PD-1 / TIGIT Binding Proteins for Cancer Treatment

Description

1 / 103 PD-1 / TIGIT Binding Proteins for Cancer Treatment FIELD

[001] The present invention relates to methods for treating cancer in a subject, which comprise administering to the subject a specific binding protein that binds to Programmed Death-1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) in an amount of about 70 mg to about 1500 mg. The present invention further provides methods for manufacturing such bispecific binding protein and compositions, including pharmaceutical compositions, comprising such bispecific protein. BACKGROUND

[002] Programmed Death-1 (PD-1) is a type I membrane protein of approximately 31 kD that is a member of the extended CD28 / CTLA4 family of T cell regulators (see Ishida et al., Induced Expression of PD-1, A Novel Member of the Immunoglobulin Gene Superfamily, Upon Programmed Cell Death, EMBO J. 1992, 11: 3887-95). PD-1 is expressed on activated T cells, B cells, and monocytes, and at low levels on natural killer (NK) T cells. PD-1 is a well-validated target for immune-mediated therapy in oncology. Antagonistic inhibition of the PD-1 / PD-L1 interaction increases T cell activation, improving recognition and elimination of tumor cells by the host immune system.

[003] The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an immune receptor present on some T cells and Natural Killer (NK) cells. TIGIT is upregulated by immune cells, including activated T cells, natural killer cells, and regulatory T cells. SUMMARY

[004] The present invention provides a method for treating Petition 870250088197, dated 09 / 29 / 2025, page 9 / 166 2 / 103 a cancer in a subject, which comprises administering to the subject bispecific binding proteins that bind specifically to PD-1 and TIGIT in an amount of about 70 mg to about 1500 mg. The bispecific binding protein comprises: a) a first binding domain that binds specifically to PD-1, wherein the first binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 1, an HCDR2 having the amino acid sequence of SEQ ID NO: 2 and an HCDR3 having the amino acid sequence of SEQ ID NO: 3, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 4, an LCDR2 having the amino acid sequence of SEQ ID NO: 5 and an LCDR3 having the amino acid sequence of SEQ ID NO: 6;(b) a second binding domain that specifically binds to TIGIT, wherein the second binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 11, an HCDR2 having the amino acid sequence of SEQ ID NO: 12 and an HCDR3 having the amino acid sequence of SEQ ID NO: 13, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 14, an LCDR2 having the amino acid sequence of SEQ ID NO: 15 and an LCDR3 having the amino acid sequence of SEQ ID NO: 16.

[005] In some respects, the amount of bispecific binding protein administered is about 70 mg, about 150 mg, about 210 mg, about 450 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1250 mg, or about 1500 mg. In some respects, the amount of bispecific binding protein administered is about 750 mg. In some respects, the amount of bispecific binding protein Petition 870250088197, dated 09 / 29 / 2025, p. 10 / 166 3 / 103 of the citric acid administered is approximately 1500 mg.

[006] In some aspects, the bispecific binding protein is administered once per treatment cycle. In some aspects, the treatment cycle is about 7 days, about 14 days, about 21 days, about 28 days, or about 35 days. In some aspects, the treatment cycle is about 7 days. In some aspects, the treatment cycle is repeated for up to 35 cycles.

[007] In some respects, the bispecific binding protein is administered to the subject as monotherapy. In some respects, the bispecific binding protein is administered via intravenous (IV) infusion. In some respects, the subject has not received a prior line of systemic therapy. In some respects, the subject has received chemotherapy previously.

[008] In some respects, cancer comprises a cancerous cell that expresses PD-L1.

[009] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having the amino acid sequence of SEQ ID NO:9.

[0010] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:9.

[0011] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having the amino acid sequence of Petition 870250088197, dated 09 / 29 / 2025, p. 11 / 166 4 / 103 SEQ ID NO:8 and a light chain having the amino acid sequence of SEQ ID NO:10.

[0012] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:8 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:10.

[0013] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having the amino acid sequence of SEQ ID NO:19.

[0014] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:19.

[0015] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having the amino acid sequence SEQ ID NO:18 and a light chain having the amino acid sequence SEQ ID NO:20.

[0016] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of Petition 870250088197, dated 09 / 29 / 2025, p. 12 / 166 5 / 103 SEQ ID NO:18 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:20.

[0017] In some respects, the bispecific binding protein is a human or humanized bispecific antibody or antigen-binding fragment thereof.

[0018] In some respects, the bispecific binding protein comprises a variant Fc region. In some respects, the variant Fc region of the bispecific binding protein comprises at least one substitution selected from 221K, 221Y, 225E, 225K, 225W, 228P, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235E, 235F, 236E, 237L, 237M, 237P, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247L, 247V, 247G, 250E, 250Q, 251F, 252L, 252Y, 254S, 254T, 255L, 256E, 256F, 256M, 257C, 257M, 257N, 262I, 262A, 262T, 262E, 263I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265A, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266I, 266A, 266T, 266M, 267Q, 267L, 268E, 269H, 269Y, 269F, 269R, 270E, 280A, 284M, 292P, 292L, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H,296G, 297S, 297D, 297E, 298A, 298H, 298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 305I, 308F, 313F, 316D, 318A, 318S, 320A, 320S, 322A, 322S, 325Q, 325L, 3251, 325D, 325E, 325A, 325T, 325V, 325H, 326A, 326D, 326E, 326G, 326M 326V, 327G, 327W, 327N, 327L, 328S 328M, 328D, 328E, 328N, 328Q, 328F, 3281, 328V, 328T,328H, 328A, 329F, 329H, 329Q, 330K, 330G, 330T, 330C, 330L, 330Y 330V, 3301, 330F, 330R, 330H, 331G, 331A, 331L, 331M, 331F 331W, 331K, 331Q, 331E, 331S, 331V, 3311, 331C, 331Y, 331H Petition: 870250088197, on September 29, 2025, page. 13 / 166 6 / 103 331R, 331N, 331D, 331T, 332D, 332S, 332W, 332F, 332E, 332N 332Q, 332T, 332H, 332Y, 332A, 333A, 333D, 333G, 333Q, 333S 333V, 334A, 334E, 334H, 334L, 334M, 334Q, 334V, 334Y, 339T 370E, 370N, 378D, 392T, 396L, 416G, 419H, 421K, 428L, 428F, 433K 433L, 434A, 434W, 434Y, 436H, 440Y and 443W as numbered by the EU index as shown in Kabat.

[0019] In some respects, the variant Fc region of the bispecific binding protein comprises one or more amino acid substitutions at selected positions of 428 and 434 as numbered by the EU index as shown in Kabat. In some respects, the variant Fc region of the bispecific binding protein comprises one or more amino acid substitutions selected from 428L, 428F, 434A, 424F, 434W, and 434Y.

[0020] In some respects, the variant Fc region of the bispecific binding protein comprises a YTE mutation (M252Y / S254T / T256E). In some respects, the variant Fc region of the bispecific binding protein comprises a triple mutation (TM) L234F / L235E / P331S.

[0021] In some respects, the Fc region of the bispecific binding protein is aglycosylated. In some respects, the Fc region of the bispecific binding protein is deglycosylated.

[0022] In some respects, the Fc region of the bispecific binding protein has reduced fucosylation or is afucosylated.

[0023] In some respects, the bispecific binding protein comprises a constant region of the kappa light chain. In some respects, the bispecific binding protein comprises a constant region of the lambda light chain.

[0024] In some respects, the bispecific binding protein is an antibody. In some respects, the antibody is an IgG antibody. In some respects, the antibody is an IgG1 antibody. In some respects Petition 870250088197, dated 09 / 29 / 2025, page 14 / 166 7 / 103 aspects, the antibody is humanized.

[0025] In some aspects, the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer. In some aspects, the cancer is non-small cell lung cancer (NSCLC). In some aspects, the NSCLC is advanced or metastatic.

[0026] In some aspects, the subject has a PD-L1 tumor proportion score greater than or equal to 1%. In some aspects, the subject has a PD-L1 tumor proportion score greater than or equal to 50%. In some aspects, the subject has never received the checkpoint inhibitor (CPI).

[0027] In some respects, the present invention further provides a pharmaceutical composition comprising a bispecific binding protein that specifically binds to PD-1 and TIGIT in an amount of about 70 mg to about 1500 mg.In some respects, the bispecific binding protein comprises: a) a first binding domain that binds specifically to PD-1, wherein the first binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 1, an HCDR2 having the amino acid sequence of SEQ ID NO: 2 and an HCDR3 having the amino acid sequence of SEQ ID NO: 3, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 4, an LCDR2 having the amino acid sequence of SEQ ID NO: 5 and an LCDR3 having the amino acid sequence of SEQ ID NO: 6; and b) a second binding domain that binds specifically to TIGIT, wherein the second binding domain comprises a variable heavy chain domain comprising an HCDR1 having the sequence. Petition 870250088197, dated 09 / 29 / 2025, page 15 / 166 8 / 103 of the amino acids from SEQ ID NO: 11, an HCDR2 with the amino acid sequence from SEQ ID NO: 12 and an HCDR3 with the amino acid sequence from SEQ ID NO: 13, and a variable light chain domain comprising an LCDR1 having the amino acid sequence from SEQ ID NO: 14, an LCDR2 with the amino acid sequence from SEQ ID NO: 15 and an LCDR3 with the amino acid sequence from SEQ ID NO: 16.

