Treatment methods for cancers that express PDGFRALFA

Description

1 / 111 Treatment methods for cancers that express PDGFRALFA Field of Invention

[001] The invention relates to proteins and compositions for the treatment of cancers that express the platelet-derived growth factor receptor alpha (PDGFRalpha) and methods of using them. Related Orders

[002] This application claims priority over provisional patent application No. US 63 / 494143 filed on April 4, 2023, and international application No. PCT / AU2023 / 050264 filed on April 4, 2023, the full content of which is incorporated herein by reference. Fundamentals of the Invention

[003] Soft tissue sarcoma (STS) originates in soft or connective tissues, such as fat, muscles, nerves, fibrous tissues, blood vessels, or deep skin tissues. STS is a heterogeneous disease for which there are relatively few effective regimens.

[004] Consequently, there is a need for new and improved methods and reagents for the treatment of STM and related cancers.

[005] Reference to any prior art in the descriptive report is not an acknowledgment or suggestion that such prior art is part of the common general knowledge in any jurisdiction or that such prior art is a legitimate practice in any jurisdiction. Petition 870250087443, dated 09 / 26 / 2025, page 32 / 171 2 / 111 could reasonably be expected to be understood, considered relevant, and / or combined with other prior techniques by a person versed in the technique. Summary of the Invention

[006] The present invention relates to reagents and methods for the treatment of cancers that express the platelet-derived growth factor receptor alpha (PDGFRalpha).

[007] In a first aspect, the present invention provides an olaratumab antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof is conjugated to a radioisotope, for: - to treat, prevent, or minimize the progression of a cancer distinguished from or associated with PDGFRalpha expression.

[008] It will be understood that an olaratumab antibody or an antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof is conjugated to a radioisotope, may also be referred to as a radiolabeled olaratumab antibody or an antigen-binding fragment thereof.

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

[0010] Preferably, the olaratumab bioconjugate Petition 870250087443, dated 09 / 26 / 2025, page 33 / 171 3 / 111 comprises an olaratumab antibody conjugated to any suitable chelating group or ligand 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 WO 2022 / 133537, or to any other chelating agent, as described in this document or known to a person skilled in the art.

[0011] In any aspect, 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.

[0012] In any aspect or embodiment contained herein, the olaratumab antibody or antigen-binding fragment Petition 870250087443, dated 09 / 26 / 2025, page 34 / 171 4 / 111 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.

[0013] 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.

[0014] 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 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 of at least about 80%, at least 81%, at least 82%, at least 83%, by less Petition 870250087443, dated 09 / 26 / 2025, page 35 / 171 5 / 111%, 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%, by less than 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 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; (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 Petition 870250087443, dated 09 / 26 / 2025, page 36 / 171 6 / 111%, 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%, 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%, 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 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%, Petition 870250087443, dated 09 / 26 / 2025, page 37 / 171 7 / 111 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 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 at 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 Petition 870250087443, dated 09 / 26 / 2025, page 38 / 171 8 / 111 established in SEQ ID NO: 12.

[0015] The olaratumab antibody or its antigen-binding fragment may also include: (i) a VH that includes a frame 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 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: 6;an FR3 that includes or is made up 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%; Petition 870250087443, dated 09 / 26 / 2025, page 39 / 171 9 / 111 at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a sequence as established 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 frame 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: 13; an FR2 that includes or is made up 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; Petition 870250087443, dated 09 / 26 / 2025, page 40 / 171 10 / 111%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to a sequence as established 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.

[0016] In another embodiment, the olaratumab antibody or antigen-binding fragment thereof comprises: i) A VH comprising a framework region (FR) 1 comprising or consisting of a sequence as set out in SEQ ID NO: 5; an FR2 comprising or consisting of a sequence as set out in SEQ ID NO: 6; an FR3 Petition 870250087443, dated 09 / 26 / 2025, page 41 / 171 11 / 111 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.

[0017] In any embodiment, the olaratumab antibody or its antigen-binding fragment comprises an HV 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: 4; and / or 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%, by Petition 870250087443, dated 09 / 26 / 2025, page 42 / 171 12 / 111 less 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 an established sequence 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.

[0018] In any embodiment, the olaratumab 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, 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 substitutions, deletions or additions of amino acid residues, compared to the amino acid sequences established in SEQ ID NO: 4 or 12, respectively; in which amino acid substitutions, deletions, or additions are not present in the CDRs, and the antigen-binding protein retains the ability to bind to PDGFRalpha.

[0019] As used herein, the terms HCDR1, HCDR2 and HCDR3 shall be understood as referring to the CDRs of the chain. Petition 870250087443, dated 09 / 26 / 2025, page 43 / 171 13 / 111 variable heavy chain; the terms LCDR1, LCDR2 and LCDR3 will be understood as referring to the CDRs of the variable light chain; and the terms HFR1, HFR2, HFR3, HFR4, LFR1, LFR2, LFR3 and LFR4 will be understood as referring to the structure regions of the heavy and light chains, respectively.

[0020] As described in this document, the olaratumab antibody or antigen-binding fragment thereof 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.

[0021] In addition, as described in this document, olaratumab or its antigen-binding fragment may be in the form of: (i) a diacorporeal body; (ii) a triacorpo; (iii) a tetrabody; (iv) a Fab; (v) an F(ab')2; (vi) a Fv; (vii) a bispecific antibody or other form of multispecific antibody; or Petition 870250087443, dated 09 / 26 / 2025, page 44 / 171 14 / 111 (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.

[0022] Optionally, the variable heavy and light regions of the antigen-binding domain are joined by means of a linker.

[0023] In any embodiment, the antigen-binding domain may include: FR1 - CDR1 - FR2 - CDR2 - FR3 — CDR3 - FR4 - ligand FR1a - CDR1a - FR2a - CDR2a - FR3a - CDR3a - FR4a.

[0024] 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.

[0025] In any aspect or embodiment of the present invention, olaratumab or its 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 a mixture 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 light chain constant region.

[0026] In one example, olaratumab or its antigen-binding fragment comprises a constant region of an IgG4 antibody or a stabilized constant region of an IgG4 antibody. In one example, olaratumab or the fragment Petition 870250087443, dated 09 / 26 / 2025, page 45 / 171 The antigen-binding 15 / 111 region comprises a constant IgG 4 region with a proline at position 241 (according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, Washington DC, U.S. Department of Health and Human Services, 1987 and / or 1991)).

[0027] In one example, olaratumab or its antigen-binding fragment comprises a heavy chain constant region, comprising a stabilized heavy chain constant region, comprising a mixture of sequences wholly or partially with or without the C-terminal lysine residue.

[0028] In other embodiments of any aspect hereof, olaratumab or its antigen-binding fragment comprises an Fc region wherein the Fc region is engineered 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.

[0029] In another embodiment, the olaratumab or antigen-binding fragment comprises an Fc region designed to: - to have increased the half-life in vitro or in vivo; - to have an increased capacity to induce Petition 870250087443, dated 09 / 26 / 2025, page 46 / 171 16 / 111 antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity; and / or - to have a reduced effector function.

[0030] 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).

[0031] 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.

[0032] In certain 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.

[0033] In other embodiments, olaratumab is in the form of an antibody and may include one or more amino acid substitutions in the constant regions in order to reduce the in vivo half-life of the antibody. The present invention, therefore, provides an olaratumab 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 (Kabat index numbering). Petition 870250087443, dated 09 / 26 / 2025, p. 47 / 171 17 / 111 EU), 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).

[0034] 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.

[0035] 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.

[0036] In another embodiment, the antibody also comprises an amino acid substitution at the Lys322 residue. Preferably, the substitution is K322A.

[0037] In particularly preferred embodiments, the olaratumab antibody comprises the K322A, H310A and H435Q substitutions.

[0038] In another preferred embodiment, the olaratumab antibody comprises amino acid substitutions at residues His310, His435 and Ile253, preferably the Petition 870250087443, dated 09 / 26 / 2025, p. 48 / 171 18 / 111 replacements are H310A, H435Q and I253E.

[0039] 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%.

[0040] 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.

