in vivo half-life of the antibody. The present invention therefore provides an olaratumab antibody with Petition 870250087401, dated 09 / 26 / 2025, page 51 / 207 18 / 139 substitutions in the CH2 and / or CH3 domains of the constant region and comprising substitutions in one or more of the residues His310, His435, Tyr436 and Ile253 (EU Kabat index numbering), thereby altering the FcRn binding affinity and / or serum half-life of said antibody (e.g., in relation to an olaratumab comprising a native CH2 and CH3 domain).

[0036] In some examples, the amino acid at position 310 and / or 435 of the antibody may be alanine, glutamic acid, aspartic acid, leucine, isoleucine, arginine, proline, glutamine, methionine, serine, threonine, lysine, asparagine, phenylalanine, tyrosine, tryptophan, cysteine, valine, or glycine.

[0037] Preferably, the residue at position 310 is selected from alanine, glutamic acid, or glutamine; or the amino acid residue 435 of the heavy chain constant region is selected from arginine, glutamine, or alanine. In other preferred embodiments, the antibody has an alanine residue at position 310 and a glutamine residue at position 435.

[0038] In another embodiment, the antibody also comprises an amino acid substitution at the Lys322 residue. Preferably, the substitution is K322A.

[0039] In particularly preferred embodiments, the olaratumab antibody comprises the K322A, H310A and H435Q substitutions. Petition 870250087401, dated 09 / 26 / 2025, page 52 / 207 19 / 139

[0040] In another preferred embodiment, the olaratumab antibody comprises amino acid substitutions at residues His310, His435 and Ile253, wherein the substitutions are preferably H310A, H435Q and I253E.

[0041] In a preferred embodiment, the binding affinity for FcRn and / or the serum half-life of the modified antibody is decreased by at least about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, or 100-fold. In a preferred embodiment of the present invention, the binding affinity for FcRn and / or the serum half-life of said modified antibody is reduced by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98%, or 99%.

[0042] In any aspect or embodiment, the antibody may also include amino acid substitutions at Ser228 and / or Leu235 equivalent residues of the constant heavy chain region, such as Ser228Pro and / or Leu235Glu.

[0043] In any aspect or modality, radiolabeled olaratumab may include any radioisotope suitable for in vivo imaging methods for the detection of tumors or cancerous masses. Examples of suitable radioisotopes include: fluorine-18 (18F), gallium-67 and gallium-68 (67Ga and 68Ga), indium-111 (111In), iodine-123 and iodine-124, technetium-99 (99mTc), terbium-155 and terbium-159 (155Tb and 159Tb), and zirconium-89. Petition 870250087401, dated 09 / 26 / 2025, page 53 / 207 20 / 139 (89Zr).

[0044] In any aspect or modality, the radioisotope can be directly conjugated to olaratumab, for example, by halogenation of amino acid residues. Preferably, the radiolabeled olaratumab radioisotope is indirectly linked to olaratumab or its antigen-binding fragment, for example, through a chelating agent or other binding moiety. In one example, olaratumab is conjugated to a chelating moiety selected from the group consisting of: TMT (6,6-bis[N,N,N'tetra(carboxymethyl)aminomethyl)-4'-(3-amino-4-methoxyphenyl)2,2':6',2-terpyridine), DOTA (1,4,7,10-tetraazacyclododecane-NN',N(N'-tetraacetic acid), TCMC, DO3A, CB-DO2A, NOTA, Diamsar, DTPA, CHX-A-DTPA, TETE, Te2A, HBED, DFO, DFOsq, DFO-NCS and HOPO, a chelating agent as described in document no. WO 2022 / 133537 (incorporated herein by reference), or another chelating agent as described in this document or known to those skilled in the art.

[0045] In another example, radiolabeled olaratumab or the antigen-binding fragment is conjugated to a bifunctional ligand, for example, bromoacetyl, thiols, succinimide ester, TFP ester, a maleimide, or using any amine or thiol-modifying chemical known in the art.

[0046] Preferably, the labeled olaratumab antibody Petition 870250087401, dated 09 / 26 / 2025, p. 54 / 207 21 / 139 radioactively or its antigen-binding fragment is 89Zr-olaratumab or an 89Zr-labeled olaratumab, preferably wherein the 89Zr is conjugated to olaratumab via a linker, such as 89Zr-DFO-olaratumab, 89Zr-DFO-NCSolaratumab or 89Zr-DFO-Sq-olaratumab.

[0047] In another aspect, a method is provided for obtaining a radiolabeled olaratumab of the first aspect of the invention, wherein the method comprises radiolabeling an olaratumab bioconjugate or antibody of the second aspect.

[0048] In a second aspect, the present invention provides a method for in vivo imaging or detection of a cancer expressing PDGFRalpha in an individual, wherein the method comprises: - administer to an individual in need of such an olaratumab radiolabeled antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described in this document, - to detect the antibody or antigen-binding fragment in the individual.

[0049] In a third aspect, the present invention provides a method for diagnosing a cancer that expresses PDGFRalpha in an individual, wherein the method comprises: - to administer to an individual in need of such, a Petition 870250087401, dated 09 / 26 / 2025, page 55 / 207 22 / 139 radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described herein, - To determine the presence or absence of the antibody or antigen-binding fragment in the individual.

[0050] According to the second or third aspects of the invention, the detection of the antibody or fragment, or the determination of the presence or absence of the antibody or fragment, can be compared to a background or standard level to determine the presence of cancer, by imaging or detecting cancer in the individual.

[0051] Alternatively, or in addition, detection or presence or absence is compared to a disease classification or disease progression model that is derived from data from one or more individuals, i.e., imaging or detection or diagnosis of cancer in the individual. The model may be derived from individuals known to have cancer or from individuals known not to have cancer (or combinations thereof).

[0052] In certain modalities, detection or determination may result in data that are used to compile training data for the development of a deep learning algorithm to enable self-learning based on artificial intelligence for Petition 870250087401, dated 09 / 26 / 2025, page 56 / 207 23 / 139 diagnosis and / or staging of cancer. Such methods are generally known in the art and are described, for example, in documents no. WO2020144134 and US 11,443,201, incorporated herein by reference.

[0053] The present invention also provides a method for producing an image of a cancer expressing PDGFRalpha in an individual, the method comprising: - administer to an individual suspected of having cancer, a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described herein, - detecting the antibody or antigen-binding fragment in the individual, thus producing an image of the cancer.

[0054] The present invention provides a method for producing an image of a cancer expressing PDGFRalpha, the method comprising: - to infuse an effective amount of a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described in this document, - to detect the antibody or its antigen-binding fragment, Petition 870250087401, dated 09 / 26 / 2025, page 57 / 207 24 / 139 thus producing an image of cancer.

[0055] Optionally, the produced cancer image is used to generate training data for the development of machine learning algorithms.

[0056] In another aspect, the present invention provides a method for classifying a cancer as sensitive to treatment with a PDGFRalpha inhibitor, the method comprises: - administer to an individual in need of such an olaratumab radiolabeled antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described in this document, - detect the antibody or antigen-binding fragment in the individual, where the cancer is classified as sensitive to treatment with a PDGFRalpha inhibitor when the detection of the antibody or its fragment is less than or equal to a baseline or threshold level; or where the cancer is classified as not sensitive to treatment with a PDGFRalpha inhibitor when the detection of the antibody or its fragment is above a background or threshold level.

[0057] In another aspect, the present invention provides a method for classifying a cancer as sensitive to treatment with a PDGFRalpha inhibitor, the method comprises: Petition 870250087401, dated 09 / 26 / 2025, page 58 / 207 25 / 139 - administer to an individual in need of such an olaratumab radiolabeled antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described in this document, - detect the antibody or antigen-binding fragment in the individual, where the cancer is classified as sensitive to treatment with a PDGFRalpha inhibitor based on the output of a deep learning algorithm, indicating the presence of cancer cells expressing PDGFRalpha in the individual, and where the cancer is not classified as sensitive to treatment with a PDGFRalpha inhibitor based on the output of a deep learning algorithm, indicating the absence of cancer cells expressing PDGFRalpha in the individual.

[0058] In another aspect, the present invention provides a method for classifying or selecting a patient for eligibility for cancer therapy with a PDGFRalpha inhibitor, the method comprising: - administer to an individual in need of such, a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described. Petition 870250087401, dated 09 / 26 / 2025, page 59 / 207 26 / 139 in this document, - detect the antibody or antigen-binding fragment in the individual, where the patient is classified / selected for cancer therapy with a PDGF-alpha inhibitor when the detection of the antibody or fragment thereof is above a background or standard level; in which the patient is not classified / selected for cancer therapy with a PDGF-alpha inhibitor when the detection of the antibody or a fragment thereof is equal to or lower than a background or standard level.

[0059] In another aspect, the present invention provides a method for classifying or selecting a patient for eligibility for cancer therapy with a PDGFRalpha inhibitor, the method comprising: - administer to an individual in need of such an olaratumab radiolabeled antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is as described in this document, - detect the antibody or antigen-binding fragment in the individual, where the patient is classified / selected for cancer therapy with a PDGF-alpha inhibitor based on the output of a deep learning algorithm, Petition 870250087401, dated 09 / 26 / 2025, page 60 / 207 27 / 139 indicating the presence of cancer cells expressing PDGFRalpha in the individual, where the patient is not classified / selected for cancer therapy with a PDGFRalpha inhibitor based on the output of a deep learning algorithm, indicating the absence of cancer cells expressing PDGFRalpha in the individual.

[0060] In another aspect, the present invention relates to methods for monitoring the treatment response of a cancer that expresses PDGFRalpha. As such, the invention provides a method for determining the treatment response of a cancer that expresses PDGFRalpha or of an individual with a cancer that expresses PDGFRalpha, the method comprising: - administer to an individual who has received or is receiving treatment for a cancer that expresses PDGFRalpha, a radiolabeled olaratumab antibody or antigen-binding fragment, preferably where the radiolabeled olaratumab is as described in this document, - to detect the antibody or antigen-binding fragment in the individual, - compare the amount of antibody or antigen-binding fragment detected in the individual with a reference amount of antibody or antigen-binding fragment detected in the individual before the Petition 870250087401, dated 09 / 26 / 2025, page 61 / 207 28 / 139 treatment, - To determine that the cancer has responded to treatment when the amount of antibody or antigen-binding fragment detected is less than the reference amount. - To determine that the cancer has not responded to treatment when the amount of antibody or antigen-binding fragment is equal to or greater than the reference amount, thus determining the treatment response of a cancer that expresses PDGFRalpha or of an individual with a cancer that expresses PDGFRalpha.

[0061] The treatment received or received by the individual may be any treatment for cancer that expresses PDGFRalpha, including but not limited to surgery, chemotherapy, immunotherapy (such as CAR-T therapy), radiotherapy (including external beam radiation or immunoradiotherapy), a PDGFRalpha inhibitor and / or combinations thereof.

[0062] In addition, the present invention provides methods for treating a cancer patient, the method comprising: - administer to a cancer patient suspected of having, or considered at risk of having, a cancer that expresses PDGFRalpha, a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably wherein the radiolabeled olaratumab is that described herein, Petition 870250087401, dated 09 / 26 / 2025, page 62 / 207 29 / 139 - to detect the antibody or antigen-binding fragment in the patient, - to classify the patient as eligible to receive cancer therapy with a PDGF-alpha inhibitor, when the detection of the antibody or a fragment thereof is above a background or standard level; - to classify the patient as ineligible to receive cancer therapy with a PDGFRalpha inhibitor when the detection of the antibody or a fragment thereof is equal to or lower than a background or standard level; - Treat the patient with a PDGFRalpha inhibitor when the patient is classified as eligible to receive cancer therapy with a PDGFRalpha inhibitor. - To determine whether or not to treat the patient with a PDGFRalpha inhibitor when patients are classified as ineligible to receive cancer therapy with a PDGFRalpha inhibitor.

[0063] In addition, the present invention provides methods for treating a cancer patient, the method comprising: - administer to a cancer patient suspected of having, or considered at risk of having, a cancer that expresses PDGFRalpha, a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably wherein the radiolabeled olaratumab is that described herein, Petition 870250087401, dated 09 / 26 / 2025, page 63 / 207 30 / 139 - to detect the antibody or antigen-binding fragment in the patient, - to classify the patient as eligible to receive cancer therapy with a PDGFRalpha inhibitor, based on the output of a deep learning algorithm derived from compiled data of individuals who responded to treatment with a PDGFRalpha inhibitor; - to classify the patient as ineligible to receive cancer therapy with a PDGFRalpha inhibitor, based on the output of a deep learning algorithm derived from compiled data of individuals who did not respond to treatment with a PDGFRalpha inhibitor; - Treat the patient with a PDGFRalpha inhibitor when the patient is classified as eligible to receive cancer therapy with a PDGFRalpha inhibitor. - To determine whether or not to treat the patient with a PDGFRalpha inhibitor when patients are classified as ineligible to receive cancer therapy with a PDGFRalpha inhibitor.

[0064] The present invention also provides methods for treating a cohort of cancer patients, the method comprising: - administer to the cohort a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is Petition 870250087401, dated 09 / 26 / 2025, page 64 / 207 31 / 139 find as described in this document, - detect the antibody or antigen-binding fragment in the cohort, - to classify patients as eligible to receive cancer therapy with a PDGFRalpha inhibitor when the detection of the antibody or a fragment thereof is above a background or standard level; - to classify patients as ineligible to receive cancer therapy with a PDGFRalpha inhibitor when the detection of the antibody or a fragment thereof is equal to or lower than a background or standard level; - Treat cohort patients with a PDGFRalpha inhibitor when patients are classified as eligible to receive cancer therapy with a PDGFRalpha inhibitor. - To determine whether to treat cohort patients with a PDGFRalpha inhibitor when patients are classified as ineligible to receive cancer therapy with a PDGFRalpha inhibitor.

[0065] The present invention also provides methods for treating a cohort of cancer patients, the method comprising: - administer to the cohort a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, preferably in which the radiolabeled olaratumab is Petition 870250087401, dated 09 / 26 / 2025, page 65 / 207 32 / 139 find as described in this document, - detect the antibody or antigen-binding fragment in the cohort, - to classify patients as eligible to receive cancer therapy with a PDGFRalpha inhibitor, based on the output of a deep learning algorithm derived from compiled data of individuals who responded to treatment with a PDGFRalpha inhibitor; - to classify patients as ineligible to receive cancer therapy with a PDGFRalpha inhibitor, based on the output of a deep learning algorithm derived from compiled data of individuals who did not respond to treatment with a PDGFRalpha inhibitor; - Treat cohort patients with a PDGFRalpha inhibitor when patients are classified as eligible to receive cancer therapy with a PDGFRalpha inhibitor. - To determine whether to treat cohort patients with a PDGFRalpha inhibitor when patients are classified as ineligible to receive cancer therapy with a PDGFRalpha inhibitor.

[0066] In any of the aspects or embodiments of the invention mentioned above, the PDGFRalpha inhibitor may be an olaratumab antibody or a functional antigen-binding fragment thereof. As such, and according to the aspects Petition 870250087401, dated 09 / 26 / 2025, page 66 / 207 33 / 139 and the aforementioned embodiments, the present invention therefore provides methods for: - to classify a cancer as sensitive to treatment with an olaratumab antibody or a functional antigen-binding fragment of the same; - to classify a patient for eligibility for cancer therapy with an olaratumab antibody or functional antigen-binding fragment thereof; - select a patient for treatment with an olaratumab antibody or functional antigen-binding fragment; or - to treat a cancer patient or cohort of cancer patients with an olaratumab antibody or a functional antigen-binding fragment thereof, wherein, preferably, the olaratumab antibody for use in a described method comprises an amino acid sequence as defined herein in Table 1. More preferably, the olaratumab antibody comprises a variable heavy chain as defined in SEQ ID NO: 4 and a variable light chain as defined in SEQ ID NO: 12.

[0067] The invention also provides a radiolabeled olaratumab antibody or antigen-binding fragment thereof, or a composition comprising it, as described herein, for use in a method of: Petition 870250087401, dated 09 / 26 / 2025, page 67 / 207 34 / 139 - In vivo imaging or detection of a cancer that expresses PDGFRalpha; - diagnosis of a cancer that expresses PDGF-alpha; - to produce an image of a cancer that expresses PDGF-alpha; - to classify a cancer as responsive to treatment with a PDGF-alpha inhibitor; - to classify or select a patient for eligibility for cancer therapy with a PDGF-alpha inhibitor; - Treating a cancer patient or cohort of cancer patients with a PDGF-alpha inhibitor; wherein the methods are those described in this document and, preferably, wherein the radiolabeled olaratumab is that described in this document.

[0068] In another aspect, the invention provides for the use of a radiolabeled olaratumab antibody or antigen-binding fragment thereof, in the manufacture of a composition for: - In vivo imaging or detection of a cancer that expresses PDGFRalpha; - diagnosis of a cancer that expresses PDGF-alpha; - to produce an image of a cancer that expresses PDGF-alpha; - to classify a cancer as responsive to treatment with a PDGF-alpha inhibitor; Petition 870250087401, dated 09 / 26 / 2025, page 68 / 207 35 / 139 - to classify or select a patient for eligibility for cancer therapy with a PDGF-alpha inhibitor; - Treating a cancer patient or cohort of cancer patients with a PDGF-alpha inhibitor; wherein the methods are those described in this document and, preferably, wherein the radiolabeled olaratumab is that described in this document.

[0069] In addition, the invention provides a radiolabeled olaratumab antibody or an antigen-binding fragment thereof, or a composition comprising it, when used in a method of: - In vivo imaging or detection of a cancer that expresses PDGFRalpha; - diagnosis of a cancer that expresses PDGF-alpha; - to produce an image of a cancer that expresses PDGF-alpha; - to classify a cancer as responsive to treatment with a PDGF-alpha inhibitor; - to classify or select a patient for eligibility for cancer therapy with a PDGF-alpha inhibitor; - Treating a cancer patient or cohort of cancer patients with a PDGF-alpha inhibitor; where the methods are those described in this document and, Petition 870250087401, dated 09 / 26 / 2025, page 69 / 207 36 / 139 preferably, where the radiolabeled olaratumab is the one described here.

[0070] In addition, the invention provides a kit for use in accordance with any method described herein, wherein the kit comprises: and a radiolabeled olaratumab antibody or antigen-binding fragment as described in this document and, optionally, instructions for its use for - In vivo imaging or detection of a cancer that expresses PDGFRalpha; - diagnosis of a cancer that expresses PDGF-alpha; - to produce an image of a cancer that expresses PDGF-alpha; - to classify a cancer as responsive to treatment with a PDGF-alpha inhibitor; - to classify or select a patient for eligibility for cancer therapy with a PDGF-alpha inhibitor; - Treating a cancer patient or cohort of cancer patients with a PDGF-alpha inhibitor.

[0071] In another aspect, a pharmaceutical composition is provided comprising an olaratumab antibody, or an antigen-binding fragment thereof, an olaratumab bioconjugate or a radiolabeled olaratumab, as described herein, optionally in combination with an excipient. Petition 870250087401, dated 09 / 26 / 2025, pp. 70 / 207 37 / 139 pharmacologically acceptable.