[0028] In some aspects, the pharmaceutical composition comprises about 70 mg, about 150 mg, about 210 mg, about 450 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1250 mg or about 1500 mg of bispecific binding protein. In some aspects, the pharmaceutical composition comprises about 750 mg of bispecific binding protein. In some aspects, the pharmaceutical composition comprises about 1500 mg of bispecific binding protein.

[0029] In some aspects where cancer is NSCLC, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having the amino acid sequence of SEQ ID NO:9.

[0030] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:9.

[0031] In some respects, the first binding domain of the pro Petition 870250088197, dated 09 / 29 / 2025, page 16 / 166 9 / 103 bispecific linker protein that specifically binds to PD-1 comprises a heavy chain having the amino acid sequence SEQ ID NO:8 and a light chain having the amino acid sequence SEQ ID NO:10.

[0032] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:8 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:10.

[0033] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having the amino acid sequence SEQ ID NO:17 and a variable light chain domain having the amino acid sequence SEQ ID NO:19.

[0034] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:19.

[0035] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having the amino acid sequence SEQ ID NO:18 and a light chain having the amino acid sequence SEQ ID NO:20.

[0036] In some respects, the second binding domain of the bispecific binding protein that binds specifically to TIGIT Petition 870250088197, dated 09 / 29 / 2025, p. 17 / 166 10 / 103 comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:18 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:20.

[0037] The present invention further provides a kit comprising any of the pharmaceutical compositions described above. In some respects, the kit also includes instructions for administering the pharmaceutical composition.

[0038] The present invention further provides a pharmaceutical composition, as defined above, for use in the treatment of cancer.

[0039] In some aspects of the pharmaceutical composition for use, the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer. In some aspects, the cancer is non-small cell lung cancer (NSCLC). In some aspects, the NSCLC is advanced or metastatic.

[0040] In some aspects of the pharmaceutical composition for use, the cancer is NSCLC and has a PD-L1 tumor proportion score greater than or equal to 1%. In some aspects of the pharmaceutical composition for use, the cancer is NSCLC and has a PD-L1 tumor proportion score greater than or equal to 50%.

[0041] In some aspects of the pharmaceutical composition for use, cancer has not been previously treated with a checkpoint inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The following drawings are part of this descriptive report and are included to further illustrate the exemplary aspects. Petition 870250088197, dated 09 / 29 / 2025, page 18 / 166 11 / 103 of the present invention.

[0043] FIG. 1 shows PD-1 receptor occupancy (RO) and predicted TIGIT percent in tumor. The minimum concentration was used in the prediction; the model assumes limited impact of ADA on PK. Low / high tumor PC = 5% / 50%, low / high tumor PD-1 RC = 3 / 30 nM, low / high tumor TIGIT RC = 4 / 40 nM. ADA = antidrug antibodies; Ig = immunoglobulin; PC = partition coefficient; PD-1 = programmed cell death-1; PK = pharmacokinetics; RC = receptor concentration; RO = receptor occupancy; TIGIT = T-cell immunoreceptor with Ig- and tyrosine-based inhibition motif domains.

[0044] FIG. 2 is a schematic diagram showing an exemplary treatment method comprising a dose escalation phase (Part A) and three dose expansion phases (Part B and Part D).

[0045] FIG. 3 is a graph of adverse events that occurred in more than 5% of the 80 subjects evaluated in the Parts A and B study described in Example 8 below. Adverse events related to AZD2936 are illustrated on the right side of the graph.

[0046] FIG. 4 is a graph of the adverse events that occurred in more than 5% of the 54 subjects dosed with AZD2936, as assessed in the Parts A and B study described in Example 8 below. Adverse events related to AZD2936 are illustrated on the right side of the graph.

[0047] FIG. 5 is a graph of adverse events occurring in more than 5% of the 83 subjects with AZD2936, as assessed in the expanded Part A and Part B study described in Example 11 below. Treatment-emergent adverse events (TEAEs) are illustrated on the left side of the graph, and treatment-related adverse events (TRAEs) are illustrated on the right side of the graph. Petition 870250088197, dated 09 / 29 / 2025, page 19 / 166 12 / 103

[0048] FIG. 6 is a graph of adverse events that occurred in the 54 subjects receiving the recommended phase 2 dose (RP2D) of AZD2936, as assessed in the expanded Part A and Part B study described in Example 11 below. TEAEs are illustrated on the left side of the graph and TRAEs are illustrated on the right side of the graph.

[0049] FIG. 7 is a cascade graph of post-baseline scans from 83 subjects as described in Example 11. The graphs are representations of the best percent change from baseline in target lesion size.

[0050] FIG. 8 is a graph of the duration of exposure to AZD2936 for each subject measured in weeks for the outcome in FIG. 7.

[0051] FIGS. 9A-9C show pharmacodynamics of two subjects treated in PR2D. FIGS. 9A and 9B are the radiographic responses of the first and second subjects at 9 weeks, respectively. FIGS. 9C is a graph of the two subjects showing a 100% reduction in circulating tumor deoxyribonucleic acid (ctDNA) at 6 weeks. Abbreviations in FIGS. 9A-9C: ctDNA, circulating tumor DNA; LN, lymph node; mVAF, mean frequency of the variant allele; PD-L1, programmed cell death ligand-1; RP2D, recommended phase 2 dose; TL, target lesion.

[0052] FIG. 10 is a graph of adverse events occurring in more than 10% of the 54 subjects treated with AZD2936 750 mg Q3W in the Part A and Part B study described in Example 8 below. Adverse events related to AZD2936 are illustrated on the right side of the graph.

[0053] FIG. 11 is a graph of adverse events occurring in more than 10% of the 19 subjects treated with AZD2936 750 mg Q3W as assessed in the Part C study described in Example 12 below. Adverse events related to AZD2936 are illustrated on the right side of the graph. Petition 870250088197, dated 09 / 29 / 2025, page 20 / 166 13 / 103

[0054] FIG. 12 is a graph of adverse events occurring in more than 10% of the 13 subjects treated with AZD2936 1500 mg Q3W as assessed in the Part D study described in Example 13 below. Adverse events related to AZD2936 are illustrated on the right side of the graph.

[0055] FIG. 13 is a graph of adverse events occurring in more than 10% of the 14 subjects treated with AZD2936 750 mg Q3W in the Part D study described in Example 13 below. Adverse events related to AZD2936 are represented on the right side of the graph.

[0056] FIG. 14 is a graph of the best percent change from baseline in target lesion size in 19 subjects dosed with AZD2936 750 mg and 1500 mg Q3W, as assessed in the Parts C and D study described in Example 12 and Example 13 below. Each bar corresponds to a subject and is color-coded to reflect the best overall response.

[0057] FIG. 15 presents a graph of the variation in target lesion size over time in 19 subjects dosed with AZD2936 750 mg and 1500 mg Q3W as evaluated in the Parts C and D study described in Example 12 and Example 13 below. Each row corresponds to a subject and is color-coded to reflect the best overall response. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0058] Unless defined otherwise in this report, scientific and technical terms used in the present invention shall have the meanings commonly understood by a person of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural terms and plural terms shall include singular terms. Petition 870250088197, dated 09 / 29 / 2025, page 21 / 166 14 / 103

[0059] As used in this report, a or an can mean one or more. As used in this report, when used in conjunction with the word comprising, the words a and an can mean one or more than one. As used in this report, another or an additional can mean at least one second or more.

[0060] The use of the term "or" in the claims is to mean "and / or," unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the invention supports a definition that refers only to alternatives and / or.

[0061] As used in this report, the terms comprise (and any variant or form of comprising, such as comprise and comprises), have (and any variant or form of having, such as have and has), include (and any variant or form of include, such as includes and include) or contain (and any variant or form of contain, such as contains and contain) are inclusive or open and do not exclude additional elements or method steps not mentioned.

[0062] Throughout this application, the term "approximately" is used to indicate that a value includes the inherent error variation for the method / device being employed to determine the value, or the variation that exists between study subjects. Typically, the term "approximately" is intended to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% or more of variability (greater than or less than the indicated value), depending on the situation. In some respects, one skilled in the art will understand the level of variability indicated by the term "approximately" due to the context in which it is used herein. It should also be understood that the use of the term Petition 870250088197, dated 09 / 29 / 2025, page 22 / 166 15 / 103 also includes the specifically mentioned value.

[0063] The use of the term for example and its corresponding abbreviation e.g. (whether italicized or not) means that the specific terms mentioned are representative examples and aspects of the invention that are not intended to be limited to the specific examples referred to or cited, unless explicitly indicated otherwise.

[0064] The ranges provided here, of any type, include all values ​​within a particular range described and values ​​around an endpoint for a particular range. As used in this report, between is a range that includes the endpoints of the range. For example, a number between x and y explicitly includes the numbers x and y, and any numbers that fit within x and y.