[0041] According to the first aspect and according to any modality, radiolabeled olaratumab is conjugated with any suitable radioisotope for the treatment of tumorous or cancerous masses. Examples of suitable radioisotopes include: actinium-225 (225Ac), astatine-211 (211At), bismuth-212 and bismuth-213 (212Bi, 213Bi), copper-64 and copper-67 (64, 67), iodine-123, -124, -125 or -131 (123I, 124I, 125I, 131I), lead-212 (212Pb), lutetium-177 (177Lu), radium-223 and radium-224 (223Ra, 224Ra), rhenium-186 and rhenium-188 (186Re and 188Re), samarium-153 (153Sm), scandium-47 (47Sc), Petition 870250087443, dated 09 / 26 / 2025, p. 49 / 171 19 / 111 strontium-90 (90Sr), terbium-149 and terbium-161 (149Tb and 161Tb) and yttrium-90 (90Y). In the preferred embodiments, the radionuclide conjugated with the antibody or a fragment thereof is actinium-225 or lutetium-177.

[0042] In any embodiment, the radiolabeled olaratumab antibody or antigen-binding fragment thereof is 89Zr-,225Ac- or 177Lu-olaratumab wherein the radioisotope is conjugated to the olaratumab antibody directly or indirectly.

[0043] 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'-(3amino-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, CHXA-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 the person Petition 870250087443, dated 09 / 26 / 2025, page 50 / 171 20 / 111 versed in the technique.

[0044] In another example, radiolabeled olaratumab or antigen-binding fragment or olaratumab antibody bioconjugate is 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.

[0045] Preferably, the radioactively labeled olaratumab antibody or its antigen-binding fragment is 177Lu-olaratumab or an olaratumab labeled with 177Lu, wherein the 177Lu is conjugated to olaratumab via a ligand, such as 177Lu-DOTA-olaratumab.

[0046] 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.

[0047] 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 a pharmacologically acceptable excipient.

[0048] In addition, a nucleic acid or a nucleic acid construct that encodes an antibody is provided. Petition 870250087443, dated 09 / 26 / 2025, page 51 / 171 21 / 111 olaratumab, or an antigen-binding fragment thereof, or an olaratumab bioconjugate as described herein.

[0049] Also provided is a host or host cell comprising a nucleic acid construct or nucleic acid of the invention.

[0050] In a fourth aspect, the present invention provides a method of treating, preventing or minimizing the progression of cancer in an individual, the method comprising: - To administer to an individual in need of it, a radioactively labeled olaratumab antibody or an antigen-binding fragment thereof, as described herein, thereby treating, preventing or minimizing the progression of cancer in the individual.

[0051] In another aspect, the present invention provides a method for minimizing, reducing or preventing the growth of a tumor in an individual, the method comprising: - To administer to an individual in need of it, a radioactively labeled olaratumab antibody or an antigen-binding fragment thereof, as described herein, thereby minimizing, reducing or preventing tumor growth in the individual.

[0052] In another aspect, the present invention provides a method for minimizing, reducing or preventing metastasis of Petition 870250087443, dated 09 / 26 / 2025, page 52 / 171 22 / 111 cancer in an individual, the method comprising: - To administer to an individual in need of it, a radioactively labeled olaratumab antibody or an antigen-binding fragment thereof, as described herein, thereby minimizing, reducing or preventing cancer metastasis in the individual.

[0053] In another aspect, the present invention provides a method for increasing the survival of an individual suffering from cancer, the method comprising: - To administer to an individual in need of it, a radioactively labeled olaratumab antibody or an antigen-binding fragment thereof, as described herein, thereby increasing the individual's survival.

[0054] In another aspect, the present invention further provides the use of a radiolabeled olaratumab or antigen-binding fragment, as described herein, in the manufacture of a medicament for: - to treat, prevent, or minimize the progression of cancer in an individual, - to minimize, reduce, or prevent the growth of a tumor in an individual, - to minimize, reduce, or prevent metastases in an individual, or Petition 870250087443, dated 09 / 26 / 2025, page 53 / 171 23 / 111 - to increase the survival rate of an individual suffering from cancer.

[0055] In another aspect, the present invention further provides the use of radiolabeled olaratumab or antigen-binding fragment, as described herein, for: - to treat, prevent, or minimize the progression of cancer in an individual, - to minimize, reduce, or prevent the growth of a tumor in an individual, - to minimize, reduce, or prevent metastases in an individual, or - to increase an individual's survival rate.

[0056] In another aspect, the present invention further provides radiolabeled olaratumab or antigen-binding fragment, as described herein, for use in: - to treat, prevent, or minimize the progression of cancer in an individual, - to minimize, reduce, or prevent the growth of a tumor in an individual, - to minimize, reduce, or prevent metastases in an individual, or - to increase an individual's survival rate.

[0057] In any aspect or embodiment of the invention, it shall be understood that the amount of radiolabeled olaratumab or antigen-binding fragment administered to a Petition 870250087443, dated 09 / 26 / 2025, page 54 / 171 24 / 111 per individual is a therapeutically effective amount of radiolabeled olaratumab or its antigen-binding fragment.

[0058] In any aspect of the invention, any drug or pharmaceutical composition described herein may be suitable for intraperitoneal, intratumoral, topical, oral, intravenous, respiratory tract administration, preferably by inhalation or intranasal, subcutaneous or intramuscular. Typically, any drug or pharmaceutical composition described herein is suitable for intravenous administration.

[0059] In any method or use described herein, radiolabeled olaratumab or its antigen-binding fragment may be administered as the sole treatment for a cancer or may be administered in combination with one or more additional treatments. Radiolabeled olaratumab or its antigen-binding fragment may be administered following prior cancer treatment (optionally, where prior treatment includes surgery, chemotherapy, immunotherapy, external beam radiation, autologous stem cell therapy, or combinations thereof). Radiolabeled olaratumab or its antigen-binding fragment may be administered concurrently or sequentially with further cancer treatment (optionally, where treatment Petition 870250087443, dated 09 / 26 / 2025, page 55 / 171 25 / 111 additional coverage includes surgery, chemotherapy, immunotherapy, external beam radiation, autologous stem cell therapy, or combinations thereof.

[0060] It will be understood that, preferably, according to the aspects and modalities mentioned above, cancer is preferentially that which expresses or overexpresses PDGFR-alpha.

[0061] Cancer can be selected from the list comprising: soft tissue sarcoma (STM), chondrosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma and rhabdomyosarcoma. The methods of the invention may allow the treatment, prevention, and minimization of the progression of a cancer distinguished by the expression of PDGFRalpha in tumor cells and / or tumor stroma.

[0062] Alternatively, the cancer may be selected from the list 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. Preferably, the cancer is ovarian cancer.

[0063] In any form, cancer can be pre- Petition 870250087443, dated 09 / 26 / 2025, page 56 / 171 26 / 111 cancerous or non-metastatic. In either case, the cancer can be malignant or metastatic.

[0064] In any modality, the methods also include identifying an individual who needs treatment, as described in this document. The method may include identifying that the individual has a cancer expressing or overexpressing PDGFR-alpha.

[0065] As used in this document, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprise," "comprise," and "comprising," are not intended to exclude other additives, components, wholes, or steps.

[0066] 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

[0067] Figure 1: Schematic representation of Olaratumab bioconjugated with DFOsq and DOTA.

[0068] Figure 2: Biacore surface plasmon resonance assay setup.

[0069] 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 expression of PDGFRA in non- Petition 870250087443, dated 09 / 26 / 2025, page 57 / 171 The fixed amount of 27 / 111 was determined by FACS.

[0070] Figure 4: Western blot showing olaratumab-mediated inhibition of the PDGFRA activation pathway.

[0071] 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.

[0072] Figure 6: Example of PET images at 24, 4, 8 and 120 hours. SUVmax, tumor:fundus ratio, tumor:liver ratio and tumor:bone ratio were measured for each image.

[0073] 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.

[0074] Figure 8: Mean tumor volume after treatment with radiolabeled olaratumab. Mean tumor volumes ± SEM measured in the treatment group (177LuOlaratumab, 10 MBq) and in the control group (cold-DOTAOlaratumab) of A204 xenograft tumors from Balb / c Nude mice until the first mouse in each group reached the tumor endpoint.