[0072] In addition, a nucleic acid or a nucleic acid construct encoding an olaratumab antibody, or an antigen-binding fragment thereof, or an olaratumab bioconjugate as described herein is provided.

[0073] Also provided is a host or host cell comprising a nucleic acid construct or nucleic acid of the invention.

[0074] In any aspect or embodiment above, the methods of the invention may further include enabling the radiolabeled olaratumab antibody or its antigen-binding fragment to concentrate at sites and / or tissues in said individual where the PDGFRalpha antigen is found in the individual, prior to the detection step.

[0075] It will be understood that the detection of the radiolabeled olaratumab antibody or its antigen-binding fragment preferably comprises the determination or detection of the presence or absence of radiation emitted by the radioisotope conjugated to the antibody. In any aspect or modality, the determination or detection of the presence or absence of radiation comprises Positron Emission Tomography (PET), SPECT imaging or combinations thereof. The methods may be supplemented with the use of computed tomography, magnetic resonance imaging or other imaging techniques. Petition 870250087401, dated 09 / 26 / 2025, page 71 / 207 38 / 139

[0076] In any aspect or modality, an individual who needs this may be any individual suspected of having or considered at risk of having a cancer that expresses PDGFRalpha. Suspicion of having cancer or consideration of risk may be based on any sign or symptom associated with cancer, a family history of cancers that express PDGFRalpha, or a cancer-associated genotype that expresses PDGFRalpha, or a combination thereof.

[0077] In any aspect or embodiment of the invention, the cancer detected, photographed, diagnosed, classified, or selected may be any cancer that expresses PDGFRalpha. Preferably, the cancer is selected from the group comprising: soft tissue sarcoma (STM), chondrosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, and rhabdomyosarcoma. Alternatively, the cancer is selected from the group comprising: gastrointestinal stromal tumor (GIST), non-small cell lung cancer (NSCLC), pancreatic cancer, hepatocellular carcinoma, breast cancer, neuroendocrine tumors, ovarian cancer, cervical cancer, uterine cancer (such as adenosquamous carcinoma of the cervix), colorectal cancer, gastric cancer, salivary gland cancer, biliary cancer, glioma, prostate cancer, and renal cell carcinoma.

[0078] As used in this document, except where the context requires otherwise, the term includes Petition 870250087401, dated 09 / 26 / 2025, page 72 / 207 39 / 139 and variations of the term, such as includes, includes and included, are not intended to exclude other additives, components, wholes or steps.

[0079] Other aspects of the present invention and other embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings. Brief Description of the Drawings

[0080] Figure 1: Schematic representation of olaratumab bioconjugated with DFOsq and DOTA.

[0081] Figure 2: Biacore surface plasmon resonance assay setup.

[0082] Figure 3: Total and surface expression of PDGFRA in KRIB, HuO9, and A-204 sarcoma cell lines. A) Total PDGFRA expression was established by western blot; B) Surface PDGFRA expression in unfixed cells was determined by FACS.

[0083] Figure 4: Western blot showing olaratumab-mediated inhibition of the PDGFRA activation pathway.

[0084] Figure 5: A) Binding of 89Zr-DFOSq-Olaratumab to A204 and HCC827 cells at 1 hour; B) Binding of 89Zr-DFOSq-Olaratumab and 177Lu-DOTA-Olaratumab to A204 cells at 1 and 4 hours. [00 85] Figure 6: Example of PET images at 24, 48 and 120 hours. SUVmax, tumor:fundus ratio, tumor:liver ratio Petition 870250087401, dated 09 / 26 / 2025, page 73 / 207 40 / 139 and the tumor:bone ratio were measured for each image.

[0086] Figure 7: Biodistribution of 89Zr-DFOsqOlaratumab at 24, 48, and 120 hours, measured by radioactivity counts in the blood and dissected lungs, heart, liver, kidneys, muscles, spleen, bones, and tumors of naked mice bearing A204. Sequence information Table 1: Summary of amino acid sequences of PDGFR alpha-binding antibodies (olaratumab) Region SEQ ID NO: Amino acid or nucleotide sequence HCDR1 (protein) (Kabat) 1 SSSYY HCDR2 (protein) (Kabat) 2 SFFYTGSTYYNPSLRS HCDR3 (protein) (Kabat) 3 QSTYYYGSGNYYGWFDR VH (protein) 4 QLQLQESGPGLVKPSETLSLTCTVSGGSINSSSYYW GWLRQSPGKGLEWIGSFFYTGSTYYNPSLRSRLTIS VDTSKNQFSLMLSSVTAADTAVYYCARQSTYYYGNY YGWFDRWDQGTLVTVSS HFR1 (protein) (Kabat) 5 QLQLQESGPGLVKPSETLSLTCTVSGGSIN HFR2 (protein) (Kabat) 6 WGWLRQSPGKGLEWIG HFR3 (protein) (Kabat) 7 RLTISVDTSKNQFSLMLSSSVTAADTAVYYCAR HFR4 (protein) (Kabat) 8 WDQGTLVTVSS LCDR1 (protein) (Kabat) 9 RASQSVSSYLA LCDR2 (protein) (Kabat) 10 DASNRAT LCDR3 (protein) (Kabat) 11 QQRSNWPPA VL (protein) 12 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWY QQKPGQAPRLLIYDASNRATGIPARFSGSGSGSGTD FTLTISSLEPEDFAVYYCQQRSNWPPAFGQGTKVEI K Petition 870250087401, dated 09 / 26 / 2025, page 74 / 207 41 / 139 LFR1 (protein) (Kabat) 13 EIVLTQSPATLSLSPGERATLSC LFR2 (protein) (Kabat) 14 WYQQKPGQAPRLLIY LFR3 (protein) (Kabat) 15 GIPARFSGSGSGTDFDFTISSLEPEDFAVYYC LFR1 (protein) (Kabat) 16 FGQGTKVEIK Constant region of the heavy chain 17 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGK Constant region of the light chain 18 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE AKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Heavy chain of olaratumab 19 QLQLQESGPGLVKPSETLSLTCTVSGGSINSSSYYW GWLRQSPGKGLEWIGSFFYTGSTYYNPSLRSRLTIS VDTSKNQFSLMLSSSVTAADTAVYYCARQSTYYYGSG NYYGWFDRWDQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK Olaratumab light chain 20 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWY QQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFT LTISSLEPEDFAVYYCQQRSNWPPAFGQGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Detailed Description of the Modalities Platelet-derived growth factor receptor alpha (PDGFRalpha)

[0087] Platelet-derived growth factor receptor alpha (PDGFRa or PDGFRalfa) is a tyrosine receptor Petition 870250087401, dated 09 / 26 / 2025, page 75 / 207 42 / 139 type III kinase. PDGFRa is fundamental for development and plays important roles in adulthood. For example, mice homozygous for a null mutation die during embryogenesis. In later stages of development, PDGFRa is expressed in many mesenchymal structures, while adjacent epithelial cells produce platelet-derived growth factors (PDGFs).

[0088] The platelet-derived growth factor family consists of five different disulfide-linked dimers, PDGF-AA, -BB, -AB, -CC, and -DD, which act via PDGFRa and PDGFRe. These growth factors are dimeric molecules composed of disulfide-linked polypeptide chains that bind to two receptor proteins simultaneously and induce receptor dimerization, autophosphorylation, and intracellular signaling. PDGFRa can form heterodimers with PDGFRp, as well as homodimers. Because PDGFRp does not bind to the PDGF-A chain with high affinity, PDGF-AA activates only the aa receptor dimers, while PDGF-AB and PDGF-CC activate the αα and αβ receptor heterodimers.

[0089] PDGFR-alpha has also been detected in some tumor and stromal cells, including sarcomas, where signaling may contribute to cancer cell proliferation, metastasis, and maintenance of the microenvironment. Petition 870250087401, dated 09 / 26 / 2025, p. 76 / 207 43 / 139 tumoral.

[0090] Olaratumab (Lartruvo™) is a fully human IgG1 monoclonal antibody that selectively binds to the human platelet-derived growth factor (PDGF) receptor α (PDGFRa). The interaction between olaratumab and PDGFR-α prevents receptor binding by PDGFAA and -BB agglutinators, as well as activation of PDGF-AA, -BB, and -CC-induced receptors and downstream PDGFR-α signaling pathway. Olaratumab exhibits antitumor activity in vitro and in vivo against selected sarcoma cell lines and disrupted the PDGFR-α signaling pathway in in vivo tumor implantation models.

[0091] In 2019, Lartruvo™ failed to meet the primary endpoint of overall survival in the confirmatory phase III study in patients with soft tissue sarcoma (ANNOUNCE study; NCT02451943). Consequently, it is necessary to develop new methods to identify patients sensitive to treatment with olaratumab.

[0092] The present invention is based on the inventors' discovery that radiolabeled olaratumab, or antigen-binding fragments, can be used to recognize PDGFRa expressed on the surface of soft tissue sarcoma (STS) cells and thus enable the detection and imaging of such cancerous cells, as well as identify patients most likely to benefit from treatment. Petition 870250087401, dated 09 / 26 / 2025, page 77 / 207 44 / 139 therapeutic with PDGFRa inhibitors, such as olaratumab. General Definitions

[0093] Throughout this descriptive report, unless specifically stated otherwise or the context requires otherwise, reference to a single step, matter composition, group of steps, or group of matter compositions will be considered as encompassing both one and a plurality (i.e., one or more) of such steps, matter compositions, groups of steps, or group of matter compositions. Thus, as used herein, the singular forms a, an, and the include plural aspects and vice versa, unless the context clearly dictates otherwise. For example, the reference to a includes a single one as well as two or more; the reference to an includes a single one as well as two or more; the reference to the includes a single one as well as two or more, and so forth.

[0094] Persons skilled in the art will appreciate that the present invention is susceptible to variations and modifications other than those specifically described. It should be understood that the invention includes all such variations and modifications. The invention also includes all steps, features, compositions and compounds referred to or indicated in this descriptive report, individually or collectively, and any and all combinations or any two or more of these steps or features.

[0095] A person versed in the technique will recognize many Petition 870250087401, dated 09 / 26 / 2025, p. 78 / 207 45 / 139 methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.

[0096] All patents and publications referenced herein are incorporated by reference in their entirety.

[0097] The present invention should not be limited in scope by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions and methods are clearly within the scope of the present invention.

[0098] Any example or embodiment of the present invention in this document shall be deemed applicable mutatis mutandis to any other example or embodiment of the invention, unless specifically indicated otherwise.

[0099] Unless specifically defined otherwise, all technical and scientific terms used herein should be considered as having the same meaning commonly understood by someone with ordinary skill in the technique (e.g., in diagnostic technology, radioimaging, cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry).

[00100] The term and / or, for example, X and / or Y must Petition 870250087401, dated 09 / 26 / 2025, pp. 79 / 207 46 / 139 should be understood as meaning X and Y or X or Y and should be understood as providing explicit support for both meanings or for either meaning. Selected definitions

[00101] The term isolated protein or isolated polypeptide is a protein or polypeptide that, by virtue of its origin or source of derivation, is not associated with naturally associated components that accompany it in its native state; it is substantially free of other proteins from the same source. A protein can be made substantially free of naturally associated components or substantially purified by isolation, using protein purification techniques known in the art. By substantially purified it is understood that the protein is substantially free of contaminating agents, for example, at least about 70% or 75% or 80% or 85% or 90% or 95% or 96% or 97% or 98% or 99% free of contaminating agents.

[00102] Recombinant means the product of artificial genetic recombination. Thus, in the context of a recombinant protein comprising an antibody antigen-binding domain, this term does not encompass an antibody that occurs naturally within an individual's body that is the product of natural recombination occurring during B cell maturation. However, if such an antibody is Petition 870250087401, dated 09 / 26 / 2025, pp. 80 / 207 47 / 139 isolated, should be considered an isolated protein comprising an antibody antigen-binding domain. Similarly, if the nucleic acid encoding the protein is isolated and expressed using recombinant means, the resulting protein is a recombinant protein comprising an antibody antigen-binding domain. A recombinant protein also encompasses a protein expressed by artificial recombinant means when it is within a cell, tissue, or individual, for example, in which it is expressed.

[00103] A protein is understood to be a single polypeptide chain, that is, a series of contiguous amino acids linked by peptide bonds or a series of polypeptide chains linked covalently or non-covalently to each other (i.e., a polypeptide complex). For example, the series of polypeptide chains may be covalently linked using a suitable chemical or a disulfide bond. Examples of non-covalent bonds include hydrogen bonds, ionic bonds, Van der Waals forces, and hydrophobic interactions.

[00104] The term polypeptide or polypeptide chain will be understood from the previous paragraph as a series of contiguous amino acids linked by peptide bonds.

[00105] As used herein, the term antigen-binding protein is used interchangeably with Petition 870250087401, dated 09 / 26 / 2025, page 81 / 207 48 / 139 antigen-binding domain and should be understood as a region of an antibody that is capable of specifically binding to an antigen, i.e., a VH or a VL or an Fv comprising a VH and a VL. The antigen-binding domain need not be in the context of an entire antibody, for example, it may be in isolation (e.g., a domain antibody) or in another form, for example, as described herein, as a scFv.

[00106] For the purposes of this disclosure, the term antibody includes a protein capable of specifically binding to one or a few closely related antigens by virtue of an antigen-binding domain contained in an Fv. This term includes four-chain antibodies (e.g., two light chains and two heavy chains), recombinant or modified antibodies (e.g., chimeric antibodies, humanized antibodies, human antibodies, CDR-grafted antibodies, primatized antibodies, deimmunized antibodies, sinesuhumanized antibodies, semiantibodies, bispecific antibodies). An antibody generally comprises constant domains, which may be arranged in a constant region or constant fragment or crystallizable fragment (Fc). Exemplary forms of antibodies comprise a four-chain structure as their basic unit. Full-length antibodies comprise two heavy chains (~50 to Petition 870250087401, dated 09 / 26 / 2025, p. 82 / 207 Antibody-mediated antibodies (49 / 139 kDa) are covalently linked and consist of two light chains (~23 kDa each). A light chain generally comprises a variable region (if present) and a constant domain, and in mammals is either a κ light chain or a λ light chain. A heavy chain generally comprises a variable region and one or two constant domains linked by a hinge region to additional constant domains. Mammalian heavy chains are of one of the following types: α, δ, ε, γ, or μ. Each light chain is also covalently linked to one of the heavy chains. For example, the two heavy chains and the heavy and light chains are held together by interchain disulfide bonds and non-covalent interactions. The number of interchain disulfide bonds can vary among different antibody types. Each chain has an N-terminal variable region (VH or VL, each ~110 amino acids long) and one or more constant domains at the C-terminus.The constant domain of the light chain (CL, which is ~110 amino acids long) is aligned and disulfide-linked to the first constant domain of the heavy chain (CH1, which is 330 to 440 amino acids long). The variable region of the light chain is aligned with the variable region of the heavy chain. The antibody heavy chain may comprise 2 or more additional CH domains (such as CH2, CH3, and similar) and may comprise a hinge region between the constant CH1 and CH2 domains. Antibodies can be of... Petition 870250087401, dated 09 / 26 / 2025, page 83 / 207 50 / 139 any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. In one example, the antibody is a murine (mouse or rat) antibody or a primate (such as human) antibody. In one example, the antibody heavy chain is missing a terminal C lysine residue. In one example, the antibody is humanized, sinumanized, chimeric, CDR-grafted, or deimmunized.

[00107] The terms full-length antibody, intact antibody, or whole antibody are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antigen-binding fragment of an antibody. Specifically, whole antibodies include those with both heavy and light chains, including an Fc region. Constant domains may be wild-type sequence constant domains (e.g., human wild-type sequence constant domains) or amino acid sequence variants.

[00108] As used herein, variable region refers to the portions of the light and / or heavy chains of an antibody, as defined herein, that are capable of specifically binding to an antigen and include amino acid sequences of complementarity-determining regions (CDRs); that is, CDR1, CDR2, and CDR3, and structure regions (FRs). For example, the variable region comprises three or Petition 870250087401, dated 09 / 26 / 2025, page 84 / 207 51 / 139 four FRs (e.g., FR1, FR2, FR3, and optionally FR4) along with three CDRs. VH refers to the variable region of the heavy chain. VL refers to the variable region of the light chain.

[00109] As used herein, the term individual should be understood as any animal, including humans, for example, a mammal. Exemplary subjects include, but are not limited to, humans and non-human primates. For example, the individual is a human.

[00110] Antibodies or immunoglobulins or Igs are gamma globulin proteins found in the blood or other body fluids of vertebrates that function in the immune system to bind to antigens, identifying and neutralizing foreign objects.

[00111] Antibodies are generally a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. Each L chain is linked to an H chain by a covalent disulfide bond. The two H chains are linked to each other by one or more disulfide bonds, depending on the isotype of the H chain. Each H and L chain also has regularly spaced intrachain disulfide bridges.

[00112] The H and L chains define specific Ig domains. More specifically, each H chain has, at the N-terminal, a variable domain (VH) followed by three constant domains (CH) for each of the α and γ chains and Petition 870250087401, dated 09 / 26 / 2025, p. 85 / 207 52 / 139 four CH domains for the μ and ε isotypes. Each L chain has at the N-terminus a variable domain (VL) followed by a constant domain (CL) at its other end. VL is aligned with VH and CL is aligned with the first constant domain of the heavy chain (CH1).

[00113] Antibodies can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains designated α, δ, ε, γ, and μ, respectively. The γ and α classes are divided into subclasses based on relatively small differences in the sequence and function of the heavy chain; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The L chain of any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.

[00114] The constant domain includes the Fc portion comprising the carboxy-terminal portions of both H chains held together by disulfide bonds. The effector functions of antibodies such as ADCC are determined by sequences in the Fc region, which is also the region recognized by Fc receptors (FcR) found on certain cell types.

[00115] The pairing of a VH and VL together forms a variable region or variable domain, including the Petition 870250087401, dated 09 / 26 / 2025, page 86 / 207 53 / 139 amino-terminal domains of the antibody's heavy or light chain. The variable domain of the heavy chain may be referred to as VH. The variable domain of the light chain may be referred to as VL. The V domain contains an antigen-binding protein that affects antigen binding and defines the specificity of a specific antibody for its specific antigen. V regions span approximately 110 amino acid residues and consist of relatively invariant stretches called framework regions (FRs) (usually about 4) of 15-30 amino acids separated by shorter regions of extreme variability called hypervariable regions (usually about 3) that are 9-12 amino acids long. FRs largely adopt a β-sheet configuration, and the hypervariable regions form loops that connect and, in some cases, are part of the β-sheet framework.

[00116] Hypervariable region, HVR or HV refers to regions of an antibody variable domain that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six hypervariable regions; three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Several hypervariable region delineations are in use and are encompassed here.