[0065] The term antibody as used in this report refers to a protein that is capable of specifically recognizing and binding to an antigen. Common or conventional mammalian antibodies comprise a tetramer, which is typically composed of two identical pairs of polypeptide chains, each pair consisting of a light chain (typically with a molecular weight of about 25 kDa) and a heavy chain (typically with a molecular weight of about 50–70 kDa). The terms heavy chain and light chain, as used in this report, refer to any immunoglobulin polypeptide having a variable domain sequence sufficient to confer specificity to a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids, which is normally responsible for antigen recognition.The carboxyl-terminal portion of each chain typically defines a constant domain responsible for the effector function. Thus, in a naturally occurring antibody, a full-length heavy-chain immunoglobulin polypeptide includes one variable domain (Vh) and three constan domains. Petition 870250088197, dated 09 / 29 / 2025, page 23 / 166 16 / 103 tes (Chi, Ch2 and Ch3) and a hinge region between Chi and Ch2, wherein the Vh domain is at the amino terminus of the polypeptide and the Ch3 domain is at the carboxyl terminus, and a full-length immunoglobulin light chain polypeptide includes a variable (Vl) domain and a constant (Cl) domain, wherein the Vl domain is at the amino terminus of the polypeptide and the Cl domain is at the carboxyl terminus. Those skilled in the art, however, would understand that the locations of the domains in a naturally occurring antibody can be modified in certain antibody-like binding protein formats without loss of antigen-binding ability. The classes of human light chains are called kappa and lambda light chains.

[0066] In some respects, the constant light chain region is a kappa chain. In some respects, the constant light chain region is a lambda chain.

[0067] Within the full-length light and heavy chains, the variable and constant domains are typically joined by a J region of about 12 or more amino acids, with the heavy chain also including a D region of about 10 more amino acids. The variable regions of each light / heavy chain pair typically form an antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved major structure (FR) regions, joined by three hypervariable regions, also called complementarity-determining regions or CDRs. The CDRs of the two chains in each pair are typically aligned by the major structure regions, which may allow binding to a specific epitope. From the amino terminus to the carboxyl terminus, both light and heavy chain variable domains typically comprise the FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 domains.

[0068] The term antibody fragment refers to a portion Petition 870250088197, dated 09 / 29 / 2025, p. 24 / 166 17 / 103 of an intact or complete chain or antibody, usually the target binding region or variable. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments. As used in this report, the term functional fragment is generally synonymous with antibody fragment and, with respect to antibodies, may refer to antibody fragments such as Fv, Fab, F(ab')2.

[0069] Reference to the amino acid residue numbering described here is made according to the EU numbering system (also described in Kabat et al. Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).

[0070] The term human antibody as used in this report includes antibodies having variable and constant regions substantially corresponding to human germline immunoglobulin sequences. In some respects, human antibodies are produced in non-human mammals, including, but not limited to, rodents such as mice and rats, and lagomorphs such as rabbits. In other respects, human antibodies are produced in hybridoma cells. In other respects, human antibodies are produced recombinantly. In some respects, the bispecific binding protein is a human or humanized antibody.

[0071] The term antigen or target antigen as used in this report refers to a molecule or a portion of a molecule that is capable of being recognized by and bound by binding proteins of the present invention. The target antigen is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. A target antigen may have one or more epitopes.

[0072] The term epitope as used in this report refers to a region or structural element of an antigen that is reco Petition 870250088197, dated 09 / 29 / 2025, p. 25 / 166 18 / 103 known and bound by a binding protein of the invention. More precisely, the epitope is the specific structure that is bound by the CDRs of the binding protein. Epitopes may comprise structural elements of proteins, carbohydrates, or even portions of lipid structures found in membranes. A binding protein is said to bind specifically to an antigen when it preferentially recognizes its antigenic target in a complex mixture of proteins and / or macromolecules. The term binds specifically refers to a binding protein that binds specifically to a molecule or a fragment thereof (e.g., antigen). A binding protein that binds specifically to a molecule or a fragment thereof may bind to other molecules with lower affinity, as determined, for example, by immunoassays, BIAcore, or other assays known in the art.In particular, antibodies or fragments that bind specifically to at least one molecule or a fragment thereof can compete with molecules that bind non-specifically. The present invention specifically comprises antibodies with multiple specificities (for example, an antibody with specificity for two or more discrete antigens). For example, a bispecific antibody may bind to two adjacent epitopes on a single target antigen or may bind to two different antigens.

[0073] The term native Fc as used in this report refers to a molecule comprising the sequence of a non-antigen-binding fragment resulting from the digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and may contain the hinge region. The original immunoglobulin source of native Fc is preferably of human origin and may be any of the immunoglobulins. Native Fc molecules are formed by monomeric polypeptides that can be linked in various forms. Petition 870250088197, dated 09 / 29 / 2025, p. 26 / 166 19 / 103 Dimeric or multimeric molecules are associated by covalent (i.e., disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules varies from 1 to 4, depending on the class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, and IgGA2). An example of a native Fc molecule is a disulfide-linked dimer resulting from papain digestion of an IgG. The term native Fc as used in this report is generic for monomeric, dimeric, and multimeric forms.

[0074] The term Fc variant as used herein refers to a molecule or sequence that is modified from a native Fc, but still comprises a binding site for the salvage receptor, FcRn (neonatal Fc receptor). Exemplary Fc variants, and their interaction with the salvage receptor, are known in the art. Thus, the term Fc variant may encompass a molecule or sequence that is humanized from a non-human native Fc. Furthermore, a native Fc comprises regions that may be removed or mutated to produce an Fc variant to alter certain residues that provide structural features or biological activity that are not required for the binding proteins of the invention.Thus, the term Fc variant comprises a molecule or sequence that does not contain one or more native Fc sites or residues, or in which one or more Fc sites or residues have been modified, affecting or being involved in: (1) disulfide bond formation, (2) incompatibility with a selected host cell, (3) N-terminal heterogeneity when expressed in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fc receptor other than a salvage receptor, or (7) antibody-dependent cellular cytotoxicity (ADCC).

[0075] The term Fc domain as used in this report Petition 870250088197, dated 09 / 29 / 2025, page 27 / 166 20 / 103 comprises native Fc and Fc variants and sequences as defined above. As with Fc variants and native Fc molecules, the term Fc domain includes molecules in monomeric or multimeric form, whether digested from the whole antibody or produced by other means.

[0076] The term treat or treatment refers to the administration of a pharmaceutical compound or composition to a subject in order to effect a change or improvement of a disease, disorder, or condition in the subject. The terms treatment and treat as used in this report may refer to both therapeutic treatment and prophylactic or preventive measures. Those in need of treatment include subjects having a disease or condition, as well as those likely to have a disease or condition, or those for whom a disease or condition should be prevented.

[0077] The term dose means a specific amount of a pharmaceutical compound or agent given in a single administration or over a specified period of time. In some aspects, a dose may be administered in two or more boluses, tablets, or injections. For example, in some aspects where subcutaneous administration is desired, the desired dose may require a volume that is not easily accommodated by a single injection. In such aspects, two or more injections may be used to achieve the desired dose. In some aspects, a dose may be administered in two or more injections to minimize injection site reaction in a subject. In other aspects, the pharmaceutical compound or agent is administered by infusion over a prolonged period of time or continuously. Doses may be stated as the amount of pharmaceutical agent per hour, day, week, or month.

[0078] The terms subject, individual, and patient are used interchangeably here to refer to a mammalian subject. In one as Petition 870250088197, dated 09 / 29 / 2025, page 28 / 166 21 / 103 In one aspect, the subject is a human being, domestic animals, farm animals, sporting animals, and zoo animals, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, etc. In one aspect, the subject is a cynomolgus monkey (Macaca fascicularis). In a preferred aspect, the subject is a human being. In the methods of the invention, the subject may not have been previously diagnosed as having cancer. Alternatively, the subject may have been previously diagnosed as having cancer. The subject may also be a person who has risk factors for disease or someone who is asymptomatic for cancer. The subject may also be a person who is suffering from or is at risk of developing cancer. Thus, in one aspect, a method of the invention can be used to confirm the presence of cancer in a subject. For example, the subject may have been previously diagnosed with cancer through alternative means.In one aspect, the subject has previously received cancer therapy. A subject who has never received a checkpoint inhibitor or never received CPI means a subject whose cancer has not been previously treated with a checkpoint inhibitor (CPI).

[0079] The term efficacy means the ability to produce a desired effect. A therapeutically effective dose or therapeutic dose is a sufficient amount to effect the desired clinical results (i.e., to achieve therapeutic efficacy). A therapeutically effective dose may be administered in one or more administrations.

[0080] The term side effects means illnesses and / or physiological conditions attributable to a treatment other than the desired effects. In some respects, side effects include injection site reactions, abnormalities in liver function tests, abnormalities in renal function, liver toxicity, renal toxicity, Petition 870250088197, dated 09 / 29 / 2025, p. 29 / 166 22 / 103 Central nervous system abnormalities, myopathies, and malaise. For example, increased serum aminotransferase levels may indicate liver toxicity or abnormal liver function. For example, increased bilirubin may indicate liver toxicity or abnormal liver function. A disease or condition refers to any condition that would benefit from treatment using the methods of the invention. Disease and condition are used interchangeably herein and include chronic and acute disorders or diseases, including those pathological conditions that predispose a patient to the disorder in question. In some respects, the disease is a tumor. In some respects, the disease is a solid tumor. In some respects, the disease is cancer.In some aspects, the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer. In some aspects, the disease is non-small cell lung cancer (NSCLC). In some aspects, the NSCLC is advanced or metastatic. In some aspects, advanced NSCLC is stage III or IV NSCLC.