[0075] Figure 9: Individual tumor volumes are shown from the first day of treatment / vehicle (day 1) to the end of the experiment on day 90. Petition 870250087443, dated 09 / 26 / 2025, page 58 / 171 28 / 111

[0076] Figure 10: Survival measured in the treatment group (177Lu-Olaratumab, 10 MBq) and control group of A204 xenograft tumors in Balb / c Nus mice. 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 QSTYYYGSGNYYH (protein) VDR1 (protein) 4 QLQLQESGPGLVKPSETLSLTCTVSGGSINSSYYWG WLRQSPGKGLEWIGSFFYTGSTYYNPSLRSRLTISVD TSKNQFSLMLSSVTAADTAVYYCARQSTYYYGNYYGW FDRWDQGTLVTVSS HFR1 (protein) (Kabat) 5 QLQLQESGPGLVKPSETLSLTCTVSGGSIN HFR2 (protein) (Kabat) 6 WGWLRQSPGKGLEWIG HFR3 (protein) (Kabat) 7 RLTISVDTSKNQFSLMLSSVTAADTAVYYCAR HFR4 (protein) (Kabat) 8STTVDQGGG (protein) (Kabat) 9 RASQSVSSYLA LCDR2 (protein) (Kabat) 10 DASNRAT LCDR3 (protein) (Kabat) 11 QQRSNWPPA VL (protein) LTISSLEPEDFAVYCQQRSNWPPAFGQGTKVEIK LFR1 (protein) (Kabat) 13 EIVLTQSPATLSLSPGERATLSC LFR2 (protein) (Kabat) 14 WYQQKPGQAPRLLIY Petition 870250087443, of 26 / 09 / 2025, p. 59 / 171 29 / 111 LFR3 (protein) (Kabat) 15 GIPARFSGSGSGTDFDFTISSLEPEDFAVYYC LFR1 (protein) (Kabat) 16 FGQGTKVEIK Constant region of the heavy chain 17 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSD IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Constant region of the light chain 18 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Heavy chain of olaratumab 19 QLQLQESGPGLVKPSETLSLTCTVSGGSINSSSYYWG WLRQSPGKGLEWIGSFFYTGSTYYNPSLRSRLTISVD TSKNQFSLMLSSSTAADTAVYYCARQSTYYYGSGNYY GWFDRWDQGTLVTVSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK Olaratumab light chain 20 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQ QKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLT ISSLEPEDFAVYYCQQRSNWPPAFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLSSPVTKSFNRGEC Detailed Description of the Modalities Platelet-derived growth factor receptor alpha (PDGFRalpha)

[0077] Platelet-derived growth factor receptor alpha (PDGFRa or PDGFRalfa) is a type III tyrosine kinase receptor. PDGFRa is essential for development and plays important roles in adulthood. For example, mice homozygous for a Petition 870250087443, dated 09 / 26 / 2025, page 60 / 171 30 / 111 null mutation cells die during embryogenesis. In later stages of development, PDGERα is expressed in many mesenchymal structures, while adjacent epithelial cells produce platelet-derived growth factors (PDGFs).

[0078] 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 PDGERp. 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 PDGFRe, as well as homodimers. Because PDGFRp does not bind to the PDGF-A chain with high affinity, PDGF-AA activates only αα receptor dimers, while PDGF-AB and PDGF-CC activate both αα and αβ receptor heterodimers.

[0079] 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 tumor microenvironment.

[0080] Olaratumab (Lartruvo™) is a fully human IgG1 monoclonal antibody that selectively binds Petition 870250087443, dated 09 / 26 / 2025, p. 61 / 171 31 / 111 to the human platelet-derived growth factor (PDGF) receptor α (PDGFRa). The interaction between olaratumab and PDGFR-α prevents receptor binding by PDGF-AA and -BB ligands, 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.

[0081] 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). However, the current inventors have surprisingly discovered that radiolabeled olaratumab, or antigen-binding fragments, may be useful for the treatment of a variety of cancers distinguished by PDGFRa expression. General Definitions

[0082] 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 one and a plurality (i.e., one or more) of these steps, matter compositions, groups of steps, or group of matter compositions. Thus, Petition 870250087443, dated 09 / 26 / 2025, page 62 / 171 32 / 111 as used here, the singular forms a, um, and o include plural aspects and vice versa, unless the context clearly dictates otherwise. For example, the reference aa includes a single one as well as two or more; the reference a um includes a single one as well as two or more; the reference ao includes a single one as well as two or more, and so on.

[0083] Those 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 specification, individually or collectively, and any and all combinations or any two or more of these steps or features.

[0084] A person skilled in the art will recognize many 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.

[0085] All patents and publications referenced herein are incorporated by reference in their entirety.

[0086] The present invention should not be limited in scope by the specific examples described herein, which are intended for purposes only. Petition 870250087443, dated 09 / 26 / 2025, p. 63 / 171 33 / 111 example. Functionally equivalent products, compositions and methods are clearly within the scope of the present invention.

[0087] 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.

[0088] 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).

[0089] The term and / or, for example, X and / or Y, 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

[0090] The term isolated protein or isolated polypeptide refers to a protein or polypeptide that, by virtue of its origin or source of derivation, is not associated with naturally occurring components that accompany it in its native state; it is substantially free of other proteins. Petition 870250087443, dated 09 / 26 / 2025, p. 64 / 171 34 / 111 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.

[0091] 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 isolated, it 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. Petition 870250087443, dated 09 / 26 / 2025, page 65 / 171 35 / 111

[0092] 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.

[0093] The term polypeptide or polypeptide chain will be understood from the previous paragraph as a series of contiguous amino acids linked by peptide bonds.

[0094] As used herein, the term antigen-binding protein is used interchangeably with 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 an scFv.

[0095] For the purposes of this disclosure, the term antibody includes a protein capable of binding Petition 870250087443, dated 09 / 26 / 2025, page 66 / 171 36 / 111 specifically 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 covalently linked heavy chains (~50 to 70 kDa) and 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... Petition 870250087443, dated 09 / 26 / 2025, page 67 / 171 37 / 111 Heavy and light chains are held together by disulfide bonds between chains and by non-covalent interactions. The number of disulfide bonds between chains can vary between different types of antibodies. Each chain has an N-terminal variable region (VH or VL, each approximately 110 amino acids long) and one or more C-terminal constant domains. The constant domain of the light chain (CL, approximately 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 domains CH1 and CH2.Antibodies can be of 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 antibody (mouse or rat) or a primate antibody (such as human). In one example, the antibody heavy chain is missing a C-terminal lysine residue. In another example, the antibody is humanized, sinumanized, chimeric, CDR-grafted, or deimmunized.

[0096] The terms full-length antibody, intact antibody, or whole antibody are used from Petition 870250087443, dated 09 / 26 / 2025, p. 68 / 171 38 / 111 interchangeable form 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 heavy and light chains, including an Fc region. Constant domains can be wild-type sequence constant domains (e.g., human wild-type sequence constant domains) or amino acid sequence variants.

[0097] 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 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.

[0098] 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.

[0099] Antibodies or immunoglobulins or Igs are gamma globulin proteins found in the blood or other Petition 870250087443, dated 09 / 26 / 2025, page 69 / 171 39 / 111 bodily fluids of vertebrates that function in the immune system to bind to the antigen, identifying and neutralizing foreign objects.

[00100] 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.

[00101] The H and L chains define specific Ig domains. More specifically, each H chain has, at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the α and γ chains and 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. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (CH1).

[00102] 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 further divided into subclasses based on Petition 870250087443, dated 09 / 26 / 2025, pp. 70 / 171 40 / 111 relatively small differences in the sequence and function of the L 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.

[00103] 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.

[00104] The pairing of a VH and VL together forms a variable region or variable domain, including the 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 71 / 171 41 / 111 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 structure.

[00105] 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 delineations of hypervariable regions are in use and are encompassed here.

[00106] As used herein, the term complementarity-determining regions (i.e., CDRs; i.e., CDR1, CDR2, and CDR3) refers to the amino acid residues of a variable region of antibody whose presence is the primary 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 herein 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 herein as CDR L1, CDR L2, and CDR L3, respectively, where CDR L1 Petition 870250087443, dated 09 / 26 / 2025, p. 72 / 171 42 / 111 corresponds to CDR 1 of VL, CDR L2 corresponds to CDR 2 of VL, and CDR L3 corresponds to CDR 3 of VL. 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 herein 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 numbering system 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. 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: 206-211 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... Petition 870250087443, dated 09 / 26 / 2025, page 73 / 171 43 / 111 five C-terminal amino acids of the CDR2 heavy chain are generally not involved in antigen binding.

[00107] 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.

[00108] A peptide for forming an antigen-binding protein generally refers to a peptide that can form a conformation that confers the 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.

[00109] An intact or whole antibody is one that comprises an antigen-binding protein as well as Petition 870250087443, dated 09 / 26 / 2025, page 74 / 171 44 / 111 a CL and at least constant heavy chain domains, CH1, CH2, and CH3. The constant domains can be native sequence constant domains (e.g., human native sequence constant domains) or their amino acid sequence variant.

[00110] Whole antibody-related structures include multimerized forms of whole antibodies.

[00111] 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.

[00112] The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (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.