[00117] As used herein, the term complementarity determining regions (abbreviated as CDRs; or Petition 870250087401, dated 09 / 26 / 2025, page 87 / 207 54 / 139, i.e., CDR1, CDR2, and CDR3) refers to the amino acid residues of a variable region of antibody whose presence is the main contributor to specific antigen binding. Each variable region domain (VH or VL) typically has three CDRs identified as CDR1, CDR2, and CDR3. VH CDRs are also referred to here as CDR H1, CDR H2, and CDR H3, respectively, where CDR H1 corresponds to VH CDR 1, CDR H2 corresponds to VH CDR 2, and CDR H3 corresponds to VH CDR 3. Similarly, VL CDRs are referred to here as CDR L1, CDR L2, and CDR L3, respectively, where CDR L1 corresponds to VL CDR 1, CDR L2 corresponds to VL CDR 2, and CDR L3 corresponds to VL CDR 3. In one example, the amino acid positions assigned to CDRs and FRs are defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 (also referred to here as the Kabat numbering system).In another example, the amino acid positions assigned to CDRs and FRs are defined according to the Enhanced Chothia Numbering Scheme (http: / / www.bioinfo.org.uk / mdex.html). The present invention is not limited to FRs and CDRs as defined by the Kabat numbering system, but includes all numbering systems, including the canonical or Chothia and Lesk J. Mol. Biol. 196: 901-917, 1987; Chothia et al., Nature 342: 877-883, 1989; and / or Al-Lazikani et al., J. Mol. Biol. numbering system. Petition 870250087401, dated 09 / 26 / 2025, pp. 88 / 207 55 / 139 273: 927-948, 1997; the numbering system of Honnegher and Plükthun J. Mol. Biol. 309: 657-670, 2001; or the IMGT system discussed in Giudicelli et al., Nucleic Acids Res. 25: 206211 1997. In one example, CDRs are defined according to the Kabat numbering system. Optionally, the heavy chain CDR2 according to the Kabat numbering system does not comprise the five C-terminal amino acids listed here, or any one or more of these amino acids are substituted by another natural amino acid. In this regard, Padlan et al., FASEB J., 9: 133-139, 1995 established that the five C-terminal amino acids of the heavy chain CDR2 are generally not involved in antigen binding.

[00118] Framework residuals or FRs are variable domain residuals that are not the hypervariable region or CDR residuals defined herein. VH FRs are also referred to herein as FR H1, FR H2, FR H3, and FR H4, respectively, where FR H1 corresponds to VH FR 1, FR H2 corresponds to VH FR 2, FR H3 corresponds to VH FR 3, and FR H4 corresponds to VH FR 4. Similarly, VL FRs are referred to herein as FR L1, FR L2, FR L3, and FR L4, respectively, where FR L1 corresponds to VL FR 1, FR L2 corresponds to VL FR 2, FR L3 corresponds to VL FR 3, and FR L4 corresponds to VL FR 4.

[00119] A peptide for forming an antigen-binding protein generally refers to a peptide that Petition 870250087401, dated 09 / 26 / 2025, p. 89 / 207 56 / 139 can form a conformation that confers specificity of an antibody for the antigen. Examples include whole antibodies or structures related to whole antibodies, whole antibody fragments including a variable domain, variable domains and their fragments including light and heavy chains, or fragments of light and heavy chains that include some, but not all, hypervariable regions or constant regions.

[00120] An intact or whole antibody is one that comprises an antigen-binding protein as well as a CL and at least heavy chain constant domains, CH1, CH2 and CH3. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or their amino acid sequence variant.

[00121] Whole antibody-related structures include multimerized forms of whole antibodies.

[00122] Whole antibody fragments including a variable domain include Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies, single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[00123] The Fab fragment consists of an entire L-strand together with the variable region domain of the H-strand. Petition 870250087401, dated 09 / 26 / 2025, pp. 90 / 207 57 / 139 (VH) and the first constant domain of a heavy chain (CHI). Each Fab fragment is monovalent with respect to antigen binding, that is, it has only one antigen-binding protein.

[00124] A Fab' fragment differs from Fab fragments by having a few additional residues at the carboxy-terminus of the CHI domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation here for Fab' in which the cysteine ​​residue(s) of the constant domains carry a free thiol group.

[00125] An F(ab')2 fragment roughly corresponds to two disulfide-linked Fab fragments with divalent antigen-binding activity and is also capable of crosslinking the antigen.

[00126] A Fv is an antibody fragment that contains a complete antigen recognition and binding site. This fragment consists of a dimer of a heavy chain variable region domain and a light chain domain in close, non-covalent association.

[00127] In a single-chain Fv species (scFv), a variable heavy-chain domain and a light-chain domain can be covalently linked by a flexible peptide linker, so that the light and heavy chains can associate in a dimeric structure analogous to that of a two-chain Fv species. From the folding of these two domains emanate Petition 870250087401, dated 09 / 26 / 2025, pp. 91 / 207 58 / 139 six hypervariable loops (3 loops each from the H and L chains) that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody.

[00128] Single-chain Fv, also abbreviated as sFv or scFv, are antibody fragments comprising the VH and VL antibody domains connected to form a single polypeptide chain. Preferably, the scFv polypeptide additionally comprises a polypeptide linker between the VH and VL domains that allows the scFv to form the desired structure for antigen binding.

[00129] A single-variable domain is half of an Fv (comprising only three antigen-specific CDRs) that has the ability to recognize and bind to the antigen, although with a lower affinity than the whole binding site.

[00130] Diabodies refers to antibody fragments with two antigen-binding sites, whose fragments comprise a variable heavy chain (VH) domain connected to a variable light chain (VL) domain on the same polypeptide chain (VH-VL). Small antibody fragments are prepared by constructing sFv fragments (see previous paragraph) with short linkers (approximately 5-10 residues) between the VH and VL domains, so that interchain pairing, but not intrachain pairing, of the domains occurs. Petition 870250087401, dated 09 / 26 / 2025, pp. 92 / 207 59 / 139 V is achieved, resulting in a bivalent fragment, that is, a fragment with two antigen-binding sites.

[00131] Diabodies can be bivalent or bispecific. Bispecific diabodies are heterodimers of two crossed sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Triabodies and tetrabodies are also commonly known in the art.

[00132] An isolated antibody is one that has been identified and separated and / or recovered from a component of its pre-existing environment. Contaminating components are materials that interfere with the therapeutic uses of the antibody and may include enzymes, hormones, and other protein or non-protein solutes.

[00133] A human antibody refers to an antibody that has an amino acid sequence that corresponds to that of an antibody produced by a human being and / or has been produced using any of the human antibody production techniques disclosed herein. This definition of human antibody specifically excludes a humanized antibody composed of non-human antigen-binding residues. Human antibodies can be produced using several known techniques, including phage display libraries. Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to Petition 870250087401, dated 09 / 26 / 2025, pp. 93 / 207 60 / 139 produce such antibodies in response to antigenic challenge, but whose endogenous loci have been deactivated.

[00134] Humanized forms of non-human antibodies (e.g., rodents) are chimeric antibodies containing minimal sequence derived from the non-human antibody. Most often, humanized antibodies are human immunoglobulins (receptor antibody) in which residues from a hypervariable region of the receptor are replaced by residues from a hypervariable region of a non-human species (donor antibody), such as a mouse, rat, rabbit, or non-human primate with the desired specificity, affinity, and antibody capacity. In some cases, residues from the structure region (FR) of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may contain residues not found in the receptor antibody or the donor antibody. These modifications are made to further refine antibody performance.In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the RFs are those of a human immunoglobulin sequence. The humanized antibody may optionally also comprise... Petition 870250087401, dated 09 / 26 / 2025, pp. 94 / 207 61 / 139 at least a portion of a constant region of immunoglobulin (Fc), typically that of a human immunoglobulin.

[00135] Monoclonal antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies that make up the population are identical, except for possible naturally occurring mutations that may be present in small quantities. Monoclonal antibodies are highly specific, being directed against a single antigenic site or antigen determinant. In addition to their specificity, monoclonal antibodies are advantageous because they can be synthesized without contamination by other antibodies. Monoclonal antibodies can be prepared by hybridoma methodology or can be made using recombinant DNA methods in eukaryotic bacterial, animal, or plant cells. Monoclonal antibodies can also be isolated from phage antibody libraries.

[00136] The monoclonal antibodies contained herein include chimeric antibodies in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular class or subclass of antibodies, while the remainder of the chain(s) is / are Petition 870250087401, dated 09 / 26 / 2025, pp. 95 / 207 62 / 139 identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another class or subclass of antibodies, as well as fragments of such antibodies, provided they exhibit the desired biological activity. Chimeric antibodies of interest herein include primatized antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g., Old World monkey, macaque, etc.) and human constant region sequences.

[00137] Binding affinity generally refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Generally, binding affinity refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Low-affinity antibodies generally bind to the antigen slowly and tend to dissociate readily, while high-affinity antibodies generally bind to the antigen more rapidly and tend to remain bound longer. A variety of measurement methods Petition 870250087401, dated 09 / 26 / 2025, pp. 96 / 207 63 / 139 binding affinity is known in the art, any of which can be used for the purposes of the present invention.

[00138] As used herein, the term binds in reference to the interaction of an antigen-binding protein or antigen-binding domain with an antigen means that the interaction depends on the presence of a specific structure (e.g., an antigenic determinant or epitope) on the antigen. For example, an antibody recognizes and binds to a specific protein structure, not to proteins in general. If an antibody binds to epitope A, the presence of a molecule containing epitope A (or free, unlabeled A) in a reaction containing labeled A and the protein will reduce the amount of labeled A bound to the antibody.

[00139] As used in this document, the term specifically binds or specifically binds should be understood to mean that an antigen-binding protein of the invention reacts or associates more frequently, more rapidly, for a longer duration and / or with greater affinity with a particular antigen or cell expressing the same than with alternative antigens or cells.

[00140] As used herein, the term does not bind detectably should be understood to mean that an antigen-binding protein, for example, a Petition 870250087401, dated 09 / 26 / 2025, pp. 97 / 207 64 / 139 antibody, binds to a candidate antigen at a level below 10%, or 8%, 6%, or 5% above the background. The background may be the level of the binding signal detected in the absence of the protein and / or in the presence of a negative control protein (e.g., an isotype control antibody) and / or the level of binding detected in the presence of a negative control antigen. The binding level is detected using biosensor analysis (e.g., Biacore) in which the antigen-binding protein is immobilized and contacted with an antigen.

[00141] As used in this document, the term "does not bind significantly" should be understood to mean that the binding level of an antigen-binding protein of the invention to a polypeptide is not statistically significantly higher than the background, for example, the binding signal level detected in the absence of the antigen-binding protein and / or in the presence of a negative control protein (e.g., an isotype control antibody) and / or the binding level detected in the presence of a negative control polypeptide. The binding level is detected using biosensor analysis (e.g., Biacore) in which the antigen-binding protein is immobilized and contacted with an antigen.

[00142] An affinity-matured antibody is Petition 870250087401, dated 09 / 26 / 2025, pp. 98 / 207 65 / 139 that with one or more alterations in one or more HVRs that result in an improvement in the antibody's affinity for the antigen, compared to an original antibody that does not have this / these alteration(s). Preferentially affinity-matured antibodies will have nanomolar or even picomolar affinities for the target antigen. Affinity-matured antibodies are produced by procedures known in the art.

[00143] ADCC refers to a process called antibody-dependent cellular cytotoxicity, which is an immune response mediated primarily by natural killer (NK) cells in humans. In ADCC, FcyRIII on the surface of an NK cell recognizes the Fe region of the antibody that is bound to the antigen displayed on the surface of a target cell. This activates the NK cell, which releases perforins and granzymes, leading to lysis and apoptosis of the target cells.

[00144] CDC refers to a complex process called complement-dependent cytotoxicity that can lead to cell death through the action of a cascade of proteins that can act through one of two main pathways.

[00145] ADCP refers to a process called antibody-dependent cell-mediated phagocytosis. In this process mediated by the Fe receptor, the target cells to which the antibodies are bound are engulfed by Petition 870250087401, dated 09 / 26 / 2025, pp. 99 / 207 66 / 139 phagocytic cells, such as macrophages, monocytes, neutrophils, and dendritic cells. Several Fc receptors are involved in this process.

[00146] A blocking antibody or an antagonist antibody is one that inhibits or reduces the biological activity of the antigen to which it binds. Preferred blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.

[00147] An agonist antibody, as used herein, is an antibody that mimics at least one of the functional activities of a polypeptide of interest.

[00148] As understood herein, an Fc region is a dimer consisting of two polypeptide chains joined by one or more disulfide bonds, each chain comprising part or all of a hinge domain plus a CH2 domain and a CH3 domain. Each of the polypeptide chains is called an Fc polypeptide chain. To distinguish the two Fe polypeptide chains, one is referred to herein as an A chain and the other is referred to as a B chain. More specifically, the Fc regions contemplated for use with the present invention are lgG Fc regions, which may be lgG1, lgG2, lgG3, or lgG4 Fc regions of mammals or humans. Among the human lgG1 Fc regions, at least two allelic types are known. Petition 870250087401, dated 09 / 26 / 2025, pp. 100 / 207 67 / 139

[00149] An Fc-containing protein, as defined herein, is a protein comprising an Fc region as described herein and a binding region that binds to a target molecule. The term Fc-containing protein encompasses an antibody or an Fc fusion protein containing an Fc region.

[00150] The words treat or treatment refer to therapeutic treatment where the objective is to slow down (reduce) an undesirable physiological change or disorder. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction in disease extent, stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or palliation of disease state, and detectable or undetectable (partial or total) remission. Treatment may also mean prolonging survival compared to the expected survival if not receiving treatment. Treatment may not necessarily result in the complete elimination of a disease or disorder, but it may reduce or minimize the complications and side effects of infection and the progression of a disease or disorder.

[00151] The expression pharmacologically acceptable indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients. Petition 870250087401, dated 09 / 26 / 2025, pp. 101 / 207 68 / 139 that make up a formulation and / or with the mammal that is treated with it. Antibodies

[00152] The present invention relates to the use of radiolabeled olaratumab or antigen-binding fragments for the detection, imaging, and diagnosis of cancers, and also for the selection, classification, and stratification of cancers and cancer patients for treatment with a PDGFRa inhibitor (wherein, in certain embodiments, PDGFRa may be olaratumab or an antigen-binding fragment or derivative thereof). As used herein, olaratumab may also be referred to as IMC-3G3 and is an antibody that specifically binds to human PDGFRa.

[00153] As used in this document, the term specifically binds or binds specifically should be understood to mean that an agent for use according to the invention reacts or associates more frequently, more rapidly, for a longer duration and / or with greater affinity with a PDGFRalpha or cell expressing it than with alternative antigens or cells. For example, an antigen-binding protein that binds to PDGFRalpha with materially greater affinity (e.g., 1.5 times or 2 times or 5 times or 10 times or 20 times or 40 times or 60 times or 80 times to 100 times or 150 times or 200 times) than to other antigens. Petition 870250087401, dated 09 / 26 / 2025, pp. 102 / 207 69 / 139

[00154] Methods for assessing binding to a protein (e.g., PDGFRalpha) are known in the art, for example, as described in Scopes (In: Protein purification: principles and practice, Third Edition, Springer Verlag, 1994). This method generally involves immobilizing the agent (e.g., antibody) and contacting it with the labeled target (in the case of an antibody, the antigen). After washing to remove non-specific bound protein, the amount of label and, consequently, the bound antigen is detected. Obviously, the antigen binding site can be labeled and the antigen immobilized. Panning assays can also be used. Alternatively or additionally, surface plasmon resonance assays can be used. Constant Regions

[00155] Any antibody and / or antigen-binding fragment, as described herein for use in the present invention, may comprise a constant region of an antibody. This includes antigen-binding fragments of an antibody fused to an Fc.

[00156] The sequences of constant regions useful for the production of antibodies or the antigen-binding fragment, as described herein, can be obtained from several different sources. In some examples, the constant region or portion thereof of the protein is derived from a human antibody. Petition 870250087401, dated 09 / 26 / 2025, pp. 103 / 207 70 / 139 The constant region, or a portion thereof, can be derived from any class of antibodies, including IgM, IgG, IgD, IgA, and IgE, and any antibody isotype, including IgG1, IgG2, IgG3, and IgG4. In one example, the constant region is the human IgG4 isotype or a stabilized IgG4 constant region.

[00157] In various embodiments of the invention, the Fc region of the antibody may comprise one or more substitutions to alter the effector function (including increasing or decreasing effector functions) and circulating half-life. Several examples of such substitutions and modifications are described in Saunders (2019) Front. Immunol. Article 1296, which is incorporated herein by reference in its entirety.

[00158] In one example, the Fc region of the constant region has a reduced capacity to induce effector function, for example, compared to a native or wild-type human IgG1 or IgG3 Fc region. In one example, the effector function is antibody-dependent cell-mediated cytotoxicity (ADCC) and / or antibody-dependent cell-mediated phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC). Methods for assessing the level of effector function of a protein-containing Fc region are known in the art and / or described herein.

[00159] In one example, the Fc region is an IgG4 Fc region (i.e., a constant IgG4 region), for example, a human IgG4 Fc region. The sequences of IgG4 Fc regions Petition 870250087401, dated 09 / 26 / 2025, pp. 104 / 207 71 / 139 suitable ones will be apparent to the knowledgeable person and / or available in publicly available databases (e.g., available at the National Center for Biotechnology Information).

[00160] In one example, the constant region is a stabilized IgG4 constant region. The term stabilized IgG4 constant region will be understood as an IgG4 constant region that has been modified to reduce Fab arm exchange or the propensity to undergo Fab arm exchange or half-antibody formation or the propensity to form half-antibody. Fab arm exchange refers to a type of protein modification for human IgG4, in which an IgG4 heavy chain and an attached light chain (half molecule) are exchanged for a heavy-light chain pair from another IgG4 molecule. Thus, IgG4 molecules can acquire two distinct Fab arms recognizing two distinct antigens (resulting in bispecific molecules). Fab arm exchange occurs naturally in vivo and can be induced in vitro by purified blood cells or reducing agents such as reduced glutathione.A half antibody is formed when an IgG4 antibody dissociates to form two molecules, each containing a single heavy chain and a single light chain.

[00161] In one example, a stabilized IgG4 constant region comprises a proline at position 241 of the hinge region according to the Kabat system (Kabat et al., Petition 870250087401, dated 09 / 26 / 2025, pages 105 / 207 72 / 139 Sequences of Proteins of Immunological Interest, Washington DC, United States Department of Health and Human Services, 1987 and / or 1991). This position corresponds to position 228 of the hinge region according to the EU numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, Washington DC, United States Department of Health and Human Services, 2001 and Edelman et al., Proc. Natl. Acad. USA, 63, 78-85, 1969). In human IgG4, this residue is usually a serine. After the substitution of serine for proline, the IgG4 hinge region comprises a CPPC sequence. In this respect, the qualified person will be aware that the hinge region is a proline-rich portion of a constant region of antibody heavy chain linking the Fc and Fab regions that confers mobility to the two Fab arms of an antibody. The hinge region includes cysteine ​​residues that are involved in heavy-chain disulfide crosslinks.It is generally defined as extending from Glu226 to Pro243 of human IgG1 according to the Kabat numbering system. The hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine ​​residues forming heavy chain disulfide (SS) crosslinks in the same positions (see, for example, WO2010 / 080538).