[0081] The terms administration and administer as used in this report refer to providing, contacting and / or administering a compound or compounds via any appropriate route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic, inhalation and implants.

[0082] The terms pharmaceutical composition and therapeutic composition Petition 870250088197, dated 09 / 29 / 2025, p. 30 / 166 23 / 103 pharmacist as used in this report refers to a compound or composition capable of inducing a desired therapeutic effect when appropriately administered to a subject. In some respects, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the binding proteins of the invention.

[0083] The terms pharmaceutically acceptable carrier and physiologically acceptable carrier as used in this report refer to one or more formulation materials suitable for carrying out or enhancing the delivery of one or more binding proteins of the invention. Cancer Treatment Methods

[0084] The invention relates to a method for treating cancer in a subject, which comprises administering to the subject bispecific binding proteins that bind specifically to PD-1 and TIGIT in an amount of about 70 mg to about 1500 mg. The invention also provides compositions, including pharmaceutical compositions, and kits, comprising such bispecific protein.

[0085] As used in this report, bispecific binding proteins have binding specificities for at least two independent antigens (or targets) or different epitopes within the same antigen. Exemplary bispecific binding proteins may bind to two different epitopes of a target or may bind to two different targets. Other binding proteins of this type may combine a first target binding site with a second binding site for another target. In some respects, the binding protein is a bispecific antibody.

[0086] In some respects, bispecific antibodies provide additive and / or synergistic therapeutic effects derived from targeting two antigens simultaneously, with the administration of Petition 870250088197, dated 09 / 29 / 2025, p. 31 / 166 24 / 103 a single molecule manufactured.

[0087] In some respects, the antibodies provided here are monovalent bispecific antibodies (MBab). The monovalent bispecific antibody base structures described here provide a superior platform for the generation of bispecific antibodies that meet all the benefits associated with bispecific antibodies while reducing the potential therapeutic risks mentioned above due to their monovalent nature. Furthermore, the MBabs provided here are readily expressed, stable, and are likely to have low immunogenicity. As used in this report, the term monovalent bispecific, which may be abbreviated as MBab, refers to bispecific antibodies where each arm can specifically bind to a different target antigen and, for a given pair of different target antigens (A and B), the MBab can bind to one of each.In some respects, monovalent bispecific antibodies can bind specifically to two independent antigens (or targets) or to two independent epitopes on the same antigen. Typically, monovalent bispecific antibodies comprise two different variable regions. In some respects, the binding affinity for the two independent antigens is approximately the same. In some respects, the binding affinities for the two independent antigens are different.

[0088] In some respects, the bispecific binding protein comprises: a) a first binding domain that specifically binds to PD-1, wherein the first binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 1, an HCDR2 having the amino acid sequence of SEQ ID NO: 2 and an HCDR3 having the amino acid sequence of SEQ ID NO: 3, and a variable light chain domain comprising an LCDR1 having the sequence Petition 870250088197, dated 09 / 29 / 2025, page 32 / 166 25 / 103 amino acid sequence of SEQ ID NO: 4, an LCDR2 having the amino acid sequence of SEQ ID NO: 5 and an LCDR3 having the amino acid sequence of SEQ ID NO: 6; and b) a second binding domain that binds specifically to TIGIT, wherein the second binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 11, an HCDR2 having the amino acid sequence of SEQ ID NO: 12 and an HCDR3 having the amino acid sequence of SEQ ID NO: 13, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 14, an LCDR2 having the amino acid sequence of SEQ ID NO: 15 and an LCDR3 having the amino acid sequence of SEQ ID NO: 16.

[0089] In some respects, the first binding domain that specifically binds to PD-1 comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO: 7 and a variable light chain domain having the amino acid sequence of SEQ ID NO: 9. In some respects, the first binding domain that specifically binds to PD-1 comprises a heavy chain having the amino acid sequence of SEQ ID NO: 8 and a light chain having the amino acid sequence of SEQ ID NO: 10.

[0090] In some respects, the first binding domain that specifically binds to PD-1 comprises a variable heavy chain domain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO: 7. In some respects, the first binding domain that specifically binds to PD-1 comprises a variable light chain domain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO: 9.

[0091] In some respects, the first linking domain that is Petition 870250088197, dated 09 / 29 / 2025, p. 33 / 166 26 / 103 specifically binds to PD-1 and comprises a heavy chain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the amino acid sequence of SEQ ID NO: 8. In some respects, the first binding domain that specifically binds to PD-1 comprises a light chain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the amino acid sequence of SEQ ID NO: 10.

[0092] In some respects, the second binding domain that specifically binds to TIGIT comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having the amino acid sequence of SEQ ID NO:19. In some respects, the second binding domain that specifically binds to TIGIT comprises a heavy chain having the amino acid sequence of SEQ ID NO:18 and a light chain having the amino acid sequence of SEQ ID NO:20.

[0093] In some respects, the second binding domain that specifically binds to TIGIT comprises a variable heavy chain domain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO: 17. In some respects, the second binding domain that specifically binds to TIGIT comprises a variable light chain domain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the amino acid sequence of SEQ ID NO: 19.

[0094] In some respects, the second binding domain that specifically binds to TIGIT comprises a heavy chain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the amino acid sequence of SEQ ID NO: 18. In some respects, the second binding domain that Petition 870250088197, dated 09 / 29 / 2025, p. 34 / 166 27 / 103 specifically links to TIGIT and comprises a light chain having an amino acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to the amino acid sequence of SEQ ID NO: 20.

[0095] In some respects, the first binding domain that specifically binds to PD-1 comprises a variable heavy chain domain that is encoded by the nucleic acid sequence of SEQ ID NO: 21 and a variable light chain domain that is encoded by the nucleic acid sequence of SEQ ID NO: 23. In some respects, the first binding domain that specifically binds to PD-1 comprises a heavy chain that is encoded by the nucleic acid sequence of SEQ ID NO: 22 and a light chain that is encoded by the nucleic acid sequence of SEQ ID NO: 24.

[0096] In some respects, the first binding domain that specifically binds to PD-1 comprises a variable heavy chain domain that is encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 21 and a variable light chain domain is encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 23.

[0097] In some respects, the first binding domain that specifically binds to PD-1 comprises a heavy chain encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 22 and a light chain is encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 24.

[0098] In some respects, the second binding domain that specifically binds to TIGIT comprises a variable heavy chain domain that is encoded by the nucleic acid sequence of Petition 870250088197, dated 09 / 29 / 2025, page 35 / 166 28 / 103 SEQ ID NO: 25 and a variable light chain domain that is encoded by the nucleic acid sequence of SEQ ID NO: 27. In some respects, the second binding domain that specifically binds to TIGIT comprises a heavy chain that is encoded by the nucleic acid sequence of SEQ ID NO: 26 and a light chain that is encoded by the nucleic acid sequence of SEQ ID NO: 28.

[0099] In some respects, the second binding domain that specifically binds to TIGIT comprises a variable heavy chain domain that is encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 25 and a variable light chain domain that is encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to ID NO: 27.

[00100] In some respects, the second binding domain that specifically binds to TIGIT comprises a heavy chain that is encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 26 and a light chain that is encoded by a nucleic acid sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to SEQ ID NO: 28.

[00101] In some respects, the Fc region is or includes a domain that is one or more of an Fc region of an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD. In some respects, the antibody is an IgG1 antibody. In some respects, the antibody is an IgG2 antibody. In some respects, the antibody is an IgG3 antibody. In some respects, the antibody is an IgG4 antibody.

[00102] In some respects, the bispecific binding protein comprises a variant Fc region. Engineering of the Fc region is widely used in the technique to prolong the half-life of therapeutic antibodies and protect against degradation in vivo. In some respects, the Petition 870250088197, dated 09 / 29 / 2025, p. 36 / 166 29 / 103 The Fc region of an IgG antibody or antigen-binding fragment can be modified in order to increase the affinity of the IgG molecule for the Fc-neonate receptor (FcRn), which mediates IgG catabolism and protects IgG molecules from degradation.

[00103] There are different aspects, a new Fc variant of the relevant specifications comprehend with menus and a selection of 221K, 221Y, 225E, 225K, 225W, 228P, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235E, 235F, 236E, 237L, 237M, 237P, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 243W, 243L, 243Y, 243R, 243Q, 244H, 245A, 247L, 247V, 247G, 250E, 250Q, 251F, 252L, 252Y, 254S, 254T, 255L 256E, 256F, 256M, 257C, 257M, 257N, 262I, 262A, 262T, 262E, 263I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265A, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266I, 266A, 266T, 266M, 267Q, 267L, 268E 269H, 269Y, 269F, 269R, 270E, 280A, 284M, 292P, 292L, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 296G, 297S, 297D, 297E, 298A, 298H, 298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H299F, 299E, 305I, 308F, 313F, 316D, 318A, 318S, 320A, 320S, 322A, 322S, 325Q, 325L, 3251, 325D, 325E, 325A, 325T, 325V, 325H, 326A, 326D, 326E, 326G 326M, 326V, 327G, 327W, 327N, 327L, 328S, 328M, 328D,328E, 328N, 328Q, 328F, 3281, 328V, 328T, 328H, 328A, 329F,329H, 329Q, 330K, 330G, 330T, 330C, 330L, 330Y, 330V, 3301, 330F, 330R, 330H, 331G, 331A, 331L, 331M, 331F, 331W, 331K, 331Q, 331E 331S, 331V, 3311, 331C, 331Y, 331H, 331R, 331N, 331D, 331T 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y 332A, 333A, 333D, 333G, 333Q, 333S, 333V, 334A, 334E, 334H 334L, 334M, 334Q, 334V, 334Y, 339T, 370E, 370N, 378D, 392T, 396L Petition: 870250088197, on September 29, 2025, page. 37 / 166 30 / 103 416G, 419H, 421K, 428L, 428F, 433K, 433L, 434A, 434W, 434Y, 436H, 440Y and 443W conform to their number in the EU como mostrado em Kabat.