[00113] 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. Petition 870250087443, dated 09 / 26 / 2025, page 75 / 171 45 / 111

[00114] 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.

[00115] 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.

[00116] 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 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.

[00117] 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 Petition 870250087443, dated 09 / 26 / 2025, page 76 / 171 46 / 111 scFv form the desired structure for antigen binding.

[00118] 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 entire binding site.

[00119] Diabodies refers to antibody fragments with two antigen-binding sites, which 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 (about 5-10 residues) between the VH and VL domains, so that interchain pairing, but not intrachain pairing of the V domains, is achieved, resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites.

[00120] 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.

[00121] An isolated antibody is one that has been identified and separated and / or recovered from a component of Petition 870250087443, dated 09 / 26 / 2025, page 77 / 171 47 / 111 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.

[00122] 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 various known techniques, including phage display libraries. Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been deactivated.

[00123] Humanized forms of non-human antibodies (e.g., rodents) are chimeric antibodies containing minimal sequences 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. Petition 870250087443, dated 09 / 26 / 2025, pp. 78 / 171 48 / 111 mouse, rabbit, or non-human primate antibodies with the desired antibody specificity, affinity, and capability. In some cases, residues in the framework (FR) region of the human immunoglobulin are replaced with corresponding non-human residues. Additionally, humanized antibodies may contain residues not found in the recipient 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 hivervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody may also optionally comprise at least a portion of an immunoglobulin constant (Fc) region, typically that of a human immunoglobulin.

[00124] “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. Petition 870250087443, dated 09 / 26 / 2025, pp. 79 / 171 49 / 111 In addition to their specificity, monoclonal antibodies are advantageous because they can be synthesized without contamination from other antibodies. Monoclonal antibodies can be prepared using the 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.

[00125] 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 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. The 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.

[00126] Binding affinity generally refers to the strength of the total sum of non-covalent interactions between a Petition 870250087443, dated 09 / 26 / 2025, page 80 / 171 50 / 111 single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Generally, binding affinity refers to the intrinsic binding affinity that 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 methods for measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention.

[00127] 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 Petition 870250087443, dated 09 / 26 / 2025, p. 81 / 171 51 / 111 Free and unlabeled A, in a reaction containing labeled A and the protein, will reduce the amount of labeled A bound to the antibody.

[00128] 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.

[00129] As used herein, the term does not bind detectably should be understood to mean that an antigen-binding protein, for example, an antibody, binds to a candidate antigen at a level less than 10%, or 8%, or 6%, or 5% above the background. The background may be the level of 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 level of binding is detected using biosensor analysis (e.g., Biacore) in which the antigen-binding protein is immobilized and contacted with an antigen.

[00130] As used in this document, the term does not Petition 870250087443, dated 09 / 26 / 2025, page 82 / 171 52 / 111 "significantly binding" should be understood as meaning 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.

[00131] An affinity-matured antibody is one with one or more alterations in one or more HVRs that result in an improved affinity of the antibody 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.

[00132] ADCC refers to a process called antibody-dependent cellular cytotoxicity, which is a primarily cell-mediated immune response. Petition 870250087443, dated 09 / 26 / 2025, page 83 / 171 53 / 111 killer (NK) antibodies 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.

[00133] 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.

[00134] ADCP refers to a process called antibody-dependent cell-mediated phagocytosis. In this process mediated by the Fe receptor, target cells to which antibodies are bound are engulfed by phagocytic cells such as macrophages, monocytes, neutrophils, and dendritic cells. Several Fc receptors are involved in this process.

[00135] 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.

[00136] An agonist antibody, as used herein, is an antibody that mimics at least one of the functional activities of a polypeptide of interest. Petition 870250087443, dated 09 / 26 / 2025, page 84 / 171 54 / 111

[00137] 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.

[00138] 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.

[00139] The words treat or treatment refer to therapeutic treatment where the objective is to slow down (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 the extent of Petition 870250087443, dated 09 / 26 / 2025, page 85 / 171 55 / 111 disease, stabilized (i.e., not worsening) disease state, delay or slowing of disease progression, improvement or palliation of disease state, and remission (partial 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 infection and the progression of a disease or disorder.

[00140] The expression pharmacologically acceptable indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients that make up a formulation and / or with the mammal that is treated with it. Antibodies

[00141] The present invention relates to the use of radiolabeled olaratumab or antigen-binding fragments that specifically bind to PDGFRa, for the treatment of cancers. As used herein, olaratumab may also be referred to as IMC-3G3 and is an antibody that specifically binds to human PDGFRa.

[00142] As used in this document, the term specifically links or specifically links should be understood to mean that an agent for use of Petition 870250087443, dated 09 / 26 / 2025, page 86 / 171 56 / 111 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.

[00143] 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

[00144] Any antibody and / or binding fragment Petition 870250087443, dated 09 / 26 / 2025, page 87 / 171 57 / 111 to the antigen, 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.

[00145] 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. The constant region or 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.

[00146] 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.

[00147] 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 Petition 870250087443, dated 09 / 26 / 2025, p. 88 / 171 58 / 111 antibody-dependent cell-mediated cytotoxicity (ADCC) and / or antibody-dependent cell-mediated phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC). The methods for assessing the level of effector function of a protein-containing Fc region are known in the art and / or described herein.

[00148] In one example, the Fc region is an IgG4 Fc region (i.e., from a constant IgG4 region), for example, a human IgG4 Fc region. The sequences of suitable IgG4 Fc regions will be apparent to the skilled in the art and / or available in publicly available databases (e.g., available from the National Center for Biotechnology Information).

[00149] 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 Petition 870250087443, dated 09 / 26 / 2025, page 89 / 171 59 / 111 bispecific molecules). Fab arm switching 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.

[00150] 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., 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 regard, a person skilled in the art 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, which confers mobility to the two Fab arms of an antibody. The hinge region includes cysteine ​​residues that are involved. Petition 870250087443, dated 09 / 26 / 2025, pp. 90 / 171 60 / 111 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).

[00151] Additional examples of stabilized IgG4 antibodies are antibodies in which arginine at position 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).

[00152] In another example, the Fc region is a modified region to have reduced effector function, that is, a non-immunostimulatory Fc region. For example, the Fc region is an IgG1 Fc region comprising a substitution in a Petition 870250087443, dated 09 / 26 / 2025, pp. 91 / 171 61 / 111 or more selected positions from the group composed of 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 G236 deletion 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. 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).

[00153] 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 replacements are L234A and L235A (LALA) (see, for example, WO 2012 / 130831). The replacements may additionally include the replacement of Petition 870250087443, dated 09 / 26 / 2025, p. 92 / 171 62 / 111 proline residue at position 329, such as a P329G mutation to disable FcR binding. Additionally, alterations can be made in 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).

[00154] 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 may 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.

[00155] 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). Petition 870250087443, dated 09 / 26 / 2025, page 93 / 171 63 / 111 Exemplary replacements include 240F, 262L, 264T, 266F, 297Q, 299A, 299K, 307P, 309K, 309M, 309P, 323F, 399S, and 427F. Additional Modifications

[00156] The present invention also contemplates further modifications to an antibody or antigen-binding protein comprising an Fc region or constant region.

[00157] The neonatal Fc receptor (FcRn) is important for the metabolic fate of IgG class antibodies in vivo. FcRn functions to salvage IgG from the lysosomal degradation pathway, 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).

[00158] 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). By Petition 870250087443, dated 09 / 26 / 2025, page 94 / 171 64 / 111 For example, the Fc region increased its 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 increased its 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.

[00159] Exemplary amino acid substitutions 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 US20070135620 or US7083784.

[00160] 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).

[00161] 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 (numbering of Petition 870250087443, dated 09 / 26 / 2025, page 95 / 171 65 / 111 Kabat index EU), thus altering the FcRn binding affinity and / or serum half-life of said antibody compared to a natural antibody.

[00162] 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.

[00163] 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.

[00164] 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%, Petition 870250087443, dated 09 / 26 / 2025, p. 96 / 171 66 / 111%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98% or 99%.

[00165] 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

[00166] The production of an antigen-binding protein of the invention generally requires an expression vector containing a polynucleotide encoding the 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.

[00167] 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, techniques Petition 870250087443, dated 09 / 26 / 2025, page 97 / 171 67 / 111 synthetic 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.

[00168] 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, operably linked to a promoter. The promoter may be heterologous. A variety of host expression vector systems can be used, and in certain systems, the transcriptional 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.In addition, 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, and BHK cells. Petition 870250087443, dated 09 / 26 / 2025, page 98 / 171 68 / 111 HeIa, COS, MDCK, 293, 3T3, W138, BT483, Hs578T, HTB2, BT2O and T47D, NSO, CRL7O3O and HsS78Bst.