[00162] Additional examples of stabilized IgG4 antibodies are antibodies in which arginine is in position Petition 870250087401, dated 09 / 26 / 2025, pp. 106 / 207 73 / 139 409 in a constant region of human IgG4 heavy chain (according to the EU numbering system) is replaced by lysine, threonine, methionine or leucine (e.g. as described in WO2006 / 033386). The Fc region of the constant region may additionally or alternatively include a residue selected from the group consisting of: alanine, valine, glycine, isoleucine and leucine at the position corresponding to 405 (according to the EU numbering system). Optionally, the hinge region comprises a proline at position 241 (i.e. a CPPC sequence) (as described above).

[00163] In another example, the Fc region is a modified region to have reduced effector function, i.e., a non-immunostimulatory Fc region. For example, the Fc region is an IgG1 Fc region comprising a substitution at one or more selected positions of the group comprising 268, 309, 330, and 331. In another example, the Fc region is an IgG1 Fc region comprising one or more of the following alterations: E233P, L234V, L235A, and deletion of G236 and / or one or more of the following alterations: A327G, A330S, and P331S (Armour et al., Eur J Immunol. 29:2613-2624, 1999; Shields et al., J Biol Chem. 276(9):6591-604, 2001). Additional examples of non-immunostimulatory Fc regions are described, for example, in Dall'Acqua et al., J Immunol. 177: 1129-1138 2006; and / or Hezareh J Virol; 75: 12161-12168, 2001). Petition 870250087401, dated 09 / 26 / 2025, pp. 107 / 207 74 / 139

[00164] Antibodies with reduced effector function include those with substitution of one or more residues in the Fc region 238, 265, 269, 270, 297, 327, and 329 (as described in U.S. Patent No. 6,737,056, incorporated herein by reference). Such Fc mutants include Fc mutants with substitutions at two or more amino acid positions 265, 269, 270, 297, and 327, including the so-called Fc DANA mutant with substitution of residues 265 and 297 for alanine (U.S. Patent No. 7,332,581). For example, an antibody variant may include an Fc region with one or more amino acid substitutions that decrease FcyR binding, for example, substitutions at positions 234 and 235 of the Fc region (EU residue numbering). For example, the substitutions are L234A and L235A (LALA) (see, for example, WO 2012 / 130831). The substitutions may additionally include the replacement of the proline residue at position 329, such as a P329G mutation to disable FcR binding.Furthermore, alterations can be made to the Fc region that result in altered (i.e., decreased) C1q binding and / or complement-dependent cytotoxicity (CDC), for example, as described in US Patent No. 6,194,551, WO 99 / 51642 and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

[00165] In some respects, the Fc region includes mutations in the complement binding sites (C1q) and / or the Fc gamma receptor (FcyR). In some respects, such mutations Petition 870250087401, dated 09 / 26 / 2025, pp. 108 / 207 75 / 139 can render the antibody incapable of antibody-directed cytotoxicity (ADCC) and complement-directed cytotoxicity (CDC). An example of a CDC-deficient antibody is one comprising a substitution in one or more of Glu318, Lys320, Pro329, Pro331, and Lys322 (e.g., K322A), wherein the numbering of residues in the Fc region conforms to the EU index, as described in Kabat et al.

[00166] In another example, the Fc region is a chimeric Fc region, for example, comprising at least one CH2 domain of an IgG4 antibody and at least one CH3 domain of an IgG1 antibody, wherein the Fc region comprises a substitution at one or more amino acid positions selected from the group consisting of 240, 262, 264, 266, 297, 299, 307, 309, 323, 399, 409 and 427 (EU numbering) (for example, as described in document no. WO2010 / 085682). Exemplary replacements include 240F, 262L, 264T, 266F, 297Q, 299A, 299K, 307P, 309K, 309M, 309P, 323F, 399S, and 427F. Additional Modifications

[00167] The present invention also contemplates further modifications to an antibody or antigen-binding protein comprising an Fc region or constant region.

[00168] The neonatal Fc receptor (FcRn) is important for the metabolic fate of IgG class antibodies in vivo. FcRn functions to save IgG from the degradation pathway. Petition 870250087401, dated 09 / 26 / 2025, pp. 109 / 207 76 / 139 lysosomal, resulting in reduced clearance and increased half-life. FcRn binds with high affinity to the CH2CH3 portion of the Fc region of an IgG class antibody. The interaction between an IgG class antibody and FcRn is pH-dependent and occurs in a 1:2 stoichiometry, i.e., one IgG antibody molecule can interact with two FcRn molecules through their two Fc heavy chain region polypeptides (see, for example, Huber, AH, et al, J. Mol. Biol. 230 (1993) 1077-1083).

[00169] In certain embodiments of the invention, an antibody may include one or more amino acid substitutions that increase the half-life of the protein. For example, the antibody comprises an Fc region comprising one or more amino acid substitutions that increase the affinity of the Fc region for the neonatal Fc region (FcRn). For example, the Fc region has increased affinity for FcRn at lower pH, for example, around pH 6.0, to facilitate Fc / FcRn binding in an endosome. In one example, the Fc region has increased affinity for FcRn at around pH 6 compared to its affinity at around pH 7.4, which facilitates the re-release of Fc into the blood after cellular recycling. These amino acid substitutions are useful for prolonging the half-life of a protein by reducing blood clearance.

[00170] Exemplary amino acid substitutions Petition 870250087401, dated 09 / 26 / 2025, pp. 110 / 207 77 / 139 include T250Q and / or M428L or T252A, T254S and T266F or M252Y, S254T and T256E or H433K and N434F according to the EU numbering system. Additional or alternative amino acid substitutions are described, for example, in documents no. US20070135620 or US7083784.

[00171] In other embodiments, the antibody comprises one or more amino acid substitutions that decrease the half-life of the protein. For example, the antibody comprises an Fc region comprising one or more amino acid substitutions that decrease or reduce the affinity of the Fc region for the neonatal Fc region (FcRn).

[00172] The present invention therefore provides an antibody with substitutions in the CH2 and / or CH3 domains of the constant region and comprising substitutions in one or more of the residues His310, His435, Tyr436 and Ile253 (EU Kabat index numbering), thereby altering the FcRn binding affinity and / or serum half-life of said antibody relative to a natural antibody.

[00173] In some examples, the amino acid at position 310 and / or 435 of the antibody may be alanine, glutamic acid, aspartic acid, leucine, isoleucine, arginine, proline, glutamine, methionine, serine, threonine, lysine, asparagine, phenylalanine, tyrosine, tryptophan, cysteine, valine, or glycine.

[00174] Preferably, the residue at position 310 is Petition 870250087401, dated 09 / 26 / 2025, page 111 / 207 78 / 139 selected from alanine, glutamic acid, or glutamine; or amino acid residue 435 of the heavy chain constant region is selected from arginine, glutamine, or alanine. In other preferred embodiments, the antibody has an alanine residue at position 310 and a glutamine residue at position 435.

[00175] In a preferred embodiment of the present invention, the binding affinity for FcRn and / or the serum half-life of the modified antibody is decreased by at least about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold. In a preferred embodiment of the present invention, the binding affinity for FcRn and / or the serum half-life of said modified antibody is reduced by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98% or 99%.

[00176] The antibody may also include amino acid substitutions at Ser228 and / or Leu235 equivalent residues of the constant heavy chain region, such as Ser228Pro and / or Leu235Glu. Protein Production

[00177] The production of an antigen-binding protein of the invention generally requires an expression vector containing a polynucleotide encoding the protein of Petition 870250087401, dated 09 / 26 / 2025, page 112 / 207 79 / 139 Antigen-binding protein of the invention. A polynucleotide encoding an antigen-binding protein of the invention can be obtained and subcloned into a vector for the production of an antigen-binding protein by recombinant DNA technology using well-known techniques, including the techniques described herein. Many different expression systems are contemplated, including the use of mammalian cells, including human cells, for the production and secretion of antigen-binding proteins. Examples of cells include 293F, CHO, and the NSO cell line.

[00178] Expression vectors containing protein-coding sequences and appropriate transcriptional and translational control signals can be constructed using methods known in the art. This includes in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. In certain embodiments, a replicable vector is provided with a nucleic acid encoding an antigen-binding protein operably linked to a promoter.

[00179] Cells transfected with an expression vector can be cultured by conventional techniques to produce an antigen-binding protein. Thus, in certain embodiments, host cells or cell transfectants containing a polynucleotide encoding an antigen-binding protein of the invention are provided. Petition 870250087401, dated 09 / 26 / 2025, pp. 113 / 207 80 / 139 operably linked to a promoter. The promoter can be heterologous. A variety of host expression vector systems can be used, and in certain systems, the transcription machinery of the vector system is particularly compatible with the host cell. For example, mammalian cells, such as Chinese hamster ovary (CHO) cells, can be transfected with a vector that includes the main early intermediate gene promoter element of human cytomegalovirus. Furthermore, or alternatively, a host cell can be used to modulate the expression of inserted sequences or to modify and process the gene product as needed, including various forms of post-translational modification. Examples of mammalian host cells with specific post-translational modification processes include CHO, VERY, BHK, HeIa, COS, MDCK, 293, 3T3, W138, BT483, Hs578T, HTB2, BT2O and T47D, NSO, CRL7O3O and HsS78Bst cells.

[00180] Depending on the intended use for the protein molecule, several bacterial expression vectors can be advantageously selected. For example, vectors that cause the expression of high levels of readily purified fusion protein products, such as the E. coli pUR278 expression vector, can be used where a large amount of an antigen-binding protein needs to be produced. The expression product can be produced in the form Petition 870250087401, dated 09 / 26 / 2025, pp. 114 / 207 81 / 139 of a fusion protein with lacZ. Other bacterial vectors include pIN and similar vectors. pGEX vectors can also be used to express foreign polypeptides as fusion proteins with glutathione-S-transferase (GST). These fusion proteins are generally soluble and can be easily purified from lysed cells by adsorption and binding to the glutathione-agarose affinity matrix, followed by elution in the presence of free glutathione. A thrombin and / or factor Xa protease cleavage site can be provided in the expressed polypeptide so that the cloned target gene product can be released from the GST portion.

[00181] The nuclear polyhedrosis virus Autographa californica (AcNPV) can be used as a vector to express foreign genes in an insect system, including Spodoptera frugiperda cells. The specific promoter used may depend on where the protein code is inserted into the sequence. For example, the sequence can be individually cloned into the polyhedrin gene and placed under the control of the polyhedrin promoter.

[00182] Virus-based expression systems can be used with mammalian cells, such as an adenovirus, where the coding sequence of interest can be ligated to the adenoviral late promoter and the tripartite leader sequence. In vitro or in vivo recombination can then be used to insert this chimeric gene into the adenoviral genome. As Petition 870250087401, dated 09 / 26 / 2025, pp. 115 / 207 82 / 139 insertions in the E1 or E3 region will result in a viable recombinant virus capable of expressing the antigen-binding protein on infected host cells. Specific initiation signals, including the ATG initiation codon and adjacent sequences, may be required for efficient translation of the inserted antigen-binding protein coding sequences. Initiation and translational control signals and codons can be obtained from a variety of sources, both natural and synthetic. Transcription enhancers and transcription terminators can be used to increase the expression efficiency of a virus-based system.

[00183] Where high-throughput and long-term recombinant protein production is required, stable expression is preferred. Generally, a selectable marker gene is used whereby, after transfection, cells are cultured for 1-2 days in an enriched medium and then transferred to a medium containing a selective marker in which cells containing the corresponding selectable marker, for example, antibiotic resistance, can be screened. The result is that cells that have stably integrated the plasmid into their chromosomes grow and form foci which, in turn, can be cloned and expanded into cell lines. The thymidine kinase, hypoxanthine-guanine phosphoribosyltransferase and genes Petition 870250087401, dated 09 / 26 / 2025, pp. 116 / 207 83 / 139 adenine phosphoribosyltransferase from herpes simplex virus are examples of genes that can be employed in tk, hgprt, or aprT cells, respectively, thus providing appropriate selection systems. The following genes: dhfr, which confers resistance to methotrexate; GPT, which confers resistance to mycophenolic acid; neo, which confers resistance to the aminoglycoside G-418; and higro, which confers resistance to hygromycin, are examples of genes that can be used in antimetabolite selection systems.

[00184] An antigen-binding protein of the invention can be purified by a recombinant expression system using known methods, including ion-exchange chromatography, affinity chromatography (especially affinity for the specific antigens Protein A or Protein G) and gel filtration column chromatography), centrifugation, differential solubility, or by any other standard technique for protein purification. Purification can be facilitated or assisted by providing the antigen-binding protein in the form of a fusion protein.

[00185] Large quantities of the antigen-binding proteins of the invention can be produced by a scalable process starting with a pilot expression system in a research laboratory that is scaled up to an analytical-scale bioreactor (typically 5 L to approximately Petition 870250087401, dated 09 / 26 / 2025, pp. 117 / 207 84 / 139 of 50 L bioreactors) or production-scale bioreactors (e.g., but not limited to 75 L, 100 L, 150 L, 300 L, or 500 L). Desirable scalable processes include those in which there are low to undetectable levels of aggregation, measured by HPSEC or rCGE, typically no more than 5% protein weight aggregation up to no more than 0.5% protein weight aggregation. In addition, or alternatively, undetectable levels of fragmentation measured in terms of the total peak area representing intact antigen-binding protein may be desired in a scalable process, such that at least 80% and up to 99.5% or more of the total peak area represents intact antigen-binding protein. In other embodiments, the scalable process of the invention produces antigen-binding proteins with production efficiencies of about 10 mg / l to about 300 mg / l or higher.

[00186] Several techniques have been developed for the production of antibody fragments, including proteolytic digestion of intact antibodies and recombinant expression in host cells. With regard to the latter, as described below, Fab, Fv, and scFv antibody fragments can be expressed and secreted from E. coli, antibody fragments can be isolated from antibody phage libraries, and Fab'-SH fragments can be recovered directly from E. coli and chemically coupled. Petition 870250087401, dated 09 / 26 / 2025, pp. 118 / 207 85 / 139 to form F(ab')2 fragments. In another approach, F(ab')2 fragments are isolated directly from recombinant host cell culture.

[00187] In another embodiment, a vector is provided including a nucleic acid described above. The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, the DNA is inserted into an appropriate restriction endonuclease site(s) using known techniques. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. The construction of suitable vectors containing one or more of these components employs standard ligation techniques known to those skilled in the art.

[00188] The antigen-binding site can be recombinantly produced not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which can be a signal sequence or another polypeptide with a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence can be a component of the vector or it can be a Petition 870250087401, dated 09 / 26 / 2025, pp. 119 / 207 86 / 139 part of the DNA encoding the antigen-binding site that is inserted into the vector. The signal sequence can be a selected prokaryotic signal sequence, for example, from the group of alkaline phosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders. For yeast secretion, the signal sequence can be, for example, the yeast invertase leader, the alpha factor leader, or the acid phosphatase or glucoamylase C. albicans leader. In mammalian cell expression, mammalian signal sequences can be used to target protein secretion, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.

[00189] The polynucleotide sequences encoding polypeptide components of the antigen-binding protein of the invention can be obtained using standard recombinant techniques, as described above. The polynucleotides can be synthesized using nucleotide synthesizer or PCR techniques. Once obtained, the sequences encoding the polypeptides are inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides in prokaryotic hosts. Many vectors available and known in the art can be used for the purpose of the present invention. The selection of an appropriate vector will depend primarily on the size of the Petition 870250087401, dated 09 / 26 / 2025, pp. 120 / 207 87 / 139 nucleic acids to be inserted into the vector and the specific host cell to be transformed with the vector. Each vector contains several components, depending on its function (amplification or expression of heterologous polynucleotide, or both) and its compatibility with the specific host cell in which it resides.

[00190] In general, plasmid vectors containing replicons and control sequences derived from species compatible with the host cell are used in connection with these hosts. Both expression and cloning vectors contain a nucleic acid sequence that allows the vector to replicate in one or more selected host cells, as well as tagging sequences that are capable of providing phenotypic selection in transformed cells. These sequences are well known for a variety of bacteria, yeasts, and viruses. The pBR322 plasmid replication origin, which contains genes encoding resistance to ampicillin (Amp) and tetracycline (Tet) and therefore provides easy means of identifying transformed cells, is suitable for most Gram-negative bacteria; the 2 pm plasmid origin is suitable for yeasts; and several viral origins (SV40, polyomavirus, adenovirus, VSV, or BPV) are useful for cloning vectors into mammalian cells.pBR322, its derivatives, or other microbial plasmids or bacteriophages may also be involved. Petition 870250087401, dated 09 / 26 / 2025, pp. 121 / 207 88 / 139 contain, or be modified to contain, promoters that can be used by the microbial organism for the expression of endogenous proteins.

[00191] Furthermore, phage vectors containing replicon and control sequences compatible with the host microorganism can be used as transforming vectors in connection with these hosts. For example, bacteriophages such as λGEM.TM.-11 can be used in the fabrication of a recombinant vector that can be used to transform susceptible host cells, such as E. coli LE392.

[00192] The expression vector of the invention may comprise two or more promoter-cistron pairs (a cistron is a segment of DNA that contains all the information for the production of a single polypeptide). A promoter is an untranslated regulatory sequence located upstream (5') of a cistron that modulates its expression. Prokaryotic promoters generally fall into two classes, inducible and constitutive. An inducible promoter is a promoter that initiates increased levels of cistron transcription under its control in response to changes in culture conditions, for example, the presence or absence of a nutrient or a change in temperature.

[00193] A large number of promoters recognized by a variety of potential host cells is well Petition 870250087401, dated 09 / 26 / 2025, pp. 122 / 207 89 / 139 known. The selected promoter can be operably ligated to cistron DNA encoding the light or heavy chain by removing the promoter from the source DNA via restriction enzyme digestion and inserting the isolated promoter sequence into the vector of the invention. Both the native promoter sequence and many heterologous promoters can be used to target the amplification and / or expression of the target genes. In some embodiments, heterologous promoters are used because they generally allow for higher transcription and higher yields of the expressed target gene compared to the native target polypeptide promoter.

[00194] Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the PhoA promoter, β-galactamase and lactose promoter systems, alkaline phosphatase, a tryptophan (trp) promoter system, and hybrid promoters such as the tac or trc promoter. Promoters for use in bacterial systems will also contain an operably DNA-linked Shine-Dalgarno (SD) sequence encoding an antigen-binding protein of the invention. However, other promoters that are functional in bacteria (such as other known bacterial or phage promoters) are also suitable. Their nucleotide sequences have been published, thus allowing a qualified person to use them. Petition 870250087401, dated 09 / 26 / 2025, pp. 123 / 207 90 / 139 connects operationally to cisternae that encodes the target light and heavy chains using binders or adapters to provide any necessary restriction locations.

[00195] In one aspect of the invention, each cistron within the recombinant vector comprises a secretory signal sequence component that directs the translocation of the expressed polypeptides across a membrane. In general, the signal sequence may be a component of the vector or may be a part of the target polypeptide DNA that is inserted into the vector. The signal sequence selected for the purpose of this invention shall be one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell. For prokaryotic host cells that do not recognize and process the native signal sequences of heterologous polypeptides, the signal sequence is replaced by a selected prokaryotic signal sequence, for example, from the group consisting of alkaline phosphatase, penicillinase, Ipp or heat-stable enterotoxin II (STII) leaders, LamB, PhoE, PeIB, OmpA and MBP.In one embodiment of the invention, the signal sequences used in both cisternae of the expression system are STII signal sequences or variants thereof.