[00104] In some respects, the variant Fc region comprises one or more modifications at selected positions of 428 and 434 as numbered by the EU index as shown in Kabat. In some respects, the variant Fc region comprises one or more amino acid substitutions at selected positions of 428 and 434 as numbered by the EU index as shown in Kabat. In some respects, the variant Fc region comprises one or more amino acid substitutions selected from 428L, 428F, 434A, 424F, 434W, and 434Y.

[00105] In some aspects, the variant Fc region of the bispecific binding protein comprises one or more amino acid substitutions at selected positions of 428 and 434 as numbered by the EU index as shown in Kabat. In some aspects, the variant Fc region of the bispecific binding protein comprises one or more amino acid substitutions selected from 428L, 428F, 434A, 424F, 434W, and 434Y. In some aspects, the variant Fc region of the bispecific binding protein comprises a YTE mutation (M252Y / S254T / T256E).

[00106] In some respects, the Fc variant antibody or its binding fragment has reduced antibody-dependent cell-mediated cytotoxicity (ADCC) when administered in vivo. In some respects, the Fc variant antibody or its binding fragment has reduced ADCC compared to an antibody or its binding variant containing a wild-type Fc region. In some respects, the Fc variant antibody or its binding fragment does not trigger ADCC when administered in vivo. In some respects, the Fc variant antibody or its binding fragment causes reduced ADCC when administered in vivo. In some Petition 870250088197, dated 09 / 29 / 2025, page 38 / 166 31 / 103 aspects, the variant Fc antibody or binding fragment thereof having reduced or no ADCC activity comprises the triple mutation (TM) L234F / L235E / P331S in the variant Fc region.

[00107] In some respects, the antibody or binding fragment thereof having reduced CDC activity has reduced toxicity when administered to a subject. In some respects, the antibody or binding fragment thereof having reduced ADCC activity has reduced toxicity when administered to a subject.

[00108] In some respects, the Fc region of the bispecific binding protein is aglycosylated. In some respects, the Fc region of the bispecific binding protein is deglycosylated. In some respects, the Fc region of the bispecific binding protein has reduced fucosylation or is afucosylated.

[00109] In some respects, the bispecific binding protein comprises a constant region of the kappa light chain. In some respects, the bispecific binding protein comprises a constant region of the lambda light chain.

[00110] In some respects, the bispecific binding protein is an antibody. In some respects, the antibody is an IgG antibody. In some respects, the antibody is an IgG1 antibody. In some respects, the antibody is an IgG2 antibody. In some respects, the antibody is an IgG3 antibody. In some respects, the antibody is an IgG4 antibody. In some respects, the antibody is humanized.

[00111] In particular aspects, the invention provides methods for inducing an immune response in a subject, as well as methods for treating or preventing a tumor and / or cancer in a subject through the administration of proteins, nucleic acid molecules and / or compositions to the subject.

[00112] In particular aspects, the invention provides a method of inducing an immune response in a subject, which comprises Petition 870250088197, dated 09 / 29 / 2025, page 39 / 166 32 / 103 administration to the subject of a bispecific protein as described herein. In one aspect, the present invention provides a method for inducing an immune response in a subject comprising administering to the subject a nucleic acid as described herein. In one aspect, a method for inducing an immune response in a subject is provided herein comprising administering to the subject a pharmaceutical composition as described herein.

[00113] In one aspect, the invention provides a bispecific protein as defined herein for use in therapy. In one aspect, the invention provides a bispecific protein as defined herein for use in cancer treatment.

[00114] In one aspect, the invention provides the use of a bispecific protein as defined herein in the manufacture of a medicament for the treatment of cancer.

[00115] In one aspect, the invention provides a nucleic acid as defined herein for use in therapy. In one aspect, the invention provides a nucleic acid as defined herein for use in the treatment of cancer.

[00116] In one aspect, the invention provides the use of a nucleic acid as defined herein in the manufacture of a medicament for the treatment of cancer.

[00117] In some respects, the binding proteins disclosed herein can be formulated with a pharmaceutically acceptable carrier, excipient, or stabilizer as pharmaceutical compositions. In certain respects, such pharmaceutical compositions are suitable for administration to a human or non-human animal via one or more routes of administration using methods known in the art. The term pharmaceutically acceptable vehicle means one or more non-toxic materials that do not interfere with the efficacy of the biological activity of the active ingredients. Such preparations may contain roti Petition 870250088197, dated 09 / 29 / 2025, p. 40 / 166 33 / 103 typically salts, buffering agents, preservatives, compatible carriers and, optionally, other therapeutic agents. Such pharmaceutically acceptable preparations may also contain compatible solid or liquid fillers, diluents or encapsulating substances that are suitable for administration to a human being. Other carriers, excipients and / or additives contemplated, which may be used in the formulations described herein, include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients such as whey albumin, gelatin, casein, salt-forming counterions such as sodium, and the like. These and other known pharmaceutical carriers, excipients and / or additives suitable for use in the formulations described herein are known in the art, for example, as listed in Remington: The Science & Practice of Pharmacy, 2nd ed., Lippincott Williams & Wilkins (2005), and in Physician's Desk Reference, 60th ed., Medical Economics, Montvale, NJ (2005). Pharmaceutically acceptable vehicles may be selected that are suitable for the desired or required route of administration, solubility, and / or stability.

[00118] In some aspects, the amount of bispecific binding protein administered is about 50 mg to about 2000 mg. In some aspects, the amount of bispecific binding protein administered is about 70 mg to about 1500 mg. In some aspects, the amount of bispecific binding protein administered is about 100 mg to about 1400 mg. In some aspects, the amount of bispecific binding protein administered is about 200 mg to about 1250 mg. In some aspects, the amount of bispecific binding protein administered is about 500 mg to about 1000 mg. In some aspects, the amount of bispecific binding protein administered is about 600 mg to about 900 mg. In some Petition 870250088197, dated 09 / 29 / 2025, page 41 / 166 34 / 103 aspects, the amount of bispecific binding protein administered is approximately 700 mg to approximately 800 mg.

[00119] In some respects, the amount of bispecific binding protein administered is approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 725 mg, approximately 750 mg, approximately 775 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1050 mg, approximately 1100 mg, approximately 1150 mg, approximately 1350 mg, approximately 1700 mg, 1200 mg, about 1550 mg, about about 1440 mg, about 1750 mg, 1250 mg, about 1600 mg, about about 1450 mg, about 1800 mg, 1300 mg, about 1650 mg, about about 1500 mg, about 1850 mg, about 1900 mg, about 1950 mg or about 2000 mg.

[00120] In some respects, the amount of bispecific binding protein administered is approximately 70 mg, approximately 150 mg, approximately 210 mg, approximately 450 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1250 mg, or approximately 1500 mg.

[00121] In some aspects, the amount of bispecific binding protein administered is approximately 750 mg. In some aspects, the amount of bispecific binding protein administered is approximately 1500 mg.

[00122] In some aspects, the amount of bispecific binding protein administered is 70 mg, 150 mg, 210 mg, 450 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg or 1500 mg.

[00123] In some aspects, the amount of bispecific binding protein administered is 750 mg. In some aspects, the amount of bispecific binding protein administered is 1500 mg. Petition 870250088197, dated 09 / 29 / 2025, page 42 / 166 35 / 103

[00124] In some aspects, the bispecific binding protein is administered once per treatment cycle. In some aspects, the bispecific binding protein is administered twice per treatment cycle. In some aspects, the bispecific binding protein is administered three times per treatment cycle.

[00125] In some aspects, the treatment cycle is approximately 7 days, 14 days, 21 days, 28 days, or 35 days. In some aspects, the treatment cycle is approximately 7 days. In some aspects, the treatment cycle is approximately 21 days.

[00126] In some aspects, the treatment cycle is repeated for up to about 10 to about 100 cycles. In some aspects, the treatment cycle is repeated for up to about 20 to about 50 cycles. In some aspects, the treatment cycle is repeated for up to about 30 to about 40 cycles. In some aspects, the treatment cycle is repeated for up to 10, 15, 20, 25, 30, 35, 40, 45 or 50 cycles. In some aspects, the treatment cycle is repeated for up to 35 cycles.

[00127] In some respects, bispecific binding protein is administered to the subject as monotherapy or combination therapy. In some respects, bispecific binding protein is administered to the subject as monotherapy.