[00169] 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 of a lacZ-binding fusion protein. Other bacterial vectors include pIN and similar vectors. pGEX vectors can also be used to express foreign polypeptides such as glutathione-S-transferase (GST) fusion proteins. 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.

[00170] 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 can Petition 870250087443, dated 09 / 26 / 2025, page 99 / 171 69 / 111 depends 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.

[00171] 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. Insertions in the E1 or E3 region will result in a viable recombinant virus that is 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.

[00172] Where high-throughput and long-term recombinant protein production is required, stable expression is preferred. Generally, a marker gene Petition 870250087443, dated 09 / 26 / 2025, pp. 100 / 171 Selective 70 / 111 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 adenine phosphoribosyltransferase genes of 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.

[00173] 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. Petition 870250087443, dated 09 / 26 / 2025, pp. 101 / 171 71 / 111 centrifugation, differential solubility, or any other standard technique for protein purification. Purification may be facilitated or aided by providing the antigen-binding protein in the form of a fusion protein.

[00174] 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 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 down to no more than 0.5% protein weight aggregation.Furthermore, 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 a production efficiency of approximately 10 mg / l. Petition 870250087443, dated 09 / 26 / 2025, pp. 102 / 171 72 / 111 300 mg / l or higher.

[00175] Several techniques have been developed for the production of antibody fragments, including proteolytic digestion of intact antibodies and recombinant expression in host cells. Regarding 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 to form F(ab')2 fragments. In another approach, F(ab')2 fragments are isolated directly from recombinant host cell culture.

[00176] 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 techniques known in the art. 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 103 / 171 73 / 111 suitable vectors containing one or more of these components employ standard bonding techniques that are known to a person skilled in the art.

[00177] 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 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 factor alpha leader, or the acid phosphatase or glucoamylase C. albicans leader.In mammalian cellular expression, mammalian signal sequences can be used to direct protein secretion, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.

[00178] The polynucleotide sequences that encode polypeptide components of the binding protein Petition 870250087443, dated 09 / 26 / 2025, pp. 104 / 171 74 / 111 to the antigen 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 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.

[00179] 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 105 / 171 75 / 111 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 various 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 contain, or be modified to contain, promoters that can be used by the microbial organism for the expression of endogenous proteins.

[00180] 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 AGEM™-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.

[00181] 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 a Petition 870250087443, dated 09 / 26 / 2025, pp. 106 / 171 76 / 111 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.

[00182] A large number of promoters recognized by a variety of potential host cells are well 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 target genes. In some embodiments, heterologous promoters are used as they generally allow for higher transcription and higher yields of the expressed target gene compared to the native target polypeptide promoter.

[00183] Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the PhoA promoter, the β promoter systems Petition 870250087443, dated 09 / 26 / 2025, pp. 107 / 171 77 / 111 galactamase and lactose, 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 a Shine-Dalgarno (SD) sequence operably linked to DNA 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 enabling a qualified person to operationally link them to cistrons encoding the target light and heavy chains using linkers or adapters to provide any necessary restriction sites.

[00184] 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 can be a component of the vector or it can be a part of the target polypeptide DNA that is inserted into the vector. The signal sequence selected for the purpose of this invention should 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 108 / 171 78 / 111 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 cistrons of the expression system are STII signal sequences or variants thereof.

[00185] 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 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.

[00186] 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 109 / 171 79 / 111 translational forces for the polypeptide components.

[00187] 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.

[00188] A vector for use in a eukaryotic host cell may also contain a signal sequence or other polypeptide with a specific cleavage site at the N-terminus of the mature protein or polypeptide of interest. The heterologous signal sequence preferably selected is 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.

[00189] The DNA for this precursor region is linked in the reading frame to the DNA that codes for the antibody.

[00190] 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.

[00191] Expression and cloning vectors typically contain a selection gene, also called Petition 870250087443, dated 09 / 26 / 2025, pp. 110 / 171 80 / 111 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.

[00192] An example of a selection scheme uses a drug to stop the growth of a host cell. Cells that are successfully transformed with a heterologous gene produce a protein that confers resistance to the drugs and thus survive the selection regime. Examples of this dominant selection use the drugs neomycin, mycophenolic acid, and hygromycin.

[00193] An example of suitable selectable markers for mammalian cells are those that allow the identification of cells competent to absorb 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 selection gene Petition 870250087443, dated 09 / 26 / 2025, pp. 111 / 171 81 / 111 DHFRs 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 for the selectable marker, such as an aminoglycoside antibiotic, for example, kanamycin, neomycin, or G418.

[00194] 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.

[00195] 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 112 / 171 82 / 111 eukaryotic genes contain an AATAAA sequence that can be the signal for adding the poly-A tail to the 3' end of the coding sequence. All of these sequences are appropriately inserted into eukaryotic expression vectors.

[00196] 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, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.

[00197] 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.

[00198] 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), and the virus of Petition 870250087443, dated 09 / 26 / 2025, pp. 113 / 171 83 / 111 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.

[00199] The transcription of DNA encoding antigen-binding protein by higher eukaryotes can be enhanced by inserting an enhancer sequence into 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.

[00200] 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 114 / 171 84 / 111 untranslated 5' and occasionally 3' regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of mRNA that encodes an antigen-binding protein.

[00201] In another embodiment, a cell is provided including a nucleic acid vector or vector described above. The nucleic acid molecule or vector may be present in the genetically modified host cell or host either as an independent molecule outside the genome, preferably as a molecule capable of replicating, or as a stable molecule in the host cell or host genome.

[00202] The host cell of the present invention can be any prokaryotic or eukaryotic cell.

[00203] 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.

[00204] Examples of suitable fungal cells are yeast cells, preferably those of the genus Saccharomyces and those of the species Saccharomyces cerevisiae.

[00205] Examples of animal cells are, for example, insect cells, vertebrate cells, preferably mammalian cells, such as, for example, HEK293, NSO, CHO, Petition 870250087443, dated 09 / 26 / 2025, pp. 115 / 171 85 / 111 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.

[00206] Other suitable cell lines known in the art can be obtained from cell line repositories, such as the American Type Culture Collection (ATCC).

[00207] 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 structures and / or Petition 870250087443, dated 09 / 26 / 2025, pp. 116 / 171 86 / 111 enhancers of a specific mammary gland gene, such as casein or beta-lactoglobulin. The animal can be non-human mammals, preferably mice, rats, sheep, calves, dogs, monkeys or apes. Radiolabeled Antibodies

[00208] The qualified person will be familiar with standard methods for conjugating a detectable moiety, such as a radionuclide (radiotracer), to an antibody or antigen-binding fragment.

[00209] As used herein, the term radionuclide may be used interchangeably with the terms radioisotope and radiotracer.

[00210] 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).

[00211] 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'-tetraazacyclododecane-N',N' ...)-aminomethyl-4'-methoxyphenyl-2,2':6',2-terpyridine), Petition 870250087443, dated 09 / 26 / 2025, pp. 117 / 171 acetic acid 87 / 111, 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), NOTA (1,4,7-triazacyclononane-triacetic acid) Diamsar ( 3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine), DTPA (pentetic acid or diethylenetriaminepentaacetic acid), CHX-A-DTPA ([(R)-2-Amino3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-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 per 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)heptano-2-yl}(carboxymethyl)amino)acetic acid), NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) and NODA (1,4,7-triazacyclononane-1,4-diacetic acid).

[00212] Other suitable chelating agents (by Petition 870250087443, dated 09 / 26 / 2025, pp. 118 / 171 88 / 111 example, including DOTA and DFO) are disclosed in WO 2022 / 133537, incorporated herein by reference.

[00213] 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.

[00214] 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 the 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)).

[00215] 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.

[00216] In another example, the antibody can be conjugated to a bifunctional ligand, for example, Petition 870250087443, dated 09 / 26 / 2025, pp. 119 / 171 89 / 111 bromoacetyl, thiols, succinimide ester, TFP ester, maleimide, or using any amine or thiol modifying chemical known in the art.

[00217] 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.

[00218] In any aspect or modality, radiolabeled olaratumab may include any radioisotope suitable for the treatment of tumors or cancerous masses. The radioisotope may be used in alpha (α), beta (β), or gamma (γ) therapy.