[00196] In another aspect, the production of immunoglobulins according to the invention can occur in the cytoplasm of the host cell and therefore does not require the Petition 870250087401, dated 09 / 26 / 2025, pp. 124 / 207 91 / 139 presence of secretion signal sequences within each cistron. In this sense, the light and heavy chains of immunoglobulins are expressed, folded, and assembled to form functional immunoglobulins within the cytoplasm. Certain host strains (e.g., E. coli trxB strains) provide cytoplasmic conditions favorable to the formation of disulfide bonds, thus allowing the proper folding and assembly of expressed protein subunits.

[00197] The present invention provides an expression system in which the quantitative proportion of expressed polypeptide components can be modulated to maximize the yield of secreted and appropriately assembled antigen-binding proteins of the invention. This modulation is achieved, at least in part, by simultaneously modulating the translational forces for the polypeptide components.

[00198] In terms of expression in eukaryotic host cells, vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence.

[00199] A vector for use in a eukaryotic host cell may also contain a signal sequence or other polypeptide with a specific cleavage site in Petition 870250087401, dated 09 / 26 / 2025, pages 125 / 207 92 / 139 N-terminal of the mature protein or polypeptide of interest. The heterologous signal sequence preferably selected is the one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell. In mammalian cellular expression, mammalian signal sequences, as well as viral secretory leaders, for example, the herpes simplex gD signal, are available.

[00200] The DNA for this precursor region is linked in the reading frame to the DNA that codes for the antibody.

[00201] Generally, a replication component origin is not required for mammalian expression vectors. For example, the SV40 origin can usually be used simply because it contains the initial promoter.

[00202] Expression and cloning vectors typically contain a selection gene, also called a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, for example, ampicillin, neomycin, methotrexate, or tetracycline, (b) compensate for auxotrophic deficiencies, or (c) provide critical nutrients not available in complex media, for example, the gene encoding D-alanine racemase for bacilli.

[00203] An example of a selection scheme uses a drug to stop the growth of a host cell. Cells that are successfully transformed with Petition 870250087401, dated 09 / 26 / 2025, pages 126 / 207 93 / 139 a heterologous gene produces a protein that confers resistance to drugs and thus survives the selection regime. Examples of this dominant selection use the drugs neomycin, mycophenolic acid, and hygromycin.

[00204] An example of suitable selectable markers for mammalian cells are those that allow the identification of cells competent to take up the nucleic acid encoding the antigen-binding protein, such as DHFR or thymidine kinase, metallothionein-I and -II, preferably primate metallothionein genes, adenosine deaminase, ornithine decarboxylase, etc. An appropriate host cell when wild-type DHFR is employed is the DHFR-deficient CHO cell line (e.g., ATCC CRL-9096), prepared and propagated. For example, cells transformed with the DHFR selection gene are first identified by culturing all transformants in a culture medium containing methotrexate (Mtx), a competitive antagonist of DHFR.Alternatively, host cells (particularly wild-type hosts containing endogenous DHFR) transformed or co-transformed with DNA sequences encoding an antibody, the wild-type DHFR protein, and another selectable marker, such as aminoglycoside 3' phosphotransferase (APH), can be selected by cell growth in a medium containing a selection agent. Petition 870250087401, dated 09 / 26 / 2025, pages 127 / 207 94 / 139 for the selectable marker, such as an aminoglycoside antibiotic, for example, kanamycin, neomycin, or G418.

[00205] Expression and cloning vectors typically contain a promoter that is operably linked to an antigen-binding protein that encodes the nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known.

[00206] Eukaryotic genes generally have an AT-rich region located approximately 25 to 30 bases upstream of the transcription initiation site. Another sequence found 70 to 80 bases upstream of the transcription start of many genes is a CNCAAT region where N can be any nucleotide. At the 3' end of most eukaryotic genes is an AATAAA sequence that can be the signal for the addition of the poly-A tail to the 3' end of the coding sequence. All these sequences are appropriately inserted into eukaryotic expression vectors.

[00207] Examples of promoter sequences suitable for use with yeast hosts include promoters for 3-phosphoglycerate kinase or other glycolytic enzymes, including enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, Petition 870250087401, dated 09 / 26 / 2025, pp. 128 / 207 95 / 139 pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase and glucokinase.

[00208] Other yeast promoters, which are inducible promoters with the added advantage of transcription controlled by growth conditions, are the promoter regions of alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for the utilization of maltose and galactose.

[00209] The transcription of vector antigen-binding proteins into mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyomavirus, avian poxvirus, adenovirus (such as adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis B virus and simian virus 40 (SV40), from heterologous mammalian promoters, for example, the actin promoter or an immunoglobulin promoter, and from heat shock promoters, provided that such promoters are compatible with host cell systems.

[00210] The transcription of DNA encoding antigen-binding protein by higher eukaryotes can be increased by the insertion of a sequence Petition 870250087401, dated 09 / 26 / 2025, pp. 129 / 207 96 / 139 enhancer in the vector. Enhancer sequences include those known from mammalian genes (globin, elastase, albumin, α-fetoprotein, and insulin). Typically, however, an enhancer from a eukaryotic cell virus is used. Examples include the SV40 enhancer on the late side of the origin of replication (bp 100-270), the cytomegalovirus early promoter enhancer, the polyome enhancer on the late side of the origin of replication, and adenovirus enhancers.

[00211] Expression vectors used in eukaryotic host cells (yeasts, fungi, insects, plants, animals, humans, or nucleated cells of other multicellular organisms) will also contain sequences necessary for transcription termination and mRNA stabilization. Such sequences are commonly available in the 5' and, occasionally, 3' untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA that encodes an antigen-binding protein.

[00212] In another embodiment, a cell is provided including a vector or nucleic acid described above. The nucleic acid molecule or vector may be present in the host cell or in the genetically modified host either as an independent molecule outside of the Petition 870250087401, dated 09 / 26 / 2025, pp. 130 / 207 97 / 139 genome, preferably as a molecule capable of replicating, or it can be stably integrated into the genome of the host cell or host.

[00213] The host cell of the present invention can be any prokaryotic or eukaryotic cell.

[00214] Examples of prokaryotic cells are those commonly used for cloning, such as E. coli or Bacillus subtilis. In addition, eukaryotic cells include, for example, fungal or animal cells.

[00215] Examples of suitable fungal cells are yeast cells, preferably those of the genus Saccharomyces and those of the species Saccharomyces cerevisiae.

[00216] Examples of animal cells are, for example, insect cells, vertebrate cells, preferably mammalian cells, such as, for example, HEK293, NSO, CHO, MDCK, U2-OS, Hela, NIH3T3, MOLT-4, Jurkat, PC-12, PC-3, IMR, NT2N, Sk-n-sh, CaSki, C33A. These host cells, for example, CHO cells, can provide post-translational modifications to the antibody molecules of the invention, including removal of leader peptides, folding and assembly of H (heavy) and L (light) chains, glycosylation of the molecule on the correct sides, and secretion of the functional molecule.

[00217] Other suitable cell lines known in the art can be obtained from cell line repositories, such as the American Type Culture Collection. Petition 870250087401, dated 09 / 26 / 2025, pp. 131 / 207 98 / 139 (ATCC).

[00218] In another embodiment, an animal including a cell described above is provided. In certain embodiments, animals and tissues containing a transgene are useful in the production of the antigen-binding proteins of the invention. The introduction of nucleic acid molecules as transgenes into non-human hosts and their subsequent expression can be employed for the production of antigen-binding proteins, for example, the expression of such a transgene in the milk of the transgenic animal provides a means of obtaining antigen-binding proteins in quantitative amounts. Useful transgenes in this respect comprise the nucleic acid molecules of the invention, for example, coding sequences for the antigen-binding proteins described herein, operatively linked to promoter and / or enhancer structures of a specific mammary gland gene, such as casein or beta-lactoglobulin.The animal can be a non-human mammal, preferably mice, rats, sheep, calves, dogs, monkeys, or apes. Radiolabeled Antibodies

[00219] A person skilled in the art will be familiar with standard methods for conjugating a detectable moiety, such as a radionuclide (radiotracer), to an antibody or antigen-binding fragment.

[00220] As used herein, the term radionuclide Petition 870250087401, dated 09 / 26 / 2025, pp. 132 / 207 99 / 139 can be used interchangeably with the terms radioisotope and radiotracer.

[00221] In any embodiment of the invention, the radiotracer can be conjugated to olaratumab or its antigen-binding fragment, directly by binding to single or multiple amino acid residues in the protein (e.g., halogenation of tyrosine residues) or indirectly (through a chelating agent or prosthetic group or linker) linked to the radioisotope (i.e., the radiotracer).

[00222] Examples of suitable chelating agents or ligands may be selected from the group consisting of: TMT (6,6-bis[N,N,N'-tetra(carboxymethyl)aminomethyl)-4'(3-amino-4-methoxyphenyl)-2,2':6',2-terpyridine), DOTA (1,4,7,10-tetra-azacyclododecane-NN',N(N'-tetraacetic acid, also known as tetraxethane), TCMC (the primary tetraamide of DOTA), DO3A (1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid)-10-(2-thioethyl)acetamide), CB-DO2A (4,10-bis(carboxymethyl)1,4,7,10-tetra-azabicyclo[5.5.2]tetradecane), NOTE (acid 1,4,7-triazacyclononane-triacetic acid) Diamsar ( 3,6,10,13,16,19-hexa-azabicyclo[6.6.6]eicosane-1,8diamine), DTPA (pentetic acid or diethylenetriaminepentaacetic acid), CHX-A-DTPA ([(R)-2-Amino3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane Petition 870250087401, dated 09 / 26 / 2025, page. 100 / 139 1,2-diamine-pentaacetic acid), (1,4,8,11-tetraazacyclotetradecane-1,4,8), 11-tetraacetic acid, Te2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane), HBED, DFO (desferrioxamine), DFOsq (DFO-quaramide) and HOPO (3,4,3-(LI-1,2-HOPO) or other chelating agent as described in this document. Other known chelating moieties include 3p-C-NETA ({4-[2(bis-carboxymethylamino)-5-(4-nitrophenyl)pentyl]-7-carboxymethyl-[1,4,7]triazanonan-1-yl} acetic acid), 5p-C-NETA (2-({1-[4,7-bis(carboxymethyl)-1,4,7-triazanonan-1-yl]-7-(4-nitrophenyl)heptane-2-yl}(carboxymethyl)amino)acetic acid), NOTE (1,4,7-triazacyclononane-1,4,7-triacetic acid) and NODA (1,4,7-triazacyclononane-1,4-diacetic acid).

[00223] In certain embodiments, olaratumab can be covalently coupled to the radioactive isotope 124l. This isotope is a positron emitter that can be linked to antibodies, for example, as described by Larsson et al. (J. Nucl. Med. 33 (1992), 2020-2023) or US 5,185,142, the contents of which are incorporated herein by reference.

[00224] In any embodiment, the radioactive labeling of a protein or antibody is performed by covalent iodination, particularly with the lodogen reagent (1,3,4,6-tetrachloro-3α,6α-diphenylglycoluryl). Lodogen labeling is a solid-phase oxidative method similar to Petition 870250087401, dated 09 / 26 / 2025, pp. 134 / 207 101 / 139 Chloramine-T method, but is generally considered milder, since the reaction occurs on the surface of the oxidant, minimizing substrate exposure (Salacinzki, PRP, et al., Anal.Biochem. 117:136 (1981)).

[00225] Chelating agents with radiometals and other halogenated radioisotopes can be linked to antibodies through one or more amino acid residues or reactive moieties in the protein / antibody, including, but not limited to, one or more lysine residues, tyrosine residues, or thiol moieties.

[00226] In another example, the antibody may be conjugated to a bifunctional ligand, for example, bromoacetyl, thiols, succinimide ester, TFP ester, maleimide, or using any amine or thiol modifying chemical known in the art.

[00227] The qualified person will be familiar with standard methods for conjugating chelating agents to antibodies and derivatives or fragments thereof. In addition, the qualified person will be familiar with approaches for selecting a chelating agent relevant for pairing with a radiometal, for example, as described in Chem. Soc. Rev., 2014, 43, 260, incorporated herein by reference.

[00228] Examples of suitable radiotracers include: fluorine-18 (18F), gallium-67 and gallium-68 (67Ga and 68Ga), Petition 870250087401, dated 09 / 26 / 2025, pp. 135 / 207 102 / 139 indium-111 (111In), iodine-123 and iodine-124, technetium-99 (99mTc), terbium-155 and terbium-159 (155Tb and 159Tb) and zirconium-89 (89Zr). Administration of Radiolabeled Olaratumab

[00229] A qualified person will appreciate that the dosage of the agent for use according to the methods of the invention will depend on several factors, including the age, sex, height and weight of the individual to whom the agent is administered, and will be dependent on the agent.

[00230] Preferably, olaratumab is administered to an individual or infused at a dose of about 1 mg to about 50 mg, preferably at a dose of about 5 mg to about 20 mg, and most preferably at a dose of about 10 mg. The specific activity of the radiolabeled antibody is preferably about 15 to about 20 MBq / mg, more preferably about 18 to about 19 MBq / mg.

[00231] In certain modalities, radiolabeled olaratumab is administered in a massive dose of approximately 5 to 20 mg of olaratumab by slow infusion.

[00232] Radiolabeled olaratumab antibody is generally administered as a pharmaceutical composition with a pharmacologically acceptable carrier, for example, physiological saline solution, optionally comprising a protein stabilizer such as human serum albumin (HSA). Radiolabeled olaratumab is preferably Petition 870250087401, dated 09 / 26 / 2025, pp. 136 / 207 103 / 139 administered by infusion.

[00233] Radiolabeled olaratumab is preferably administered intravenously, preferably by infusion or intravenous injection. Antibody administration by infusion is preferably carried out over a period of up to about 30 minutes, more preferably in about 15 minutes. Obviously, radiolabeled olaratumab can also be administered intraperitoneally or intramuscularly. Detection Methods

[00234] It will be noted that the methods of detection or imaging of radiolabeled olaratumab for use in accordance with the invention will depend on the nature of the detectable fraction (radiolabel) of the antibody.

[00235] The detection step is preferably performed using PET, SPECT or any other suitable method. Optionally, the detection method comprises PET / SPECT, PET / CT imaging or PET / MRI scanning.

[00236] Examples of in vivo methods for determining the presence or expression of PDGFRa in a tumor include the use of in vivo / partial or whole-body imaging techniques, such as Positron Emission Tomography (PET) and single-photon emission computed tomography (SPECT). Immuno-PET and immuno-SPECT imaging generally include the use of PDGFRa-binding molecules, such as olaratumab, which are conjugated Petition 870250087401, dated 09 / 26 / 2025, pp. 137 / 207 104 / 139 is a radioisotope used to enable non-invasive imaging of tissues and tumors expressing PDGFRa.

[00237] The in vivo detection step in the methods described above may be whole-body imaging or local imaging at specific locations, such as, but not limited to, sites of anticipated or probable solid tumor growth.

[00238] In the case of SPECT, radiolabeled olaratumab typically comprises a detectable agent in the form of a gamma-emitting radioisotope (radionuclide), usually administered via injection into the bloodstream. Typically, gamma-emitting radioisotopes for use in SPECT include 99mTc (technetium), 123I or 131I (iodine), indium-111 (111In)67Ga (gallium), and terbium-155 (155Tb).

[00239] In any modality, the detection method may include Positron Emission Tomography (PET). In these cases, the radiolabeled olaratumab typically comprises a detectable agent in the form of a positron-emitting radioisotope (radionuclide), usually injected into the bloodstream. Examples of radioisotopes for use in PET include gallium-68 (68Ga), zirconium-89 (89Zr), and terbium-152 (152Tb).

[00240] After administration (preferably by infusion) of radiolabeled olaratumab, it may be practical to wait a period of time to allow the agent to accumulate at the site of the cancer cells that Petition 870250087401, dated 09 / 26 / 2025, pp. 138 / 207 105 / 139 express tumors. Typically, the time period will be at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days. Preferably, the time between administration of the agent and detection of the agent (e.g., by PET or other method described here), the period is normally not more than about 10 days, or not more than about 15 days, or not more than about 20 days.

[00241] In the case of imaging or cancer detection being done by PET, PET imaging can preferably be performed within 7 ± 2 days after infusion of the radioactively labeled agent, especially 5 ± 2 days after infusion, in order to obtain the best imaging results, including the accumulation of the agent in the locations where PDGFRa is present. Cancers to be detected, photographed, diagnosed, or classified.

[00242] The present invention provides methods for identifying, detecting, or imaging cancers in vivo and / or classifying such cancers for treatment. It is expected that such methods will be useful in diagnosing cancers expressing PDGFRalpha, especially soft tissue sarcomas, preferably without the need for advanced techniques. Petition 870250087401, dated 09 / 26 / 2025, pp. 139 / 207 106 / 139 additional and invasive procedures (such as biopsy collection and testing) are needed to confirm the diagnosis.

[00243] Thus, in a preferred embodiment, the methods of the invention allow the diagnosis of any cancer mentioned herein, as the sole, principal or main mode of cancer diagnosis and, preferably, without the need for additional invasive diagnostic methods, including methods related to biopsy.

[00244] The methods of the invention are also expected to be useful for staging the progression of a cancer or for the success of cancer treatment. Again, these methods provide the benefit of providing a non-invasive means of evaluating cancer in an individual.

[00245] In other modalities, the methods are to identify cancers that are likely to be responsive to treatment with olaratumab or to select patients for subsequent treatment with a PDGFRa inhibitor, such as olaratumab.

[00246] As used herein, the term cancer refers to a malignant growth or tumor resulting from uncontrolled cell division. The term cancer includes primary tumors and metastatic tumors.

[00247] An individual for whom the diagnosis, detection, or imaging of cancer described herein may be suspected of having or being at risk of having cancer. An individual Petition 870250087401, dated 09 / 26 / 2025, pp. 140 / 207 107 / 139 suspected of having cancer may present one or more symptoms of cancer, may have a family history of cancer, or may have one or more genetic markers indicating a risk or likelihood of developing cancer. An individual considered at risk of having cancer may present one or more symptoms of cancer, may have a family history of cancer, or may have one or more genetic markers indicating a risk or likelihood of developing cancer.

[00248] Cancer expressing PDGFRa for which diagnosis, detection, or imaging is necessary, classification, treatment selection, or for which treatment success must be determined, may be selected from the group consisting of: soft tissue sarcoma (STS), chondrosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, rhabdomyosarcoma, or any other cancer associated with PDGFRa expression. Soft tissue sarcomas originate in tissues such as fat, muscles, nerves, tendons, and blood and lymphatic vessels.