[00128] In one aspect, the method comprises administering to the subject a therapeutically effective amount of the binding proteins disclosed herein in combination with an additional anticancer compound. In some aspects, the anticancer compound is a small molecule drug. In some aspects, the anticancer compound is pemetrexed, carboplatin, gemcitabine, cisplatin, paclitaxel, or combinations thereof. In some aspects, the binding protein and additional anticancer treatment are administered simultaneously. In some aspects, the binding protein and additional anticancer treatment are not administered simultaneously, but rather during the Petition 870250088197, dated 09 / 29 / 2025, page 43 / 166 36 / 103 same treatment cycle.

[00129] In some respects, bispecific binding protein is suitable for oral administration or parenteral administration, such as subcutaneous, intravenous or intramuscular injection or infusion. In some respects, bispecific binding protein is administered via intravenous (IV) infusion.

[00130] In some respects, the subject has not received a prior line of systemic therapy. In some respects, the subject has received chemotherapy previously. In some respects, the chemotherapy includes platinum-based chemotherapy. In some respects, the prior line of systemic therapy includes checkpoint inhibitor (CPI) therapy.

[00131] In some respects, cancer comprises a cancerous cell that expresses PD-L1. In some respects, cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.

[00132] In some respects, the cancer is non-small cell lung cancer (NSCLC). In some respects, the NSCLC is advanced or metastatic.

[00133] In aspects where the cancer is NSCLC, the subject has a PD-L1 tumor proportion score greater than or equal to 1%. In some aspects where the cancer is NSCLC, the subject has a PD-L1 tumor proportion score greater than or equal to 50%.

[00134] In some respects, the subject never received a checkpoint inhibitor (CPI), meaning that the subject did not previously receive a CPI. Pharmaceutical Compositions

[00135] In some respects, the present invention also provides a Petition 870250088197, dated 09 / 29 / 2025, p. 44 / 166 37 / 103 pharmaceutical composition comprising a bispecific binding protein that specifically binds to PD-1 and TIGIT in an amount of about 70 mg to about 1500 mg. In some aspects, the bispecific binding protein comprising: a) a first binding domain that specifically binds to PD-1, wherein the first binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 1, an HCDR2 having the amino acid sequence of SEQ ID NO: 2 and an HCDR3 having the amino acid sequence of SEQ ID NO: 3, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 4, an LCDR2 having the amino acid sequence of SEQ ID NO: 5 and an LCDR3 having the amino acid sequence of SEQ ID NO: 6;(b) a second binding domain that binds specifically to TIGIT, wherein the second binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 11, an HCDR2 having the amino acid sequence of SEQ ID NO: 12 and an HCDR3 with the amino acid sequence of SEQ ID NO: 13, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 14, an LCDR2 having the amino acid sequence of SEQ ID NO: 15 and an LCDR3 having the amino acid sequence of SEQ ID NO: 16.

[00136] In some aspects, the amount of bispecific binding protein administered is about 50 mg to about 2000 mg. In some aspects, the amount of bispecific binding protein administered is about 70 mg to about 1500 mg. In some aspects, the amount of bispecific binding protein administered is about 100 mg to about 1400 mg. In some aspects, the amount of bispecific binding protein administered is about 200 mg to Petition 870250088197, dated 09 / 29 / 2025, page 45 / 166 38 / 103 approximately 1250 mg. In some aspects, the amount of bispecific binding protein administered is approximately 500 mg to approximately 1000 mg. In some aspects, the amount of bispecific binding protein administered is approximately 600 mg to approximately 900 mg. In some aspects, the amount of bispecific binding protein administered is approximately 700 mg to approximately 800 mg.

[00137] In some respects, the amount of bispecific binding protein administered is approximately 50 mg, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 550 mg, approximately 600 mg, approximately 650 mg, approximately 700 mg, approximately 725 mg, approximately 750 mg, approximately 775 mg, approximately 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1350 mg, about 1700 mg, 1200 mg, about 1550 mg, about about 1440 mg, about 1750 mg, 1250 mg, about 1600 mg, about about 1450 mg, about 1800 mg, 1300 mg, about 1650 mg, about about 1500 mg, about 1850 mg, about 1900 mg, about 1950 mg or about 2000 mg.

[00138] In some respects, the amount of bispecific binding protein administered is approximately 70 mg, approximately 150 mg, approximately 210 mg, approximately 450 mg, approximately 750 mg, approximately 800 mg, approximately 850 mg, approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1250 mg, or approximately 1500 mg.

[00139] In some aspects, the amount of bispecific binding protein administered is approximately 750 mg. In some aspects, the amount of bispecific binding protein administered is approximately 1500 mg.

[00140] In some respects, the amount of bispecific binding protein administered is 70 mg, 150 mg, 210 mg, 450 mg, 750 mg, Petition 870250088197, dated 09 / 29 / 2025, page 46 / 166 39 / 103 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1250 mg or 1500 mg.

[00141] In some aspects, the amount of bispecific binding protein administered is 750 mg. In some aspects, the amount of bispecific binding protein administered is 1500 mg.

[00142] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having the amino acid sequence of SEQ ID NO:9. In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:9.

[00143] In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having the amino acid sequence of SEQ ID NO:8 and a light chain having the amino acid sequence of SEQ ID NO:10. In some respects, the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:8 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:10.

[00144] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having the sequence Petition 870250088197, dated 09 / 29 / 2025, p. 47 / 166 40 / 103 of the amino acids of SEQ ID NO:17 and a variable light chain domain having the amino acid sequence of SEQ ID NO:19. In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:19.

[00145] In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having the amino acid sequence of SEQ ID NO:18 and a light chain having the amino acid sequence of SEQ ID NO:20. In some respects, the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:18 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:20.

[00146] In some respects, the pharmaceutical compositions described in the present invention may be formulated with a pharmaceutically acceptable carrier, excipient, or stabilizer. In certain respects, such pharmaceutical compositions are suitable for administration to a human or non-human animal via one or more routes of administration using methods known in the art. The term pharmaceutically acceptable vehicle means one or more non-toxic materials that do not interfere with the efficacy of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible vehicles, etc. Petition 870250088197, dated 09 / 29 / 2025, page 48 / 166 41 / 103 vehicles and, optionally, other therapeutic agents. Such pharmaceutically acceptable preparations may also contain compatible solid or liquid fillers, diluents or encapsulating substances suitable for administration to a human being. Other vehicles, excipients and / or additives contemplated, which may be used in the formulations described herein, include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients such as whey albumin, gelatin, casein, salt-forming counterions such as sodium and the like. These and other known vehicles, excipients and / or pharmaceutical additives suitable for use in the formulations described herein are known in the art, for example, as listed in Remington: The Science & Practice of Pharmacy, 2nd ed., Lippincott Williams & Wilkins (2005) and in the Physician's Desk Reference, 60th ed., Medical Economics, Montvale, NJ (2005).Pharmaceutically acceptable vehicles may be selected that are suitable for the desired or required mode of administration, solubility and / or stability.

[00147] The present invention further provides a pharmaceutical composition, as defined above, for use in the treatment of cancer. In some respects, the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma and lung cancer. In some respects, the cancer is non-small cell lung cancer (NSCLC). In some respects, the NSCLC is advanced or metastatic. Kits

[00148] In some aspects, the present invention further provides a kit comprising any of the pharmaceutical compositions described above. In some aspects, the kit comprises instructions for Petition 870250088197, dated 09 / 29 / 2025, page 49 / 166 42 / 103 to administer the pharmaceutical composition. In some respects, the kit comprises an additional anticancer agent as described herein. Bispecific Binding Molecule Sequences