[00219] Examples of suitable radioisotopes include: actinium-225 (225Ac), astatine-211 (211At), bismuth-212 and bismuth-213 (212Bi,213Bi), copper-64 and copper-67 (64,67), iodine-123, -124, -125 or -131 (123I,124I,125I,131I) (123I), lead-212 (212Pb), lutetium-177 (177Lu), radium-223 and radium-224 (223Ra,224Ra), rhenium-186 and rhenium-188 (186Re and188Re), samarium-153 (153Sm), scandium-47 (47Sc), strontium-90 (90Sr), terbium-149 and terbium-161 (149Tb and 161Tb) and yttrium-90 (90Y). In preferred embodiments, the radionuclide is conjugated with the antibody or Petition 870250087443, dated 09 / 26 / 2025, pp. 120 / 171 90 / 111 of it is actinium-225 or lutetium-177.

[00220] In any embodiment, the radiolabeled olaratumab antibody or antigen-binding fragment thereof is 89Zr-,225Ac- or 177Lu-olaratumab wherein the radioisotope is conjugated to the olaratumab antibody directly or indirectly. Administration of radiolabeled olaratumab and treatment methods

[00221] Methods for preparing an antigen-binding protein in a form suitable for administration to an individual (e.g., a pharmaceutical composition) are known in the art and include, for example, methods as described in Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Co., Easton, Pa., 1990) and in document no. US Pharmacopeia: National Formulary (Mack Publishing Company, Easton, Pa., 1984).

[00222] Radiolabeled olaratumab antibody is generally administered as a pharmaceutical composition with a pharmacologically acceptable carrier, for example, physiological saline solution or other aqueous carrier, optionally comprising a protein stabilizer such as human serum albumin (HSA). The compositions may contain pharmaceutically acceptable ancillary substances as necessary to approximate physiological conditions, such as pH adjusting and buffering agents, Petition 870250087443, dated 09 / 26 / 2025, pp. 121 / 171 91 / 111 toxicity adjusting agents and so forth, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and so forth. The concentration of an antigen-binding protein according to the present invention in these formulations may vary widely and will be selected primarily based on fluid volumes, viscosities, body weight and the like, according to the particular mode of administration selected and the patient's needs. Exemplary carriers include water, saline solution, Ringer's solution, dextrose solution and 5% human serum albumin. Non-aqueous vehicles, such as mixed oils and ethyl oleate, may also be used. Liposomes may also be used as carriers. The vehicles may contain small amounts of additives that improve isotonicity and chemical stability, for example, buffers and preservatives.

[00223] Administration refers to the physical introduction of a composition comprising a therapeutic agent to an individual using any of the various delivery methods and systems known to those skilled in the art, including those described herein. Pharmaceutical compositions may be formulated from active agents of the invention, as described in this document, for any appropriate route of administration.

[00224] Radiolabeled olaratumab is Petition 870250087443, dated 09 / 26 / 2025, pp. 122 / 171 92 / 111 is preferably administered intravenously, preferably by infusion or intravenous injection. Administration of the antibody by infusion is preferably carried out over a period of up to approximately 30 minutes, more preferably over approximately 15 minutes. Obviously, radiolabeled olaratumab can also be administered by subcutaneous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion techniques.

[00225] The phrase therapeutically effective amount or effective amount generally refers to an amount of radiolabeled olaratumab or antigen-binding fragment thereof that (i) treats the specific disease, condition or disorder, (ii) attenuates, improves or eliminates one or more symptoms of the specific disease, condition or disorder, or (iii) delays the onset of one or more symptoms of the specific disease, condition or disorder described herein. Undesirable effects, for example, side effects, sometimes occur along with the desired therapeutic effect; therefore, a practitioner balances the potential benefits with the potential risks when determining what constitutes an appropriate effective amount.

[00226] For example, for the treatment of tumors, a therapeutically effective amount of the radioactively labeled antibodies or compositions described herein Petition 870250087443, dated 09 / 26 / 2025, pp. 123 / 171 93 / 111 document can inhibit tumor growth by 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 80%, or at least about 90% or more, compared to untreated individuals. Alternatively, the treatments described herein may cause complete regression of the tumor mass. In other embodiments of the invention, tumor regression can be observed and continue for a period of at least about 10 days, at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days or more.

[00227] A therapeutically effective amount of a drug may also include a preventive or prophylactically effective amount, which is any amount of radiolabeled olaratumab or antigen-binding fragment administered to an individual at risk of developing cancer (e.g., an individual with a pre-malignant condition) or of experiencing cancer recurrence, that inhibits the development or recurrence of cancer. In certain modalities, the prophylactically effective amount completely prevents the development or recurrence of cancer. Petition 870250087443, dated 09 / 26 / 2025, pp. 124 / 171 94 / 111 Inhibiting or preventing the development or recurrence of cancer means decreasing the likelihood of cancer developing or recurring, or preventing cancer from developing or recurring altogether.

[00228] The terms treatment or treatment of an individual include the application or administration of a compound of the invention to an individual with the aim of delaying, slowing, stabilizing, curing, alleviating, relieving, altering, remedying, lessening, improving, enhancing or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) disease or condition. The term treatment refers to any indication of success in treating or improving an injury, pathology or condition, including any objective or subjective parameter such as reduction; remission; decrease in the rate of worsening; decrease in the severity of the disease; stabilization, decrease in signs or symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the endpoint of degeneration less debilitating; or enhancing the physical or mental well-being of an individual.

[00229] As used herein, minimizing or preventing cancer progression means treating the individual in such a way as to prevent or delay the recurrence or metastasis of a tumor, or to prevent the growth of an existing tumor. Petition 870250087443, dated 09 / 26 / 2025, pages 125 / 171 95 / 111 Minimizing or preventing cancer progression includes preventing or delaying cancer recurrence, or preventing the growth of an existing tumor after cancer treatment. Recurrence being prevented includes, for example, recurrence in the tumor bed after surgical excision. Alternatively, recurrence includes metastasis of the cancer to another part of the body. The terms recurrence prevention and relapse prevention, as used in this document, are interchangeable.

[00230] The present invention also includes methods for preventing the development of cancer in an individual. For example, the individual for whom cancer prevention is necessary may be considered at risk of developing cancer but does not yet have detectable cancer. An individual at risk of developing cancer may be an individual with a family history of cancer and / or an individual for whom genetic or other tests indicate a high risk or high probability of developing cancer. The individual may have cancerous stem cells but not yet have detectable tumors. It will be understood that methods for preventing the development of cancer include methods for delaying the onset of cancer in an individual.

[00231] In some embodiments of the present disclosure, the cancer to be treated or prevented, or for which minimization of progression is desired, is a tissue sarcoma. Petition 870250087443, dated 09 / 26 / 2025, pp. 126 / 171 96 / 111 moles, chondrosarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, or rhabdomyosarcoma. In other embodiments of the present disclosure, the cancer to be treated or prevented, or for which minimization of progression is desired, is a 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, or renal cell carcinoma. In one embodiment of the present disclosure, the cancer is a primary tumor. In one embodiment, the cancer is a metastatic cancer. In other embodiments, the cancer has metastasized.

[00232] The terms soft tissue sarcoma or STS, as used herein, are a type of cancer that begins in the tissues that connect, support, and surround other structures in the body. This includes fat, muscles, fibrous tissues, blood vessels, nerves, tendons, joint linings, or deep tissues of the skin and / or joint lining. They can be found anywhere in the body. There are more than 50 subtypes of soft tissue sarcoma. Types of STS include, but are not limited to: angiosarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, stromal tumor Petition 870250087443, dated 09 / 26 / 2025, pp. 127 / 171 97 / 111 gastrointestinal (GIST), Kaposi's sarcoma, liposarcoma, malignant peripheral nerve sheath tumors, myxofibrosarcoma, rhabdomyosarcoma, solitary fibrous tumor, synovial sarcoma, or undifferentiated pleomorphic sarcoma.

[00233] In any aspect or modality herein, radiolabeled olaratumab may be administered in combination with (i.e., sequentially, concurrently, or after) the administration of another cancer treatment. In any modality, the treatment may be any cancer treatment, optionally selected from: surgery, immunotherapy, external beam radiation, chemotherapy, or radioimmunotherapy.

[00234] Chemotherapeutic agents are chemical agents or drugs that are selectively destructive to cancerous cells and tissues. Chemotherapeutic agents may include, but are not limited to, compounds such as taxane compounds, compounds that act through taxane mechanisms, platinum compounds, anthracycline compounds, antimetabolites, epipodophyllotoxin compounds, camptothecin compounds, or any combination thereof.