[00249] Alternatively, PDGFRa-expressing cancer for which diagnosis, detection or imaging, classification, treatment selection, or determination of treatment success is necessary, may be selected from the group consisting of: gastrointestinal stromal tumor (GIST), non-small cell lung cancer (NSCLC), cancer of Petition 870250087401, dated 09 / 26 / 2025, pp. 141 / 207 108 / 139 pancreas, hepatocellular carcinoma, breast cancer, neuroendocrine tumors, ovarian cancer, cervical cancer, uterine cancer (such as adenosquamous carcinoma of the cervix), colorectal cancer, gastric cancer, salivary gland cancer, biliary cancer, glioma, prostate cancer, and renal cell carcinoma.

[00250] Tumors can be hormone / androgen dependent or hormone / androgen independent and may have originated, for example, from the prostate, breast, or lung.

[00251] Primary bone tumors to be classified or detected according to the invention include, but are not limited to, osteosarcomas, chondrosarcomas, fibrosarcomas, and hemangiosarcomas. Notably, secondary malignant (metastatic) tumors are far more common than primary bone tumors. Metastatic bone tumors to be classified or detected according to the invention may arise from various sources, the most common being prostate, breast, or lung cancers. The origin of a metastatic bone cancer will usually be apparent from the patient's history. The tumors may be osteoblastic or osteolytic. PDGF-dependent bone tumors may also be classified or detected according to the invention, as well as bone marrow-dependent tumors.

[00252] Cancer imaging or diagnosis Petition 870250087401, dated 09 / 26 / 2025, p. 142 / 207 109 / 139 will typically be evaluated after administration of radiolabeled olaratumab and its detection, qualitatively assessing the detection of radiolabeled olaratumab compared to conventional imaging. Quantitative assessment can be performed by lesion, including standardized uptake values ​​(SUV) (SUVmax and SUVmean), lean mass-corrected SUV (SUL), metabolic tumor volume (MTV), and tumor-to-fund ratio (TBR).

[00253] The tumor-to-fund ratio (TBR) will normally be defined as the ratio of the standardized lesion uptake values ​​(SUVmax) to the SUV reference region (liver, blood pool, etc.). A comparison will be made between the number, size, and other characteristics of lesions detected by PET scan and standard imaging modalities, including high-resolution CT / MRI and other potential images per patient (depending on tumor type), lesion type, and indication.

[00254] Qualitative visual imaging analysis (presence or absence of localized uptake of the agent associated with the tumor, as observed on CT, MRI, or contrast-enhanced PET / CT) can be used to assess the concordance of tumor lesion detection between agent-specific PET / CT and conventional imaging. RECIST 1.1 criteria for conventional imaging can be used as the primary tool for concordance comparison versus PET. Petition 870250087401, dated 09 / 26 / 2025, pp. 143 / 207 110 / 139

[00255] In addition to the above, all tumor lesions visible on conventional imaging can also be compared to the result of PET imaging. Patient Selection / Classification and Response Monitoring

[00256] According to the invention, patients for whom cancer is detected according to the methods of the invention can be selected or classified for subsequent treatment with a PDGFRa inhibitor or antagonist. The present invention also provides methods for identifying cancers that are likely to be sensitive to treatment with a PDGFRa inhibitor. Thus, the invention also provides methods for identifying patients who would benefit from treatment for a cancer comprising a PDGFRa inhibitor, including associated treatment methods.

[00257] As used herein, a cancer that is sensitive to treatment with a PDGFRa inhibitor should be understood as a cancer that is inhibited (i.e., no longer proliferates) or is killed after administration of the PDGFRa inhibitor to the patient. It will be understood that sensitivity to treatment does not necessarily mean complete eradication of the cancer, but rather a cessation or slowing of tumor growth or proliferation, prevention of metastasis, or even tumor cell lysis / death. Petition 870250087401, dated 09 / 26 / 2025, pp. 144 / 207 111 / 139

[00258] A PDGFRa antagonist can be an extracellular antagonist or an intracellular antagonist, and more than one antagonist can be employed. Extracellular antagonists include, but are not limited to, proteins or other biological molecules that bind to PDGFRa or one or more of its ligands (e.g., PDGF-AA, -AB, -BB, -CC). In one embodiment of the invention, an extracellular antagonist inhibits the binding of PDGFRa to its ligands. In one embodiment, the antagonist is an anti-PDGFRa antibody, such as, for example, IMC-3G3 (also known as olaratumab). In another embodiment, the binding protein is a soluble ligand-binding fragment of PDGFRa. Intracellular IGF-IR antagonists can be biological molecules, but are generally small molecules. In one embodiment, the intracellular PDGFRa antagonist is AG1296. AG1296 (Calbiochem) is an inhibitor of PDGFs, PDGFPs and c-KIT, and also reacts with Flt3.Other small molecules that target PDGFRs include STI-571 (imatinib mesylate, Gleevec®, Novartis) and SU11248 (sunitinib malate, SUTENT®, Pfizer).

[00259] Preferably, the PDGFRa inhibitor neutralizes PDGFRa and in certain embodiments may be an anti-PDGFRa antibody. The binding of a ligand, for example, PDGF-AA, PDGF-AB, PDGF-BB or PDGF-CC, to an extracellular domain of PDGFRa stimulates receptor dimerization, Petition 870250087401, dated 09 / 26 / 2025, pp. 145 / 207 112 / 139 autophosphorylation, activation of the receptor's internal cytoplasmic tyrosine kinase domain, and initiation of multiple signal transduction and transactivation pathways involved in the regulation of DNA synthesis (gene activation) and cell cycle progression or division. Anti-PDGFRa antibodies typically block ligand binding and / or receptor dimerization and inhibit one or more autophosphorylation, tyrosine kinase activity activation, and signal transduction. The anti-PDGFRa antibodies of the present invention may be specific for the extracellular ligand-binding region of PDGFRa and prevent binding of a PDGFRa ligand. Preferably, these anti-PDGFRa antibodies, or fragments thereof, bind to PDGFRa at least as strongly as natural PDGFRa ligands. Alternatively or additionally, the antibodies may be specific for a region of the receptor monomer that would otherwise form a receptor dimer interface.These antibodies block dimer formation, although ligand binding to a receptor monomer may or may not be blocked.

[00260] In one embodiment of the invention, anti-PDGFRa antibodies reduce PDGFRa phosphorylation by at least about 75%. In other embodiments, phosphorylation is reduced by at least about 85% or at least about 90%. In one embodiment of the invention, as a result of the inhibition of PDGFRa signal transduction, phosphorylation or a Petition 870250087401, dated 09 / 26 / 2025, pp. 146 / 207 113 / 139 component of the downstream signal transduction pathway (e.g., Akt, p42 / p44, etc.) is reduced by at least about 40%, at least about 60%, or at least about 80%. Receptor neutralization can be determined using defined ligands (e.g., PDGF-AA, -AB, -BB, -CC), mixtures of such ligands, or preparations such as bone marrow aspirates comprising PDGFs as well as other stimulatory growth factors.

[00261] PDGFRa neutralization includes inhibition, reduction, inactivation, and / or interruption of one or more of these activities normally associated with signal transduction. Thus, PDGFRa neutralization has several effects, including inhibition, reduction, inactivation, and / or interruption of growth (proliferation and differentiation), angiogenesis (recruitment, invasion, and metastasis of blood vessels), and cell motility and metastasis (cell adhesion and invasiveness).

[00262] Ex vivo assays, as described above, can also be used to determine PDGFRa neutralization. For example, human leiomyosarcoma cells SKLMS-1 (American Type Culture Collection (ATCC), Rockville, Md.; ATCC HTB-88™) or glioblastoma cells U118 (ATCC HTB-15™) stimulated with PDGF-AA can be used to test PDGFRa inhibition. Growth inhibition can be verified using human tumor cells expressing Petition 870250087401, dated 09 / 26 / 2025, pp. 147 / 207 114 / 139 PDGFRa injected into a SCID mouse.

[00263] PDGFRa antagonists work by inhibiting signal transduction by PDGFRa expressed in the tumor cells themselves, or by inhibiting PDGFRa expressed in surrounding stromal cells that are otherwise subject to paracrine stimulation by PDGFs expressed from tumor cells. Thus, antibodies such as EMC-3G3 (olaratumab) and other PDGFRa antagonists are useful for treating tumors distinguished by autocrine and / or paracrine PDGFRa stimulation.

[00264] The methods of the present invention also find utility in monitoring an individual's response to cancer treatment. The present invention includes monitoring the effectiveness of a treatment for a cancer that expresses PDGFRa, wherein the treatment includes, but is not limited to, the administration of one or more of: surgery, chemotherapy, immunotherapy, autologous stem cell transfer (ASCT), external beam radiation, immunoradiation, a PDGFRa inhibitor, or combinations thereof.

[00265] Typically, methods for monitoring treatment response involve comparing a detectable amount of cancer after or during treatment with the detectable amount of cancer before treatment or at an earlier time during treatment. According to the methods of the present invention, this Petition 870250087401, dated 09 / 26 / 2025, pp. 148 / 207 115 / 139 typically involves comparing the amount of radiolabeled olaratumab detected in the patient or cancer at different time points.

[00266] In certain modalities, the detection, determination, or imaging methods described herein may result in data that are used to compile training data for the development of a deep learning algorithm to enable AI-based self-learning for cancer diagnosis and / or staging. This includes the use of such AI-based methods to compile data from each patient throughout their therapy in order to assess treatment progress.

[00267] In addition, the methods may involve the use of deep learning algorithms to stratify or classify a cancer, or an individual with cancer, as likely or unlikely to respond to treatment with a PDGFRalpha inhibitor. In certain examples, the training data (or reference dataset on which the deep learning algorithm is based) may include data from one or more individuals who have previously responded to treatment with a PDGFRalpha inhibitor; in other examples, the training data (or reference dataset on which the deep learning algorithm is based) may include data from one or more individuals who have not Petition 870250087401, dated 09 / 26 / 2025, pp. 149 / 207 116 / 139 responded to treatment with a PDGFRalpha inhibitor. Training data may include data from a combination of patients who had different responses to treatment with a PDGFRalpha inhibitor.

[00268] In certain modalities, the image or detection data obtained from the methods described herein can be evaluated against a disease classification model that was generated using machine learning techniques using training data (or reference dataset on which the deep learning algorithm is based), comprising data from one or more individuals who previously responded to treatment with a PDGFRalpha inhibitor; and / or from one or more individuals who did not respond to treatment with a PDGFRalpha inhibitor.

[00269] Thus, the AI-based approaches described here can serve as a platform upon which a variety of tools and techniques for detecting, assessing, and predicting cancer status for patients can be built. Furthermore, since AI-based tools, as described here, can identify a variety of important tissue regions throughout a patient's body and then transfer these identifications (e.g., segmentation maps) from anatomical images to various functional images, they can be used as a building block for AI-based analysis techniques. Petition 870250087401, dated 09 / 26 / 2025, pp. 150 / 207 117 / 139 a variety of different imaging methods that achieve contrast through a variety of different radiopharmaceuticals.

[00270] The use of AI-based technologies using machine learning techniques (such as Convolutional Neural Networks) and the like to stratify patients for treatment, monitor disease progression, or assess or diagnose cancer based on the imaging techniques described herein, are generally known in the art and are described, for example, in documents no. WO2020144134 and US 11,443,201, which are incorporated herein by reference.

[00271] As used herein, a level or quantity that is greater than the reference data set or quantity generally refers to a quantity that is at least more than about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least 100% or more.

[00272] As used herein, a level or quantity lower than the reference data set or quantity generally refers to a quantity that is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about Petition 870250087401, dated 09 / 26 / 2025, pp. 151 / 207 118 / 139 80%, at least about 90%, or at least 100% or more, lower than the value in the reference dataset.

[00273] The same level quantity or higher or lower quantity generally refers to a quantity that differs by no more than about 5%, preferably no more than 10%, from the reference dataset.

[00274] A person skilled in the art will be familiar with methods for determining statistically significant differences between the level or amount of detectable radiolabeled olaratumab for comparison purposes required for the present invention.

[00275] According to this descriptive report, determining the treatment response of a cancer expressing PDGFRalpha or of an individual with a cancer expressing PDGFRalpha (or when the individual is considered to have responded to treatment) includes stabilization of the disease or slowing or cessation of disease progression. Treatment response refers to therapeutic treatment where the objective is to slow (reduce) an undesirable physiological change or disturbance. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction in disease extent, stabilized (i.e., non-worsening) disease state, delay or slowing of disease progression, improvement or palliation of disease state, and remission (partial Petition 870250087401, dated 09 / 26 / 2025, pp. 152 / 207 119 / 139 or total), detectable or undetectable. Treatment can also mean prolonging survival compared to the expected survival if not receiving treatment. Treatment may not necessarily result in the complete elimination of a disease or disorder, but it can reduce or minimize the complications and side effects of the infection and the progression of a disease or disorder.

[00276] As used herein, a positive response of an individual to a treatment includes an increase in the individual's progression-free survival. Alternatively, a positive response of an individual to a treatment includes an increase in the individual's overall survival. Thus, the present invention also finds utility in predicting the overall survival or progression-free survival of an individual receiving / requiring treatment for a cancer that expresses PDGFRa.

[00277] As used herein, overall survival (OS) refers to the period of time from the date of diagnosis or the start of treatment for a cancer that patients diagnosed with the cancer are still alive. In a clinical trial, measuring overall survival is a way to see how a new treatment works.

[00278] Overall survival or OS is well known to a person versed in the technique and refers to the fate of the patient after an event, preferably after the start or end of a treatment regimen, despite the possibility that Petition 870250087401, dated 09 / 26 / 2025, pp. 153 / 207 120 / 139 The cause of death in a patient is not directly due to the effects of the disease (cancer). In other words, it refers to the prognosis that the patient will not die from cancer that expresses PDGFRa, preferably within at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, or at least 15 years.

[00279] As used herein, progression-free survival (PFS) refers to the period of time during and after treatment for a disease, such as cancer, that a patient lives with the disease but it does not worsen. In a clinical trial, measuring progression-free survival is a way to see how a new treatment works.

[00280] Responding to a treatment regimen refers to a clinically or biochemically detectable favorable response to a treatment. Typically, a favorable response is measured survival at a later time point after treatment, for example, 1, 2, 3, or 4 years after treatment. Kits

[00281] In another embodiment, a manufacturing kit or article is provided, including a radiolabeled olaratumab or antigen-binding fragment, as described above, preferably provided for use in a method or use described herein. Petition 870250087401, dated 09 / 26 / 2025, pp. 154 / 207 121 / 139

[00282] Optionally, the kit also includes a label or leaflet with instructions for use.

[00283] The kit or manufactured article may include a container and a label or package insert on or attached to the container. Suitable containers include, for example, vials, bottles, syringes, blisters, etc. Containers may be formed from a variety of materials, such as glass or plastic. The container contains a diagnostic composition that is effective for imaging or detection as described in this document and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial for injections with a stopper that can be pierced by a hypodermic injection needle). The label or package insert indicates that the composition is used to diagnose or detect the condition of choice. In one embodiment, the label or package insert includes instructions for use.

[00284] Alternatively, or additionally, the kit may also include a second container containing a pharmacologically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may also include other materials that are commercially and user-desirable, including other buffers, diluents, filters, needles, and syringes.

[00285] In certain modalities, the composition Petition 870250087401, dated 09 / 26 / 2025, pages 155 / 207 122 / 139 diagnostic composition may be supplied in the form of a device, disposable or reusable, including a receptacle to contain the diagnostic composition. In one embodiment, the device is a syringe. The device may contain 1-2 ml of the therapeutic composition. The diagnostic composition may be supplied in the device in a ready-to-use state or in a state requiring mixing or the addition of other components.

[00286] In other modalities, a kit is provided for use in a therapeutic application mentioned above, the kit including: - a container containing a diagnostic composition in the form of radioactively labeled olaratumab or an antigen-binding fragment thereof; - a label or leaflet with instructions for use.

[00287] The kit may include: (a) A diagnostic composition; and (b) a second container with a second diagnostic agent or second label contained therein. It may also include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, etc.

[00288] It will be understood that the invention disclosed and defined in this descriptive report extends to all alternative combinations of two or more of the individual features mentioned or evident in the text or drawings. Petition 870250087401, dated 09 / 26 / 2025, pages 156 / 207 123 / 139 All these different combinations constitute various alternative aspects of the invention.

[00289] The following examples are intended to illustrate, but in no way limit, the present invention. Examples Example 1: Synthesis and Characterization of Bioconjugates

[00290] An olaratumab immunoglobulin antibody comprising a VH as set forth in SEQ ID NO: 4 and a VL as set forth in SEQ ID 12 was used to generate olaratumab bioconjugates in the form of DOTA-Olaratumab and DFOsq-Olaratumab.

[00291] Bioconjugation of DOTA-Olaratumab and DFOsqOlaratumab was performed using standard methods. 30 mg of each conjugate were synthesized and analytical characterization of the conjugates was performed. Table 2: Conjugation reaction of olaratumab with ester DOTA-NHS Antibody Reagents: 0.2 mg DOTA-NHS Ester: MW 501.5 g / mol @ 35 mg / ml; 25-30 eq per mAb Buffer: Sodium borate 100 mM, pH 9 Reaction Conditions Time: 2 hours Temperature: 22 °C

[00292] The DOTA-NHS conjugate demonstrated high monomeric purity (>98%) and values ​​of 4.4 and 4.3 for DOTA-Olaratumab 1 and DOTA-Olaratumab 2 (generated using two Petition 870250087401, dated 09 / 26 / 2025, pages 157 / 207 124 / 139 different cell culture methods, respectively); antibody labeling degree (DOL) value (data not shown). Table 3: Conditions for the Conjugation Reaction of Olaratumab with DFO-sq Antibody Reagents: 0.2 mg DFO-sq: MW 684.8 g / mol @ 5 mg / ml; 16-18 eq per mAb Buffer: 100 mM sodium borate, pH 9 Organic cosolvent: 10% DMSO Reaction Conditions Time: 3 hours Temperature: 22 °C

[00293] Size exclusion chromatography (SEC) screening of the DFOsq-olaratumab conjugate with DFPsq indicated high monomeric purity (>98%) after conjugation (data not shown).

[00294] Olaratumab conjugated with DFOsq was evaluated for the characteristics listed below in Table 3. Table 4: Analytical characterization of bioconjugates DOTA and DFOsq produced in stable and transient transfection cell lines DOTA DFOsq Analysis Lot Number TEPH-2187-MI002-2 TEPH-2187-MI002-3 Purity SEC > 99.5% monomeric > 99.1% monomeric Endotoxins 0.12 EU / mg 0.03 EU / mg Identity and DOL LC-MS DAR 3.8 DAR 2-3 UV Concentration 2.5 mg / ml 3.44 mg / ml Petition 870250087401, dated 09 / 26 / 2025, pp. 158 / 207 125 / 139 Formulation and storage: 50 mM sodium acetate, 150 mM sodium chloride, pH 5.5, 80°C PBS, pH 7.1, 80°C Biacore antibody and conjugate screening for PDGFRa binding.