[00149] Aspects of the invention include bispecific binding proteins in DuetMab format that bind to PD-1 and TIGIT created using the sequences in Table 1 below. The CDRs in Table 1 are determined based on the system in Kabat. Table 1. Sequences for PD1 / TIGIT Bispecific Bonding Molecules PD1LO115 HCDR1 SEQ ID NO: 1 DYGMH PD1LO115 HCDR2 SEQ ID NO: 2 YISSGSYTIYSADSVKG PD1LO115 HCDR3 SEQ ID NO: 3 RAPNSFYEYYFDY PD1 LO115 LCDR1 SEQ ID NO: 4 SASSKHTNLYWSRHMY PD1 LO115 LCDR2 SEQ ID NO: 5 LTSNRAT PD1 LO115 LCDR3 SEQ ID NO: 6 QQWSSNPFT PD1 LO115 Variable heavy chain SEQ ID NO: 7 EVQLVESGGGLVQPGGSLRLSC AASGFTFSDYGMHWVRQAPGK GLEWVAYISSGSYTIYSADSVKG RFTISRDNAKNSLYLQMNSLRAE DTAVYYCARRAPNSFYEYYFDY WGQGTTVTVSS PD1 LO115 Whole heavy chain SEQ ID NO: 8 EVQLVESGGGLVQPGGSLRLSC AASGFTFSDYGMHWVRQAPGK GLEWVAYISSGSYTIYSADSVKG RFTISRDNAKNSLYLQMNSLRAE DTAVYYCARRAPNSFYEYYFDY WGQGTTVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPPCPAPEFEGGPS VFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVKFNWYVDGVE Petition 870250088197, dated 09 / 29 / 2025, page 50 / 166 43 / 103 LO115 cadeia live value SEQ ID NO: 9 QIVLTQSPATLSLSPGERATLSC SASSKHTNLYWSRHMYWYQQK PGQAPRLLIYLTSNRATGIPARF SGSGSGTDFTLTISSLEPEDFAV YYCQQWSSNPFTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC TIGIT HCDR1 SEQ ID NO: 11 SQNQRPS TIGIT LCDR3 SEQ ID NO: 16 AVWDDIGRVLQ TIGIT cadeia pesada variável SEQ ID NO: 17 QVQLVESGGGVVQPGRSLRLS CAASGFTFSSYAMHWVRQAPG KGLEWVAVISYAGEVKYYADSV KGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCARDPLPLHYYGMDVWGQGTTVTVSS TIGIT heavy chain SEQ ID NO: 18 QVQLVESGGGVVQPGRSLRLS Petition 870250088197, dated 09 / 29 / 2025, p. 51 / 166 44 / 103 da Knob CAASGFTFSSYAMHWVRQAPG KGLEWVAVISYAGEVKYYADSV KGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCARDPLPLHYYGMD VWGQGTTVTVSSASTKGPSVCP LAPSSKSTSGGTAALGCLVKDY FPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVE PKSVDKTHTCPPPCAPEFEGGP SVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNK ALPASIEKTISKAKGQPREPQVY TLPPCREEMTKNQVSLWCLVKG FYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYT QKSLSLSPGK TIGIT variable light chain SEQ ID NO: 19 QSVLTQPPSASGTPGQRVTISC SGSSSNIGRRPVNWYQQLPGTA PKLLIYSQNQRPSGVPDRFSGS QSGTSASLAISGLQSEDEADYFC AVWDDIGRVLQLGGGTQLTVL TIGIT engineered Lambda light chain SEQ ID NO: 20 QSVLTQPPSASGTPGQRVTISC SGSSSNIGRRPVNWYQQLPGTA PKLLIYSQNQRPSGVPDRFSGS QSGTSASLAISGLQSEDEADYFC AVWDDIGRVLQLGGGTQLTVLG QPKAAPSVTLFPPCSEELQANK ATLVCLISDFYPGAVTVAWKADS SPVKAGVE1 1 1 PSKQSNNKYAA SSYLSLTPEQWKSHRSYSCQVT HEGSTVEKTVAPTEVS PD1 LO115 heavy chain variable SEQ ID NO: 21 GAGGTGCAGCTGGGTGGAATCC GGCGGAGGACTGGTGCAGCCT Petição 870250088197, de 29 / 09 / 2025, pág. 52 / 166 45 / 103 GGCGGCTCCCTGAGACTGTCT TGCGCCGCCTCCGGCTTCACA TTCTCCGACTACGGCATGCACT GGGTCCGACAGGCCCCTGGAA AGGGCCTGGAATGGGTGGCCT ACATCTCCTCCGGCTCCTACAC CATCTACTCCGCCGACTCCGT GAAGGGCCGGTTCACCATCTC CCGGGACAACGCCAAGAACTC CCTGTACCTGCAGATGAACTC CCTGCGGGCCGAGGACACAG CCGTGTACTACTGTGCCAGAC GGGCCCCTAACTCCTTCTACG AGTACTACTTCGACTACTGGG GCCAGGGCACCACCGTGACCG TGTCCTCT PD1 LO115 Cadeia pesada inteira SEQ ID NO: 22 GAGGTGCAGCTGGTGGAATCC GGCGGAGGACTGGTGCAGCCT GGCGGCTCCCTGAGACTGTCT TGCGCCGCCTCCGGCTTCACA TTCTCCGACTACGGCATGCACT GGGTCCGACAGGCCCCTGGAA AGGGCCTGGAATGGGTGGCCT ACATCTCCTCCGGCTCCTACAC CATCTACTCCGCCGACTCCGT GAAGGGCCGGTTCACCATCTC CCGGGACAACGCCAAGAACTC CCTGTACCTGCAGATGAACTC CCTGCGGGCCGAGGACACAG CCGTGTACTACTGTGCCAGAC GGGCCCCTAACTCCTTCTACG AGTACTACTTCGACTACTGGG GCCAGGGCACCACCGTGACCG TGTCCTCTGCTAGCACCAAAG GTCCGAGCG 1 1 III CCGCTGG CACCGAGCAGCAAAAGCACCT CTGGTGGCACCGCAGCACTGG GTTGTCTGGTGAAAGATTA T T T Petition 870250088197, of 29 / 09 / 2025, p. 53 / 166 46 / 103 TCCGGAACCGGTTACCG IIICI TGGAATAGCGGTGCCACTGACC AGCGGTGTTCATACC TTT CCG GCAGTTCTGCAGAGCAGCGGT CTGTATAGCCTGTCTAGCGTTG TTACCGTTCCGAGCAGCAGCC TGGGCACCCAGACCTATA iiiG CAATGTGAATCCATAAACCGAGCGAGCAACCAGTTGAAACGTTG TTGAACCGAAAAGCTGTGACAA AACTCACACGTGCCCACCGTG CCCAGCACCTGAGTTCGAGGG GGGACCGTCAGTCTTCCTCTT CCCCCCAAAACCCAAGGACAC CCTCATGATCTCCCGGACCCC TGAGGTCACATGCGTGGTGGT GGACGTGAGCCACGAGGACCAGCAGCAGCCTT GTGGACGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGG GAGGAGCAGTACAACAGCACG TACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGG CTGAATGGCAAGGAGTACAAG TGCAAGGTCCCAACAAAGCC CTCCCAGCCAGCATCGAGAACCAACCAACCAAGA CAGCCCCGAGAACCACAGGTC TGCACCCTGCCCCCATCCCGG GAGGAGATGACCAAGAACCAG GTCAGCCTGAGCTGCGCGGTC AAAGGCTTCTATCCCAGCGAC ATCGCCGTGGAGTGGGAGAGC AATGGGCAGCCGGAGAACAAC TACAAGACCACGCCCCCCCCGGTCCCGGTCCCG TTCCTCGTTAGCAAGCTCACCG TGGACAAGAGCAGGTGGCAGC Petition 870250088197, of 29 / 09 / 2025, p. 54 / 166 47 / 103 AGGGGAACGTCTTCTCATGCT CCGTGATGCATGAGGCTCTGC ACAACCACTACACGCAGAAGA GCCTCTCCCTGTCTCCGGGTA AATGA PD1 LO115 cadeia leve variável SEQ ID NO: 23 CAGATCGTGCTGACCCAGTCC CCTGCCACCCTGTCCCTGAGC CCTGGCGAGAGAGCCACCCTG AGCTGCTCCGCCTCCTCCAAG CACACCAACCTGTACTGGTCC CGGCACATGTACTGGTATCAG CAGAAGCCCGGCCAGGCCCCT CGGCTGCTGATCTACCTGACC TCTAACCGGGCCACCGGCATC CCTGCCAGATTCTCCGGCTCT GGCTCCGGCACCGACTTCACC CTGACCATCTCCAGCCTGGAA CCCGAGGACTTCGCCGTGTAC TACTGCCAGCAGTGGTCCTCC AACCCCTTCACCTTCGGCCAG GGCACCAAGCTGGAAATCAAG PD1 LO115 cadeia leve Kappa do tipo selvagem SEQ ID NO: 24 CAGATCGTGCTGACCCAGTCC CCTGCCACCCTGTCCCTGAGC CCTGGCGAGAGAGCCACCCTG AGCTGCTCCGCCTCCTCCAAG CACACCAACCTGTACTGGTCC CGGCACATGTACTGGTATCAG CAGAAGCCCGGCCAGGCCCCT CGGCTGCTGATCTACCTGACC TCTAACCGGGCCACCGGCATC CCTGCCAGATTCTCCGGCTCT GGCTCCGGCACCGACTTCACC CTGACCATCTCCAGCCTGGAA CCCGAGGACTTCGCCGTGTAC TACTGCCAGCAGTGGTCCTCC AACCCCTTCACCTTCGGCCAG GGCACCAAGCTGGAAATCAAG Petição 870250088197, de 29 / 09 / 2025, pág. 55 / 166 48 / 103 CGTACGGTGGCTGCACCATCT GTCTTCATCTTCCCGCCATCTG ATGAGCAGTTGAAATCTGGAAC TGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAG GCCAAAGTACAGTGGAAGGTG GATAACGCCCTCCAATCGGGT AACTCCCAGGAGAGTGAGCCACA GGAGGAGGAGCGACA ACCTACAGCCTCAGCAGCACC CTGACGCTGAGCAAAGCAGAC TACGAGAAACACAAAGTCTACG CCTGCGAAGTCACCCATCAGG GCCTGAGCTCGCCCGTCACAA AGAGCTTCAACAGGGGAGAGT GTTAG TIGIT heavy chain variable SEQ ID NO: 25 CAGGTGGAGGGGGGGGGGGGGGCT GGGAGGTCCCTGAGACTCTCC TGTGCAGCCTCTGGATTCACCT TCAGTAGCTATGCTATGCACTG GGTCCGCCAGGCTCCAGGCAA GGGGCTGGAGTGGGTGGCAG TTATATCATATGCGGGGGAGG TGAAATACTACGCAGACTCCGT GAAGGGCCGATCCACCCAGATCCA GCTGTATCTCTGCAAATGAACAGC CTGAGAGCTGAGGACACGGCT GTGTATTACTGTGCGAGAGAC CCGCTACCGCTACATTACTACG GTATGGACGTCTGGGGCCAAG GGACCACGGTCACCGTCTCCT CA TIGIT cadeia pesada Knob SEQ ID NO: 26 CAGGTGAGCTGGCGCT GGAGGAGGCGTGGTCCAGCCCT GGGAGGTCCCTGAGACTCTCC Petition 870250088197, of 29 / 09 / 2025, p. 56 / 166 49 / 103 TGTGCAGCCTCTGGATTCACCT TCAGTAGCTATGCTATGCACTG GGTCCGCCAGGCTCCAGGCAA GGGGCTGGAGTGGGTGGCAG TTATATCATATGCGGGGGAGG TGAAATACTACGCAGACTCCGT GAAGGGCCGATTCACCATCTC CAGAGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGC CTGAGAGCTGAGGACACGGCT GTGTATTACTGTGCGAGAGAC CCGCTACCGCTACATTACTACG GTATGGACGTCTGGGGCCAAG GGACCACGGTCACCGTCTCCT CAGCGTCGACCAAAGGTCCGA GCGTGTGCCCGCTGGCACCGA GCAGCAAAAGCACCTCTGGTG GCACCGCAGCACTGGGTTGTC TGGTGAAAGATTA1 III CCGGA ACCGGTTACCG T T T CTTGGAAT AGCGGTGCACTGACCAGCGGT GTTCATACC T T T CCGGCAGTCC TGCAGAGCAGCGGTCTGTATA GCCTGTCTAGCGTTGTTACCGT TCCGAGCAGCAGCCTGGGCAC CCAGACCTATA T T T GCAATGTG AATCATAAACCGAGCAATACCA AAGTTGATAAACGCGTTGAACC GAAAAGCGTGGACAAAACTCA CACGTGCCCACCGTGCCCAGC ACCTGAGTTCGAGGGGGGACC GTCAGTCTTCCTCTTCCCCCCA AAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTC ACATGCGTGGTGGTGGACGTG AGCCACGAAGACCCTGAGGTC AAGTTCAACTGGTACGTGGAC GGCGTGGAGGTGCATAATGCC Petição 870250088197, de 29 / 09 / 2025, pág. 57 / 166 50 / 103 AAGACAAAGCCGCGGGAGGAG CAGTACAACAGCACGTACCGT GTGGTCAGCGTCCTCACCGTC CTGCACCAGGACTGGCTGAAT GGCAAGGAGTACAAGTGCAAG GTCTCCAACAAAGCCCTCCCA GCCAGCATCGAGAAAACCATC TCCAAAGCCAAAGGGCACCAG CGAGATCACCACCTA CTGCCCCCATGCCGGGAGGAG ATGACCAAGAACCAGGTCAGC CTGTGGTGCCTGGTCAAAGGC TTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGG CAGCCGGAGAACAACTACAAG ACACCGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCAGCTCAGTCAGCT AGAGCAGGTGGCAGCAGGGG AACGTCTTCTCATGCTCCGTGA TGCATGAGGCTCTGCACAACC ACTACACGCAGAAGAGCTTAA GCCTGTCTCCGGGTAAATGA TIGIT cadeia leve variavel SEQ ID NO: 27 CAGTCTGTGCTGACTCAGCCT CCCTCAGCCGCCGGGCCATGGCC TGTTCTGGAAGCAGCTCCAATA TCGGAAGGAGGCCTGTAAACT GGTACCAGCAGCTCCCAGGAA CGGCCCCCAAACTCCTCATCT ATAGTCAGAATCAGCGGCCCT CAGGGGTCCCTGACCGATTCT CTGGCTCCCAGTCTGGCACCT CAGCCTCCCTGGCCATCAGTGGGTCGATTGA IICIGI GCAG IIIG GGATGACATCGGCCGCGTCCT GCAGIIAGGCGGAGGCACCCA Petition 870250088197, of 29 / 09 / 2025, p. 58 / 166 51 / 103 GCTGACCGTCCTA TIGIT light chain Lambda engineered SEQ ID NO: 28 CAGTCTGTGCTGACTCAGCCT CCCTCAGCGTCTGGGACCCCC GGGCAGAGGGTCACCATCTCT TGTTCTGGAAGCAGCTCCAATA TCGGAAGGAGGCCTGTAAACT GGTACCAGCAGCCAGCCAGCCCACCATCCATCCATCC ATAGTCAGAATCAGCGGCCCT CAGGGGTCCCTGACCGATTCT CTGGCTCCCAGTCTGGCACCT CAGCCTCCCTGGCCATCAGTG GGCTCCAGTCTGAGGATGAGG CTGATTAI IICIGI GCAG IIIG GGATGACATCGGCCGTCCT GCAGIIAGGCGGAGCCAGCCAGCCAGCCAGCC CAAGGCGGCCCCCICGGICAC ICIGIICCCGCCCIGCICIGA GGAGCIICAAGCCAACAAGGC CACACTGGTGTGTCTCATAAGT GACTTCTACCCGGGAGCCGTG ACAGIGGCCIGGAAGGCAGAI AGCAGCCCCGICAAGGCGGGA GIGGAGACCACCACACCACACACACAACAAGCAAGCAGA CGGCCAGCAGCIACCIGAGCC IGACGCCIGAGCAGIGGAAGI CCCACAGAAGCIACAGCIGCC AGGICACGCAIGAAGGGAGCA CCGIGGAGAAGACAGIGGCCC CIACAGAAGIGICAIGA