[00235] In any aspect of the invention, radiolabeled olaratumab and additional cancer treatment can be administered simultaneously. Alternatively, they can be administered Petition 870250087443, dated 09 / 26 / 2025, pp. 128 / 171 98 / 111 sequentially. For example, additional therapy (e.g., chemotherapy) may be administered before radiolabeled olaratumab, or radiolabeled olaratumab may be administered before additional therapy (e.g., chemotherapy). Alternatively, treatment with additional therapy (e.g., chemotherapy) and / or radiolabeled olaratumab may be staggered.

[00236] The appropriate dosages of radiolabeled olaratumab or antigen-binding fragment for use according to the present invention vary depending on the condition being treated and / or the individual being treated. It is within the ability of a skilled physician to determine an appropriate dosage, for example, starting with a suboptimal dosage and incrementally modifying the dosage to determine an optimal or useful dosage. Alternatively, to determine an appropriate dosage for treatment / prophylaxis, data from cell culture assays or animal studies are used, where an appropriate dose is within a range of circulating concentrations that include the ED50 of the active compound with little or no toxicity. The dosage may vary within this range depending on the pharmaceutical form employed and the route of administration used. A therapeutically / prophylactically effective dose can be initially estimated from cell culture assays.One dose might be enough. Petition 870250087443, dated 09 / 26 / 2025, pp. 129 / 171 99 / 111 was formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration or amount of the compound that achieves a semi-maximal inhibition of symptoms) as determined in cell culture. This information can be used to determine more precise useful doses in humans. Plasma levels can be measured, for example, by high-performance liquid chromatography.

[00237] A person skilled in the art will appreciate that the dosage of the agent for use according to the methods of the invention will depend on several factors, including age, sex, height and weight of the individual to whom the agent is administered and depending on the agent.

[00238] 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.

[00239] In certain modalities, radiolabeled olaratumab is administered in a massive dose of approximately 5 to 20 mg of olaratumab by slow infusion.

[00240] In some embodiments, an effective amount of antibody or antigen-binding fragment of Petition 870250087443, dated 09 / 26 / 2025, pp. 130 / 171 100 / 111 is administered to the patient identified as having cancer at a loading dose of approximately 15 mg / kg, or approximately 20 mg / kg, or approximately 25 mg / kg on each of days 1 and day 8 of a first 21-day cycle or on each of days 1 and day 8 of a first 28-day cycle, followed by administration of a standard dose of the antibody or antigen-binding fragment of the same to the patient, at approximately 15 mg / kg, approximately 20 mg / kg, or approximately 25 mg / kg on each of days 1 and 8 of a subsequent 21-day cycle or on each of days 1 and 8 of a subsequent 28-day cycle.

[00241] In some embodiments, the radiolabeled olaratumab or antigen-binding fragment disclosed herein is continued for a minimum period of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years. In some embodiments, treatment with the radiolabeled olaratumab or antigen-binding fragment disclosed herein is continued for a maximum period of up to about 18 months, 16 months, 14 months, 12 months, 10 Petition 870250087443, dated 09 / 26 / 2025, pp. 131 / 171 101 / 111 months, 8 months or 6 months. The duration of treatment can be any of these minimum durations to any of these maximum durations, for example, from 1 to 18 months.

[00242] As used in this document, the terms individual, individual, and patient will be understood as interchangeable. Although the invention finds application in humans, the invention is also useful for veterinary therapeutic purposes. The invention is useful for domestic or farm animals, such as cattle, sheep, horses, and poultry; for companion animals, such as dogs and cats; and for zoo animals. Kits

[00243] 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.

[00244] Optionally, the kit also includes a label or information leaflet with instructions for use.

[00245] The kit or manufacturing article may include a container and a label or information leaflet on or attached to the container. Suitable containers include, for example, bottles, vials, syringes, blisters, etc. Containers may be formed from a variety of materials, such as glass or plastic. The container contains a therapeutic composition that is effective for the Petition 870250087443, dated 09 / 26 / 2025, pp. 132 / 171 102 / 111 treatment of the disease 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 leaflet indicates that the therapeutic composition is used to treat the condition of choice. In one embodiment, the label or package leaflet includes instructions for use.

[00246] The kit may include: a) A therapeutic composition; and b) A second container with a second active ingredient or substance contained therein. The kit in this embodiment of the invention may also include a package insert indicating that the other active ingredient can be used to treat a disorder or prevent a complication arising from cancer. Alternatively, or additionally, the kit may include a second (or third) 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 desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[00247] In certain embodiments, the therapeutic composition may be provided in the form of a device, disposable or reusable, including a container to hold the therapeutic composition. In one embodiment, the Petition 870250087443, dated 09 / 26 / 2025, pp. 133 / 171 The 103 / 111 device is a syringe. The device can hold 1-2 ml of the therapeutic composition. The therapeutic composition may be supplied in the device in a ready-to-use state or in a state that requires mixing or the addition of other components.

[00248] 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. All these different combinations constitute various alternative aspects of the invention.

[00249] The following examples are intended to illustrate, but in no way limit, the present invention. Examples Example 1: Synthesis and Characterization of Bioconjugates

[00250] An olaratumab immunoglobulin antibody (e.g., 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 DOTAOlaratumab and DFOsq-Olaratumab.

[00251] Bioconjugation of DOTA-Oloratumab and DFOsqOloratumab 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 Petition 870250087443, dated 09 / 26 / 2025, pp. 134 / 171 104 / 111 DOTA-NHS Reagents: Antibody 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.

[00252] 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 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 Reagents: Antibody 0.2 mg DFO-sq: MW 684.8 g / mol @ 5 mg / ml; 16-18 eq per mAb. Buffer: Sodium borate 100 mM, pH 9. Organic cosolvent: 10% DMSO. Reaction conditions: Time: 3 hours. Temperature: 22 °C.

[00253] Size exclusion chromatography (SEC) screening of the DFOsq-olaratumab conjugate with DFPsq indicated high monomeric purity (>98%) after conjugation (data not shown). Olaratumab conjugated with DFOsq was evaluated for the characteristics listed below in Table 3. Petition 870250087443, dated 09 / 26 / 2025, pages 135 / 171 105 / 111 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 Concentration UV 2.5 mg / ml 3.44 mg / ml 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.

[00254] 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. Petition 870250087443, dated 09 / 26 / 2025, pages 136 / 171 106 / 111 Analysis: 1:1 linkage with double reference subtraction.

[00255] 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) 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 3, 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 Example 2: Validation of PDGFRa expression in selected cell lines

[00256] 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.

[00257] 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 were found to have a Petition 870250087443, dated 09 / 26 / 2025, pp. 137 / 171 107 / 111 is the smaller proportion of the total amount of PDGFRA located in the plasma membrane.

[00258] 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 in vivo xenograft model

[00259] The growth properties of the KRIB and A204 cell lines were tested in a xenograft model in Balb / c Nude mice. Both cell lines showed reproducible growth and good take-up rates. The A204 cell clone was selected for subsequent biodistribution studies, given the greater radiosensitivity of this cell line to ionizing radiation.

[00260] 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.

[00261] 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 in 1 hour, Petition 870250087443, dated 09 / 26 / 2025, pp. 138 / 171 108 / 111 and no binding to negative control cells (specific activity at 1 MBq / 4 μg). 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). 30-50% of the total binding was found to be internalized after 1 h (Figure 5, B). Example 4: Imaging and biodistribution studies

[00262] 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 recreated 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).

[00263] Imaging and biodistribution analyses demonstrated that radiolabeled Olaratumab is targeted to 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: Efficacy studies in a tumor model of Petition 870250087443, dated 09 / 26 / 2025, pp. 139 / 171 109 / 111 xenograft

[00264] 20 Balb / c Nus mice were subcutaneously implanted in the right flank with A204 cells. Of these, 16 mice were subsequently treated with 10 MBq of 177Lu-DOTA-Olaratumab, at an antibody mass dose of 40 pg. 4 mice received vehicle (non-radiolabeled DOTA-Olaratumab).

[00265] Tumor volumes (Figures 8 and 9) and mouse survival (Figure 10) were monitored for several weeks.

[00266] The A204 xenograft model showed exponential growth in the vehicle control group (cold-DOTA-Olaratumab) with a doubling time of approximately 7 days. Treatment with 10 MBq of 177LuDOTA-Olaratumab induced initial stasis and gradual regression and suppression of the tumor (Figures 8 and 9), with 3 mice still alive at the end of the study on day 90 (Figure 10), 2 mice reaching the tumor endpoint (days 50 and 68), and 2 sacrificed due to weight loss.