[00295] The comparative binding of the produced conjugates and Olaratumab to PDGFRa (Sino Biological, # 10556H08H, Lot # LC15MY0708) was tested using Biacore MCK, a surface plasmon resonance-based technology (Figure 2). The instrument used was the Biacore T200. Running buffer: HBS-P+ buffer containing 1 mg / ml BSA. Chip: Protein A capture sensor chip. Analysis temperature: 25 °C. Flow rate: 30 µl / min. Ligand: purified antibody ~ 80 RU at 10 µl / min. Analyte: human PDGFRa. Dilution range: 8-point dilution 3 times from 270 nM to 0.123 nM. Analyte injection time: 240 s. Analyte dissociation time: 1200 s. Regeneration: glycine pH 1.5. Analysis: 1:1 double-reference subtraction binding.

[00296] The results indicated that all antibodies tested bind with similar affinity to PDGFRa (Table 5). Table 5: Characterization of the binding of olaratumab nu, conjugated with DOTA and DFOsq to PDGFRa Ligand Ka (1 / ms) Kd (1 / s) Kd (M) Rmax Chi2 (RU2) Petition 870250087401, dated 09 / 26 / 2025, pp. 159 / 207 126 / 139 Olaratumab 3.39E+05 2.07E-03 6.11E-09 37.6 0.259 DOTA-Olaratumab 3.88E+05 2.09E-03 5.38E-09 32.3 0.305 DFOSq-Olaratumab 3.75E+05 2.10E-03 5.61E-09 35.8 0.328 Olaratumab 3.31E+05 1.93E-03 5.83E-09 43.8 0.362 DOTA-Olaratumab 7.82E+05 2.07E-03 5.41E-09 35.9 0.181 DFOsq-Olaratumab 3.62E+05 2.01E-03 5.56E-09 32.1 0.203

[00297] Example 2: Validation of PDGFRa expression in selected cell lines

[00298] The selection of cell lines for subsequent testing in xenograft tumor models was based on data published by Lowery et al, 2017, where the efficacy of olaratumab was demonstrated in HuO9 (osteosarcoma) and A-204 (embryonal rhabdomyosarcoma) cell lines.

[00299] Figure 3 shows that total and surface expression of PDGFRA was verified in the KRIB, HuO9, and A-204 sarcoma cell lines. All three cell lines expressed PDGFRA, which was most abundant in HuO9; however, HuO9 cells showed a lower proportion of the total amount of PDGFRA located in the plasma membrane.

[00300] PDGF-AA stimulation of all three cell lines triggered AKT phosphorylation at serine 473. This was abolished by prior incubation with olaratumab (Figure 4). Example 3: Development of the xenograft model in Petition 870250087401, dated 09 / 26 / 2025, pp. 160 / 207 127 / 139 live

[00301] The growth properties of the KRIB and A204 cell lines were tested in a xenograft model in Balb / c Nus mice. Both cell lines showed reproducible growth and good acceptance rates. The A204 cell clone was selected for subsequent biodistribution studies, given the greater radiosensitivity of this cell line to ionizing radiation.

[00302] Radioactive labeling of DFOSq-Olaratumab yielded 94% radiochemical purity, as assessed by quality control methods. Surface binding and internalization of radiolabeled antibodies to the chosen reference cell line were evaluated in the immunoreactive fraction (IRF) binding assay.

[00303] The activity ratio for the cells was based on the initial pilot which showed similar saturated binding with 1.25 and 2.5 kBq / 5 million cells at 1 hour, and no binding to negative control cells (specific activity at 1 MBq / 4 pg). Saturated binding (IRF) was established at approximately 40% in A204 cells at 1 h and ~3% binding in the negative control line (HCC827) (Figure 5, A). It was found that 30-50% of the total binding was internalized after 1 h (Figure 5, B). Example 4: Imaging and biodistribution studies Petition 870250087401, dated 09 / 26 / 2025, pp. 161 / 207 128 / 139

[00304] Naked Balb / c mice (N=4) were injected with 5.03 MBq at a mass dose of 20 μg of antibodies, and PET images were taken 1, 2, 4, and 6 days post-injection (Figure 6). For blocking, 344 μg (a nominal excess of 17 times) of unlabeled antibody conjugate were co-injected. Blocking mice were photographed 1 day post-injection and re-rescued at subsequent time(s) or harvested for biodistribution. Mice were euthanized and tissues harvested for biodistribution 1, 2, and 4 days post-injection (n = 4 per time point) (Figure 7).

[00305] Imaging and biodistribution analyses demonstrated that olaratumab targets tumors with a high tumor-to-background ratio during the test period. A high tumor uptake of ~55% ID / g was observed 120 hours after injection and demonstrated a tumor-to-background ratio of ~20. Example 5: Clinical trial of 89Zr-olaratumab (89ZrTLX300-CDx) in patients with soft tissue sarcoma. Objectives Primary objectives: - to evaluate the clinical safety and tolerability of 89Zr-TLX300-CDx - to evaluate the pharmacokinetic biodistribution and radiation dosimetry of 89Zr-TLX300-CDx Petition 870250087401, dated 09 / 26 / 2025, pp. 162 / 207 129 / 139 Secondary Objectives - to determine an appropriate antibody mass for administration Exploratory - to evaluate the correlation between tumor uptake of 89Zr- TLX300-CDx and the expression of PDGFRa - Compare tumor uptake and lesion detection between 89Zr-TLX300-CDx and standard treatment imaging. Outcomes Primary outcomes - adverse events (AEs), changes in clinical laboratory tests, ECG, physical examination and vital signs - Uptake of 89Zr-TLX300-CDx in the tumor and organs - blood radioactivity - blood levels of olaratumab Secondary outcomes - radioactivity uptake in tumor lesions and organs - whole-body absorption and effective radiation dose - blood levels of olaratumab Exploratory outcomes - PDGFRa expression in previous / archived tumor tissue and / or surgically resected tumor samples - Uptake of 89Zr-TLX300-CDx in tumor lesions - Uptake of 89Zr-TLX300-CDx in tumors and organs - localization of tumor deposits in images Petition 870250087401, dated 09 / 26 / 2025, pp. 163 / 207 Conventional 130 / 139 (CT, MRI and / or FDG-PET) Methodology: Study design

[00306] Open-label Phase 1 imaging study, the first in humans.

[00307] The target population is histologically confirmed STM. The study includes three parts: proof-of-concept tumor targeting of 89Zr-TLX300CDx (Part A), evaluation of the biodistribution of 89Zr-TLX300CDx and tumor uptake (Part B), and radiation dosimetry (Part C).

[00308] All participants undergo a formal screening visit (Visit 1), during which the study schedule is planned and participant consent is obtained. The screening period of up to 30 days (day -30 to day -1) includes study qualification assessments. Part A - Proof-of-concept tumor targeting of 89Zr-TLX300-CDx

[00309] Three (3) participants with PDGFRa-positive STS are recruited for Cohort 1 to receive a single administration of 37 MBq (±10%)89Zr-TLX300-CDx, containing a massive 25 mg dose of olaratumab.

[00310] The study team evaluates emerging Positron Emission Tomography (PET) / Computed Tomography (CT) data from Cohort 1 and determines whether enrollment Petition 870250087401, dated 09 / 26 / 2025, pp. 164 / 207 131 / 139 additional participants are needed to refine the level of mass dose administered. Additional participants may be recruited for Cohort 1 (for a total of 6 participants in Cohort 1) or for additional cohorts of 36 participants, where the cohorts may cover different antibody mass doses ranging from 1 to 100 mg of olaratumab, each with an activity of 37 MBq (±10%)89zirconium.

[00311] Screening window: up to 30 days before administration of 89Zr-TLX300-CDx Study period: - Intervention: 89Zr-TLX300-CDx administered on Day 1 as a slow intravenous (IV) bolus injection over 3 to 5 minutes. - Imaging period: Static whole-body PET / CT 5 days ± 1 day after injection, with an optional additional time point at 4 h ± 0.5 h after injection. - Blood radioactivity and total antibody quantification: pre-injection, 4 h ± 0.5 h, 5 days ± 1 day post-injection - Visit EOS within 30 days after Visit 2 (i.e., administration of 89Zr-TLX300-CDx).

[00312] Part A is completed as soon as an adequate antibody mass dose is identified by the study team after reviewing emerging PET / CT data. A maximum of 15 participants are enrolled in Part A. Petition 870250087401, dated 09 / 26 / 2025, pages 165 / 207 132 / 139

[00313] The safety data is reviewed by an independent SRC after completion of Part A. A participant is considered safety-evaluable if they have received 89ZrTLX300-CDx and completed the EOS visit.

[00314] Once Part A is completed and the antibody mass dose is selected, Parts B and C are opened in parallel for enrollment. Part B - Evaluation of the biodistribution of 89Zr-TLX300CDx and tumor uptake.

[00315] Up to 20 participants are enrolled in Part B (regardless of their PDGFRa expression status in previous / archive tissue) to assess biodistribution and potential variations in tumor uptake.

[00316] Once the first 10 participants are enrolled in Part B, tumor absorption rates are calculated.

[00317] Screening window: up to 30 days before administration of 89Zr-TLX300-CDx Study period: - Intervention: 89Zr-TLX300-CDx administered on Day 1 as a slow intravenous (IV) bolus injection over 3 to 5 minutes. - Imaging period: Static whole-body PET / CT 5 days ± 1 day after injection, with an optional additional time point at 4 h ± 0.5 h after injection. - Blood radioactivity and total quantification of Petition 870250087401, dated 09 / 26 / 2025, pp. 166 / 207 133 / 139 antibodies: pre-injection, 4 h ± 0.5 h and 5 days ± 1 day after injection. - Visit EOS within 30 days after Visit 2 (i.e., administration of 89Zr-TLX300-CDx). Part C - Radiation Dosimetry

[00318] Six (6) participants (3 men, 3 women) are initially enrolled in Part C at selected sites for radiation dosimetry. Part C participants are enrolled regardless of their PDGFRa expression status in previous / archival tissue. The study team evaluates emerging PET / CT data and determines if enrollment of additional participants is necessary (a maximum of 15 participants may be enrolled in Part C).

[00319] Screening window: up to 30 days before administration of 89Zr-TLX300-CDx Study period: - Intervention: 89Zr-TLX300-CDx administered on Day 1 as a slow IV bolus injection over 3 to 5 minutes. - Imaging period: Sequential static whole-body PET / CT imaging at 24 h ± 4 h, 3 days ± 1 day, and 6 days ± 1 day post-injection, with optional dynamic imaging 15 min ± 2 min post-injection at selected sites and optional static imaging at 4 h ± 0.5 h post-injection at any site. - Blood radioactivity and total quantification of Petition 870250087401, dated 09 / 26 / 2025, pages 167 / 207 134 / 139 antibodies: pre-injection, 4 h ± 0.5 h, 24 h ± 4 h, 3 days ± 1 day and 6 days ± 1 day after injection, with an optional additional time point at 7 h ± 1 h post-injection. - Visit EOS within 30 days after Visit 2 (i.e., administration of 89Zr-TLX300-CDx)

[00320] In addition, for participants in whom the target tumor is resected within 30 days of Visit 2 (i.e., administration of 89Zr-TLX300-CDx), resected tumor samples will be collected for exploratory analyses. The end-of-study visit (EOS) will take place: - after the last point in the imaging timeline (may be on the same day) - within 30 days of Visit 2 (i.e., administration of 89Zr-TLX300-CDx) - before surgical resection of the target tumor (if applicable, which may be on the same day as surgery). Inclusion criteria

[00321] Participants are eligible to be included in the study only if all of the following criteria apply: 1. ^18 years of age at the time of signing the informed consent. 2. Histologically confirmed diagnosis of soft tissue sarcoma (STS). 3. At least one mass with a largest diameter greater than 2 cm. Petition 870250087401, dated 09 / 26 / 2025, pp. 168 / 207 135 / 139 observed in the standard image (CT, MRI and / or FDG-PET). 4. For Part A: Participants must have confirmed tumor expression of PDGFRa by IHC. Participants must have consented to provide prior / archived FFPE tumor tissue.

[00322] For Parts B and C: all participants will be included regardless of their PDGFRa expression status in prior / archived tissue (unless otherwise specified). Participants must have consented to provide prior / archived FFPE tumor tissue. 5. Adequate hematologic function, defined by an absolute neutrophil count (ANC) > 1500 / μl, hemoglobin > 9.0 g / dl and a platelet count of 100,000 / μl. 6. Adequate liver function, defined by a total bilirubin < 1.5 mg / dl, and aspartate transaminase (AST) and alanine transaminase (ALT) ≥ 3.0 times the upper limit of normal (ULN). 7. Adequate renal function, defined by serum creatinine, is 1.5 times the institutional ULN. If creatinine is above the ULN, the participant's creatinine clearance is > 45 ml / min. 8. Performance status of the Eastern Cooperative Oncology Group (ECOG) from 0 to 2. Petition 870250087401, dated 09 / 26 / 2025, pp. 169 / 207 136 / 139 9. Life expectancy of at least 6 months. 10. Female participants with the potential to become pregnant must have negative pregnancy tests at screening, as well as confirmation of a negative pregnancy test result within 24 hours before receiving 89Zr-TLX300CDx. Female participants with the potential to become pregnant or male participants with partners with the potential to become pregnant must: to be willing to practice full and true sexual abstinence; or to be surgically / permanently sterile or have a history of hysterectomy for women; or to be willing to practice highly effective contraception using: a non-oral, injected or implanted progesterone-based hormonal method without estrogen, male condom, vaginal diaphragm, cervical cap, intrauterine device, for 3 months after administration of 89ZrTLX300-CDx. 11. Capable of giving signed informed consent that includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion criteria

[00323] Participants are excluded from the study if any of the following criteria apply: Petition 870250087401, dated 09 / 26 / 2025, pp. 170 / 207 137 / 139 1. Known or suspected hypersensitivity to olaratumab, DFOsq, 89Zr or any of the excipients. 2. IgE antibodies against galactose-α-1,3-galactose (αGal) above the upper limit of normal, >0.7 kU / L. 3. Exposure to any investigational diagnostic or therapeutic drug within 30 days of the planned administration date of 89Zr-TLX300-CDx. 4. Surgery ^ 2 weeks prior to administration of 89Zr-TLX300-CDx or significant ongoing complications from surgery. Biopsy is permitted ^ 2 weeks prior to administration of 89Zr-TLX300-CDx. 5. Exposure to any radiopharmaceutical within 10 half-lives prior to administration of 89Zr-TLX300-CDx. 6. Ongoing toxicity Grade 2 or higher from previous standard or trial therapies (Common Terminology Criteria for Adverse Events [CTCAE] version 5). 7. Planned to initiate systemic antineoplastic therapies, immunotherapy, targeted therapy, radiotherapy and / or surgery for the period between the administration of 89ZrTLX300-CDx and the last imaging time point. 8. Serious non-malignant disease (e.g., psychiatric, infectious, autoimmune, or metabolic) or any disease that may interfere with the objectives of the study or with the safety or adherence of the participant, as judged by the Investigator. 9. Pregnant or breastfeeding women. Petition 870250087401, dated 09 / 26 / 2025, pp. 171 / 207 138 / 139 10. Participants unable to provide meaningful informed consent on their own (e.g., with a legal guardian for mental disorders) or unable to tolerate the study procedures. Example 6: Imaging of ovarian cancer

[00324] Imaging studies using 89-Zr-olaratumab are performed to evaluate the ability of the imaging reagent to detect ovarian cancer.

[00325] First, experiments will test the ability of 89-Zr-olaratumab to bind to various ovarian cancer cell lines. These results will demonstrate the ability of olaratumab to bind to various types of ovarian cancer cells that express PDGFRa, although the degree of binding in vitro will be variable.

[00326] Subsequently, mice bearing xenografts of the A2780 cell line (approximately n=4) will be administered intravenously with 89-Zrolaratumab.

[00327] At 24 and 72 hours after intravenous injection of 89-Zr-olaratumab into xenograft-bearing mice, the mice are subjected to PET / CT to determine the ability of 89Zr-olaratumab antibodies to detect ovarian cancer cells in vivo.

[00328] The results will show that the antibodies 89Zr-olaratumab are able to bind to xenografts of Petition 870250087401, dated 09 / 26 / 2025, pp. 172 / 207 139 / 139 ovarian tumor. In other words, the results will demonstrate that the antibodies 89Zr-olaratumab are capable of binding to target ovarian tumor cells in an in vivo setting and with similar affinity to in vitro.

[00329] These results will indicate that the antibodies 89Zr-olaratumab are suitable for use in producing an image of ovarian cancer types in vivo and are therefore useful as a non-invasive diagnostic reagent for the diagnosis and detection of cancers other than soft tissue sarcomas. Petition 870250087401, dated 09 / 26 / 2025, pp. 173 / 207

Claims

1 / 26 CLAIMS 1. Olaratumab antibody bioconjugate or olaratumab antibody, characterized in that it is suitable for radiolabeling with a diagnostic radioisotope.

2. Olaratumab bioconjugate, according to claim 1, characterized in that the bioconjugate comprises an olaratumab antibody conjugated to a chelating or linking group selected from: TMT (6,6-bis[N,N,N'-tetra(carboxymethyl)aminomethyl)-4'-(3amino-4-methoxyphenyl)-2,2':6',2-terpyridine), DOTA (1,4,7,10-tetra-azacyclododecane-NN',N(N'-tetra-acetic acid), TCMC, DO3A, CB-DO2A, NOTA, Diamsar, DTPA, CHX-A-DTPA, olaratumab-TETE, Te2A, HBED, DFO, DFOsq, DFO-NCS and HOPO.

3. Olaratumab antibody or an antigen-binding fragment thereof, characterized in that it is conjugated to a radioisotope suitable for in vivo imaging, for: - detecting or imaging tumors expressing PDGFRalpha in an individual; - diagnosing a cancer expressing PDGFRalpha in an individual; - imaging a cancer expressing PDGFRalpha in an individual; - classifying a cancer as sensitive to treatment with a PDGFRalpha inhibitor; Petition 870250087401, dated 09 / 26 / 2025, page 174 / 207 2 / 26 - classifying or selecting a patient for eligibility for cancer therapy with a PDGFRalpha inhibitor; or - monitoring the treatment response of a cancer expressing PDGFRalpha or of an individual with a cancer expressing PDGFRalpha.

4. Olaratumab antibody or antigen-binding fragment, or antibody bioconjugate, according to any one of claims 1 to 3, characterized in that it comprises an antigen-binding domain that competitively inhibits the binding of an antibody comprising a VH comprising a sequence as set forth in SEQ ID NO: 4 and a VL comprising a sequence as set forth in SEQ ID NO:

12.

5. Olaratumab antibody or antigen-binding fragment thereof or bioconjugate, according to any one of claims 1 to 4, characterized in that the antibody or fragment thereof comprises an HCDR1, an HCDR2 and an HCDR3 of an antigen-binding domain with a variable heavy chain, as defined in SEQ ID NO: 4 and an LCDR1, LCDR2 and LCDR3 of an antigen-binding domain with a VL defined in SEQ ID NO:

12.

6. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 1 to 5, characterized in that Petition 870250087401, dated 09 / 26 / 2025, p. 175 / 207 3 / 26 antibody or antigen-binding fragment comprises an antigen-binding domain comprising: i) a VH that includes a complementarity-determining region (CDR) 1 comprising a sequence that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 1, a CDR2 comprising a sequence that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%,at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence defined in SEQ ID NO: 2, and a CDR3 comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, .... less than 99% identical to a sequence established in Petition 870250087401, dated 09 / 26 / 2025, p. 176 / 207 4 / 26 SEQ ID NO: 3; ii) a VH comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%,at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 4; iii) a VL that includes a CDR1 that includes a sequence of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 9, a CDR2 comprising a sequence of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, by less than 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 10 and a CDR3 comprising a sequence of at least approximately 80%, per Petition 870250087401, dated 09 / 26 / 2025, page 177 / 207 5 / 26 less 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 11; iv) a VL comprising a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%,at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 12; (v) a VH comprising a CDR1 comprising a sequence established in SEQ ID NO: 1, a CDR2 comprising a sequence established in SEQ ID NO: 2 and a CDR3 comprising a sequence established in SEQ ID NO: 3; (vi) a VH comprising a sequence established in SEQ ID NO: 4; (vii) a VL comprising a CDR1 comprising a sequence established in SEQ ID NO: 9, a CDR2 comprising a sequence established in SEQ ID NO: 10 and a CDR3 comprising a sequence established in SEQ ID NO: 11; (viii) a VL comprising a sequence established in SEQ ID NO: 12; (ix) A VH comprising a CDR1 comprising a sequence set at SEQ ID NO: 1, a CDR2 comprising a sequence set at SEQ ID NO: 2,and a CDR3 comprising a sequence set at SEQ ID NO: 3; and a VL comprising a CDR1 comprising a set of sequences SEQ ID NO: 9, a CDR2 comprising a sequence set at SEQ ID NO: 10, and a CDR3 comprising a sequence set at SEQ ID NO: 11; or (x) a VH comprising a sequence set at SEQ ID NO: 4, and a VL comprising a sequence set at SEQ ID NO: 12., 7. Olaratumab antibody or antigen-binding fragment thereof, according to claim 6, characterized in that it further includes: i) an HV that includes a framework region (FR) 1 comprising or consisting of a sequence that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% and at least 99% identical to a sequence as set forth in SEQ ID NO: 5;an FR2 that includes or is constituted by a sequence of at least 80%, by Petition 870250087401, of 09 / 26 / 2025, page 179 / 207 7 / 26 less 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% at least 99% identical to a sequence as set out in SEQ ID NO: 6; an FR3 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 7;an FR4 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 8;and ii) a VL that includes a framework region (FR) 1 comprising or consisting of a sequence of at least approximately 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% and at least 99% identical to a sequence as set out in SEQ ID NO: 13;an FR2 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 14; an FR3 that includes or is composed of a sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence as set out in SEQ ID NO: 15;an FR4 that includes or is composed of a sequence of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a sequence as set out in SEQ ID NO: 16.; 8. Olaratumab antibody or antigen-binding fragment thereof, according to claim 6, characterized in that it further includes: i) A VH comprising a framework region (FR) 1 comprising or consisting of a sequence as set forth in SEQ ID NO: 5; an FR2 comprising or consisting of a sequence as set forth in SEQ ID NO: 6; an FR3 comprising or consisting of a sequence as set forth in SEQ ID NO: 7; an FR4 comprising or consisting of a sequence as set forth in SEQ ID NO: 8, and ii) a VL comprising a framework region (FR) 1 comprising or consisting of a sequence as set forth in SEQ ID NO: 13; an FR2 comprising or consisting of a sequence as set forth in SEQ ID NO: 14; an FR3 comprising or consisting of a sequence as set forth in SEQ ID NO: 15; an FR4 comprising or consisting of a sequence as set forth in SEQ ID NO:

16.

9. Olaratumab antibody or antigen-binding fragment thereof, in accordance with any of the Petition 870250087401, dated 09 / 26 / 2025, p. 182 / 207 10 / 26 claims 1 to 8, characterized in that the antibody or antigen-binding fragment thereof comprises a VH comprising a sequence that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to a sequence established in SEQ ID NO: 4;and / or a VL comprising a sequence that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a sequence established in SEQ ID NO: 12; wherein the sequence variation between the VH and the VL and the sequence of SEQ ID NO: 4 and 12 is not in the CDRs and wherein the antibody or antigen-binding fragment retains the ability to bind to PDGFRalpha.

10. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 1 to 9, characterized in that the antibody or antigen-binding fragment thereof comprises a VH and / or a VL comprising no more than 1, no more than 2, no more than 3, no more than 4, no more than 5, no more than 6, 7, 8, 19, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid residue substitutions, deletions or additions, compared to the amino acid sequences set forth in SEQ ID NO: 4 or 12, respectively; in which substitutions, deletions, or additions of amino acids are not present in the CDRs, and the antibody or antigen-binding fragment retains the ability to bind to PDGFRalpha.

11. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 1 to 10, characterized in that the antibody or antigen-binding fragment is presented in the form of: (i) a single-domain antibody (sdAb); (ii) a single-chain Fv fragment (scFv); (iii) a dimeric scFv (di-scFv); or (iv) one of ii) or iii) linked to a constant region of an antibody, Fc, or a heavy chain (CH) 2 and / or CH3 constant domain.

12. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 1 to 10, characterized in that the antibody or antigen-binding fragment is presented in the form of: Petition 870250087401, dated 09 / 26 / 2025, page 184 / 207 12 / 26 i) a diabody; ii) a triabody; iii) a tetrabody; (iv) a Fab; (v) an F(ab')2; (vi) an Fv; vii) a bispecific antibody or other form of multispecific antibody; or viii) one of i) to vii) linked to a constant region of an antibody, Fc or to a constant domain of heavy chain (CH) 2 and / or CH3.

13. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 1 to 12, characterized in that the antibody or antigen-binding fragment is presented in the form of an immunoglobulin, such as IgG1, IgG2, IgG3 or IgG4.

14. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 1 to 13, characterized in that the olaratumab antibody comprises a heavy chain constant region, as defined in SEQ ID NO: 17, and / or a light chain constant region, as defined in SEQ ID NO:

18.

15. Olaratumab antibody or the antigen-binding fragment thereof, according to any one of claims 1 to 14, characterized in that the olaratumab antibody comprises a heavy chain as set forth in SEQ ID NO: 19 and / or a light chain as set forth in SEQ ID NO:

20.

16. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 13 to 15, characterized in that the antibody or antigen-binding fragment comprises one or more amino acid substitutions in the constant region, so as to reduce the in vivo half-life of the antibody.

17. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 13 to 16, characterized in that the antibody or antigen-binding fragment thereof includes substitutions at one or more of the His310, His435, Tyr436 and Ile253 residues of the constant region of the antibody (EU Kabat index numbering).

18. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 13 to 17, characterized in that the antibody or antigen-binding fragment thereof includes an amino acid substitution at position 310 selected from alanine, glutamic acid or glutamine (EU Kabat index numbering). Petition 870250087401, dated 26 / 09 / 2025, pp. 186 / 207 14 / 26 19. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 13 to 18, characterized in that the antibody or antigen-binding fragment thereof comprises an amino acid substitution at position 435 selected from arginine, glutamine or alanine (EU Kabat index numbering).

20. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 13 to 19, characterized in that the antibody or antigen-binding fragment comprises an alanine residue at position 310 and a glutamine residue at position 435 (EU Kabat index numbering).

21. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 13 to 19, characterized in that the antibody or antigen-binding protein comprises an amino acid substitution at the Ser228 and / or Leu235 position, preferably wherein the substitution is Leu235Glu and / or Ser228Pro.

22. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 16 to 21, characterized in that the binding affinity for FcRn and / or the serum half-life of the antibody or antigen-binding fragment is decreased by at least about 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold or 100-fold; or in which the binding affinity for FcRn and / or the serum half-life of said modified antibody is reduced by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98% or 99%, compared with an immunoglobulin that does not comprise the same substitutions.

23. Olaratumab antibody or antigen-binding fragment, according to any one of claims 3 to 12, characterized in that the antibody or antigen-binding fragment thereof includes a radioisotope suitable for in vivo imaging methods for detecting tumors or cancerous masses.

24. Olaratumab antibody or antigen-binding fragment thereof, according to claim 23, characterized in that the radioisotope is selected from: fluorine-18 (18F), gallium-67 and gallium-68 (67Ga and 68Ga), indium-111 (111In), iodine-123 and iodine-124, technetium-99 (99mTc), terbium-155 and terbium-159 (155Tb and 159Tb) and zirconium-8 (89Zr).

25. Olaratumab antibody or antigen-binding fragment thereof, according to any one of claims 23 to 24, characterized in that the radioisotope is directly conjugated to the antibody or antigen-binding fragment, for example, by halogenation of amino acid residues.

26. Olaratumab or antigen-binding fragment thereof, according to any one of claims 23 to 24, characterized in that the radioisotope is indirectly linked to the antibody or antigen-binding fragment, for example, through a chelating agent or other binding fraction.

27. Olaratumab, according to claim 26, characterized in that the antibody or antigen-binding fragment is conjugated to a chelating moiety, selected from the group consisting of: TMT (6,6bis[N,N,N'-tetra(carboxymethyl)aminomethyl)-4'-(3-amino-4-methoxyphenyl)-2,2':6',2-terpyridine), DOTA (1,4,7,10-tetra-azacyclododecane-NN',N(N'-tetraacetic acid), TCMC, DO3A, CB-DO2A, NOTA, Diamsar, DTPA, CHX-A-DTPA, TETE, Te2A, HBED, DFO, DFOsq, DFO-NCS and HOPO or other chelating agent known to those skilled in the art.

28. Olaratumab, according to claim 27, characterized in that the radioactively labeled olaratumab is 89Zr-olaratumab or an 89Zr labeled with olaratumab, wherein the 89Zr is conjugated to olaratumab by means of a ligand, such as 89Zr-DFO-olaratumab, 89Zr-DFO-NCSolaratumab or 89Zr-DFO-Sq-olaratumab.

29. Method for in vivo imaging or detection of a cancer expressing PDGFRalpha in an individual characterized by Petition 870250087401, dated 09 / 26 / 2025, pp. 189 / 207 17 / 26, the fact that the method comprises: - administering to an individual in need of such a radioactively labeled olaratumab antibody or an antigen-binding fragment, preferably an olaratumab antibody or an antigen-binding fragment as defined in any of claims 3 to 28, - detecting the antibody or antigen-binding fragment in the individual, - thereby performing imaging or cancer detection in the individual.

30. Method for diagnosing a cancer expressing PDGFRalpha in an individual, characterized in that the method comprises: - administering to an individual in need of such a radioactively labeled olaratumab antibody or an antigen-binding fragment, preferably an olaratumab antibody or an antigen-binding fragment as defined in any of claims 3 to 28, - determining the presence or absence of the antibody or its antigen-binding fragment in the individual, - thereby diagnosing the cancer in the individual.

31. Method, according to claim 29 or 30, characterized in that the detection of the antibody or fragment, or the presence or absence of the antibody or fragment, is compared to a background level or standard for Petition 870250087401, dated 09 / 26 / 2025, pp. 190 / 207 18 / 26 to determine the presence of cancer, therefore, imaging or detection or diagnosis of cancer in the individual.

32. Method, according to claim 29 or 30, characterized in that the detection or presence or absence is compared to a disease classification model or disease progression that is derived from data from one or more individuals, therefore, imaging or detection or diagnosis of cancer in the individual.

33. Method for producing an image of a cancer expressing PDGFRalpha in an individual, characterized in that the method comprises: - administering to an individual suspected of having the cancer, a radioactively labeled olaratumab antibody or an antigen-binding fragment thereof, preferably an olaratumab antibody or an antigen-binding fragment according to any of claims 3 to 28, - detecting the antibody or antigen-binding fragment in the individual, thereby producing an image of the cancer.

34. Method for producing an image of a cancer expressing PDGFRalpha characterized in that the method comprises: - infusing an effective amount of a radioactively labeled olaratumab antibody or an antigen-binding fragment thereof, preferably an olaratumab antibody or an antigen-binding fragment, as defined in any of claims 3 to 28, - detecting the antibody or its antigen-binding fragment, - thereby producing an image of the cancer.

35. A method according to claim 33 or 34, characterized in that the produced cancer image is used to generate training data for the development of a disease progression or classification model, optionally wherein the model is a machine learning model based on neural networks.

36. Method for classifying a cancer as sensitive to treatment with a PDGFRalpha inhibitor, characterized in that it comprises: - administering to an individual in need of such treatment a radioactively labeled olaratumab antibody or an antigen-binding fragment, preferably an olaratumab antibody or an antigen-binding fragment as defined in any of claims 3 to 28, - detecting the antibody or antigen-binding fragment in the individual, - wherein the cancer is classified as sensitive to treatment with a PDGFRalpha inhibitor when the detection of the antibody or fragment thereof is less than or equal to a background or threshold level; or Petition 870250087401, dated 26 / 09 / 2025, pp. 192 / 207 20 / 26 - wherein the cancer is classified as not sensitive to treatment with a PDGFRalpha inhibitor when the detection of the antibody or fragment thereof is above a background or threshold level.

37. Method for classifying a cancer as sensitive to treatment with a PDGFRalpha inhibitor, characterized in that it comprises: - administering to an individual in need of such a radioactively labeled olaratumab antibody or an antigen-binding fragment, preferably an olaratumab antibody or an antigen-binding fragment as defined in any of claims 3 to 28, - detecting the antibody or antigen-binding fragment in the individual, - wherein the cancer is classified as sensitive to treatment with a PDGFRalpha inhibitor based on the output of a deep learning algorithm indicating the presence of cancer cells expressing PDGFRalpha in the individual, - wherein the cancer is not classified as sensitive to treatment with a PDGFRalpha inhibitor based on the output of a deep learning algorithm indicating the absence of cancer cells expressing PDGFRalpha in the individual.

38. Method for classifying or selecting a patient Petition 870250087401, dated 09 / 26 / 2025, page.193 / 207 21 / 26 for eligibility for cancer therapy with a PDGFRalpha inhibitor characterized in that the method comprises: - administering to an individual in need of such a radioactively labeled olaratumab antibody or an antigen-binding fragment, preferably an olaratumab antibody or an antigen-binding fragment as defined in any of claims 3 to 28, - detecting the antibody or antigen-binding fragment in the individual, - wherein the patient is classified / selected for cancer therapy with a PDGFRalpha inhibitor when the detection of the antibody or fragment thereof is above a background or standard level; - wherein the patient is not classified / selected for cancer therapy with a PDGFRalpha inhibitor when the detection of the antibody or fragment thereof is equal to or below a background or standard level.

39. Method for classifying or selecting a patient for eligibility for cancer therapy with a PDGFRalpha inhibitor, characterized in that the method comprises: - administering to an individual in need of such a radioactively labeled olaratumab antibody or an antigen-binding fragment, preferably an antibody. Petition 870250087401, dated 09 / 26 / 2025, p.194 / 207 22 / 26 olaratumab or an antigen-binding fragment as defined in any of claims 3 to 28, - detect the antibody or antigen-binding fragment in the individual, - wherein the patient is classified / selected for cancer therapy with a PDGFRalpha inhibitor based on the output of a deep learning algorithm indicating the presence of cancer cells expressing PDGFRalpha in the individual, - wherein the patient is not classified / selected for cancer therapy with a PDGFRalpha inhibitor based on the output of a deep learning algorithm indicating the absence of cancer cells expressing PDGFRalpha in the individual.

40. Method for determining the response to treatment of a cancer expressing PDGFRalpha or of an individual with a cancer expressing PDGFRalpha, characterized in that the method comprises: - administering to an individual who has received or is receiving treatment for a cancer expressing PDGFRalpha, a radiolabeled olaratumab antibody or antigen-binding fragment, preferably an olaratumab antibody or antigen-binding fragment, as defined in any of claims 3 to 28, - detecting the antibody or antigen-binding fragment. Petition 870250087401, dated 09 / 26 / 2025, p.195 / 207 23 / 26 antigen in the individual, - compare the amount of antibody or antigen-binding fragment detected in the individual compared to a reference amount of antibody or antigen-binding fragment detected in the individual before treatment, - determine that the cancer has responded to treatment when the amount of antibody or antigen-binding fragment detected is less than the reference amount, - determine that the cancer has not responded to treatment when the amount of antibody or antigen-binding fragment is equal to or greater than the reference amount, - thus determine the treatment response of a cancer that expresses PDGFRalpha or of an individual with a cancer that expresses PDGFRalpha.

41. A method according to claim 40, characterized in that the treatment received or being received by the individual is selected from: surgery, chemotherapy, immunotherapy (such as CAR-T therapy), radiotherapy (including external beam radiation or immunoradiotherapy), a PDGFRalpha inhibitor and / or combinations thereof.

42. Method, according to any one of claims 33 to 39 or 41, characterized in that the PDGFRalpha inhibitor is an olaratumab antibody or functional antigen-binding fragment thereof.

43. Method according to claim 42, characterized in that the olaratumab antibody comprises a heavy variable chain as defined in SEQ ID NO: 4 and a light variable chain as defined in SEQ ID NO:

12.

44. Use of a radioactively labeled olaratumab antibody or an antigen-binding fragment thereof, preferably an olaratumab antibody or an antigen-binding fragment, as defined in any one of claims 3 to 28, characterized in that it is for the manufacture of a medicament for: - in vivo imaging or detection of a cancer expressing PDGFRalpha; - diagnosis of a cancer expressing PDGFRalpha; - producing an image of a cancer expressing PDGFRalpha; - classifying a cancer as sensitive to treatment with a PDGFRalpha inhibitor; or - classifying or selecting a patient for eligibility for cancer therapy with a PDGFRalpha inhibitor.

45. Method, according to any one of claims 29 to 43, characterized in that the method comprises allowing the radiolabeled olaratumab antibody or antigen-binding fragment thereof to concentrate at sites and / or tissues in said individual where the PDGFRalpha antigen is found in the individual, prior to the detection step.

46. ​​A method according to any one of claims 29 to 43, characterized in that the detection of the radiolabeled olaratumab antibody or antigen-binding fragment comprises Positron Emission Tomography (PET), SPECT imaging, or combinations thereof.

47. A method according to any one of claims 29 to 43, or use according to claim 44, characterized in that an individual who needs it is an individual suspected of having, or considered to be at risk of having, a cancer that expresses PDGFRalpha.

48. A method according to any one of claims 29 to 43, or a use according to claim 44, characterized in that the cancer detected, photographed, diagnosed, classified or selected is selected from the group consisting of: soft tissue sarcoma (STM), chondrosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma and rhabdomyosarcoma.

49. A method according to any one of claims 29 to 43, or a use according to claim 44, characterized in that the cancer detected, photographed, diagnosed, classified or selected is selected from the group consisting of: gastrointestinal stromal tumor (GIST), non-small cell lung cancer (NSCLC), pancreatic cancer, hepatocellular carcinoma, breast cancer, neuroendocrine tumors, ovarian cancer, cervical cancer, uterine cancer (such as adenosquamous carcinoma of the cervix), colorectal cancer, gastric cancer, salivary gland cancer, biliary cancer, glioma, prostate cancer and renal cell carcinoma. 199 / 207

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