[00267] The differences in tumor volume (change from day 1) between the groups were statistically significant on day 20 (P = 0.0003 unpaired t-test), after which the differences continued to increase (but could not be statistically tested because the mice reached the endpoint). Petition 870250087443, dated 09 / 26 / 2025, pages 140 / 171 110 / 111 Example 6: Treatment of ovarian cancer

[00268] Efficacy studies using 177Lu-DOTAOlaratumab (e.g., comprising a VH as set forth in SEQ ID NO: 4 and a VL as set forth in SEQ ID 12) are conducted to evaluate the ability of the radiolabeled antibody to treat ovarian cancers.

[00269] First, experiments test the ability of 177Lu-DOTA-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 is variable.

[00270] Subsequently, mice bearing an A2780 cell line xenograft (approximately n = 4 / group) are administered intravenously with 177LuDOTA-Olaratumab or vehicle.

[00271] Ten days after intravenous injection of 177Lu-DOTA-Olaratumab into xenograft-bearing mice, the mice are evaluated to determine the efficacy of the therapeutic intervention with the radiolabeled antibody.

[00272] The results will show that radioactively labeled olaratumab antibodies are able to bind to ovarian tumor xenografts and will result in reduced tumor volume and increased survival, compared to Petition 870250087443, dated 09 / 26 / 2025, pages 141 / 171 111 / 111 mice bearing the same ovarian tumor xenografts and treated with vehicle only.

[00273] These results will indicate that antibodies with radiolabeled olaratumab are suitable for use in the treatment of ovarian cancer. Petition 870250087443, dated 09 / 26 / 2025, pages 142 / 171

Claims

1 / 19 CLAIMS 1. Olaratumab antibody bioconjugate or olaratumab antibody, characterized in that it is suitable for radiolabeling with a therapeutic 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'-tetraacetic acid), TCMC, DO3A, CB-DO2A, NOTA, Diamsar, DTPA, CHX-A-DTPA, 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 therapeutic use, for: - treating, preventing or minimizing the progression of a cancer distinguished from or associated with PDGFRalpha expression.

4. Olaratumab antibody or antigen-binding fragment thereof, 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 composed of 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 antibody 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 the 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 Petition 870250087443, dated 09 / 26 / 2025, page 144 / 171 3 / 19 comprising a sequence of 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%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least (i) a VH comprising a sequence that is 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 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: 4; (iii) a VL that includes a CDR1 that includes a sequence of at least 80%, at least 81%, at least 82%, per Petition 870250087443, dated 09 / 26 / 2025, p. 145 / 171 4 / 19 less than 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%, 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 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: 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%,(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 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 Petition 870250087443, dated 09 / 26 / 2025, page 147 / 171 6 / 19 SEQ ID NO: 4, and a VL comprising a sequence established in 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 frame 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 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: 6; an FR3 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%, Petition 870250087443, dated 09 / 26 / 2025, page 148 / 171 7 / 19 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: 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 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: 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.

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 Petition 870250087443, dated 26 / 09 / 2025, pp. 150 / 171 9 / 19 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: 8.O: 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, according to any one of claims 1 to 8, characterized in that the antibody or antigen-binding fragment thereof comprises an HV comprising a sequence of 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 Petition 870250087443, dated 09 / 26 / 2025, p.151 / 171 10 / 19 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 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.

10. Olaratumab antibody or antigen-binding fragment, 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 the amino acid substitutions, deletions or additions are not in the CDRs and the antigen-binding protein 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 or antigen-binding fragment, according to any one of claims 1 to 10, characterized in that the antibody or antigen-binding fragment is in the form of: (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 heavy chain (CH) 2 and / or CH3 constant domain.

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

14. Olaratumab antibody or its antigen-binding fragment, according to claim 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 its antigen-binding fragment, according to claim 13 or 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 its antigen-binding fragment, according to any one of claims 13 to 15, characterized in that the antibody or antigen-binding fragment thereof comprises one or more amino acid substitutions in the constant regions, 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 in 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 its antigen-binding fragment, according to any one of claims 13 to 17, characterized in that the antibody or its antigen-binding fragment includes an amino acid substitution at position 310 selected from alanine, glutamic acid or glutamine (EU Kabat index numbering).

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 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 20, characterized in that the antibody or antigen-binding fragment thereof comprises an amino acid substitution at the Lys322 residue, preferably wherein the substitution is K322A.

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 wherein 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 thereof, according to any of claims 3 to 22, characterized in that the antibody or antigen-binding fragment is conjugated to a radioisotope suitable for the treatment of tumorous or cancerous masses.

24. Olaratumab antibody or antigen-binding fragment thereof, according to claim 23, characterized in that the radioisotope is selected from: actinium-225 (225Ac), astatine-211 (211At), bismuth-212 and bismuth-213 (212Bi, 213Bi), copper-64 and copper-67 (64, 67), iodine-123, -124, -125 or -131 (123I, 124I, 125I, 131I), lead-212 (212Pb), lutetium-177 (177Lu), radium-223 and radium-224 (223Ra, 224Ra), rhenium-186 and rhenium-188 (186Re and 188Re), samarium-153 (153Sm), scandium-47 (47Sc), strontium-90 (90Sr), terbium-149 and terbium-161 (149Tb and 161Tb) and yttrium-90 (90Y).

25. Olaratumab antibody or its antigen-binding fragment, according to claim 24, characterized in that the radioisotope is actinium225 or lutetium-177 and in that the radioisotope is conjugated to the antibody or its antigen-binding fragment, directly or indirectly.

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

27. Olaratumab, according to any one of claims 23 to 25, characterized in that the radioisotope is indirectly linked to the antibody or antigen-binding fragment thereof, for example, by means of a chelating agent or other binding moiety.

28. Olaratumab, according to claim 27, 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.

29. Radioactively labeled olaratumab antibody or antigen-binding fragment, according to any one of claims 24 to 28, characterized in that the antibody is 177Lu-olaratumab or an olaratumab labeled with 177Lu, preferably wherein the 177Lu is conjugated to olaratumab via a ligand.

30. A method for treating, preventing, or minimizing cancer progression in an individual, characterized in that the method comprises: Petition 870250087443, dated 09 / 26 / 2025, pp. 158 / 171 17 / 19 - administering to an individual in need thereof a radioactively labeled olaratumab antibody or an antigen-binding fragment, as defined in any of claims 3 to 29, thereby treating, preventing, or minimizing cancer progression in the individual.

31. A method for minimizing, reducing, or preventing the growth of a tumor in an individual, characterized in that the method comprises: - administering to an individual in need thereof a radioactively labeled olaratumab antibody or an antigen-binding fragment, as defined in any one of claims 3 to 29, thereby minimizing, reducing, or preventing the growth of a tumor in the individual.

32. Method for minimizing, reducing or preventing cancer metastasis in an individual characterized by the method comprising: - administering to an individual in need thereof a radioactively labeled olaratumab antibody or an antigen-binding fragment, as defined in any of claims 3 to 29, thereby minimizing, reducing or preventing cancer metastasis in the individual.

33. Method for increasing the survival of an individual Petition 870250087443, dated 09 / 26 / 2025, pp. 159 / 171 18 / 19 suffering from cancer, characterized in that the method comprises: - administering to an individual in need thereof a radioactively labeled olaratumab antibody or an antigen-binding fragment, as defined in any of claims 3 to 29, thereby increasing the individual's survival.

34. Use of a radioactively labeled olaratumab or antigen-binding fragment, according to any one of claims 3 to 29, characterized in that it is used in the manufacture of a medicament to: - treat, prevent or minimize the progression of cancer in an individual, - minimize, reduce or prevent the growth of a tumor in an individual, - minimize, reduce or prevent metastases in an individual, or - increase the survival of an individual suffering from cancer.

35. Method according to claims 30 to 33, or use according to claim 34, characterized in that the cancer is selected from the list comprising: soft tissue sarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, liposarcoma and rhabdomyosarcoma. Petition 870250087443, dated 09 / 26 / 2025, pp. 160 / 171 19 / 19 36. Method, according to any one of claims 30 to 33, or 35, characterized in that cancer is distinguished by the expression of PDGFRalpha in tumor cells and / or tumor stroma.

37. A method, according to any one of claims 30 to 33, characterized in that the cancer is selected from a list 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, or renal cell carcinoma.

38. A method or use, according to any one of claims 35 to 37, characterized in that the tumor or cancer is not metastatic.

39. Method or use, according to any of claims 35 to 37, characterized in that the cancer is malignant or metastatic. Petition 870250087443, dated 09 / 26 / 2025, pp. 161 / 171

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