[00150] The use of a bispecific anti-TIGIT / anti-PD-1 antibody is an innovative approach to targeting both TIGIT / PD-1 receptors simultaneously. This approach has several potential advantages compared to the co-administration of separate anti-TIGIT and anti-PD-1 / PD-L1 antibodies. In addition to ease of administration Petition 870250088197, dated 09 / 29 / 2025, p. 59 / 166 52 / 103 drug administration (a single administration replacing two administrations), there is certainty of equal biodistribution of a single molecule that targets both receptors. Furthermore, the design of a bispecific antibody allows for two potentially different modes of action, one targeting both receptors in close proximity on the same cell (cis effect) and another targeting two receptors on two neighboring cells with the generation of a prolonged immune synapse simultaneously with checkpoint inhibition (trans effect).

[00151] All references cited herein, including patents, patent applications, articles, textbooks and the like, and the references cited therein, to the extent that they are not already, are incorporated herein by reference in their entirety.

[00152] Without limiting the invention, various aspects of the invention are described herein for illustrative purposes. EXAMPLES

[00153] The following examples are illustrative of specific aspects of the invention and its various uses. They are shown for explanatory purposes only and should not be construed as limiting the scope of the invention in any way.

[00154] AZD2936 is provided for treatment in the Examples. AZD2936 is a humanized, monovalent, bispecific immunoglobulin G (IgG) 1 monoclonal antibody (mAb) with a crystallizable fragment (Fc) domain engineered to reduce the effector function of Fc (triple mutation of IgG1). AZD2936 specifically binds to human T-cell immunoreceptors with immunoglobulin- and tyrosine-based inhibitory motif domains (TIGIT) and to programmed cell death protein 1 (PD-1), which are part of a complex system of cell surface receptors that, when bound to their cognate ligands, provide co-inhibition signals to cells. Petition 870250088197, dated 09 / 29 / 2025, page 60 / 166 53 / 103 T cells to modulate their activity. In preclinical studies, dual blockade of TIGIT and PD-1 by AZD2936 improved human T cell function and promoted antitumor immune responses. AZD2936 is used in the treatment of subjects with advanced or metastatic non-small cell lung cancer (NSCLC) expressing programmed cell death ligand 1 (PD-L1; tumor proportion score [TPS] ^1%). AZD2936 is described in International Patent Application Publication WO2022 / 229919, which is incorporated herein by reference. Example 1: Prediction of TIGIT and PD-1 receptor occupancy for AZD2936 in patients with solid tumors.

[00155] As described in the Examples below, monotherapy with AZD2936 is being investigated at dose levels ranging from 70 to 1500 mg Q3W intravenously. High intratumoral receptor occupancy (RO) in the tumor is believed to be necessary for efficacy in patients. Model simulation can be used to predict the RO for PD-1 and TIGIT at different dose levels and support the recommended phase 2 dose (RP2D) and dose optimization approach for AZD2936.

[00156] The model was developed by connecting a two-compartment pharmacokinetic model representing the clearance and transport of AZD2936 in the central and peripheral compartments, a tumor compartment, and two independent target-mediated drug disposition (TMD) modules in the central and tumor compartments to capture drug concentration and receptor binding dynamics. The parameters of the two-compartment pharmacokinetic model were estimated in a separate population pharmacokinetic analysis. The tumor compartment was considered an effect compartment, which assumes that the distribution of AZD2936 in the tumor does not affect its blood concentration. Petition 870250088197, dated 09 / 29 / 2025, page 61 / 166 54 / 103

[00157] Sensitivity analysis was performed to identify mechanisms that have a significant impact on the intratumoral OR of PD-1 and TIGIT. To predict OR among the patient population, simulations were performed incorporating variability attributed to these mechanisms in addition to pharmacokinetic variabilities. The predicted OR was compared between different dose levels of AZD2936 and with approved anti-PD-1 compounds.

[00158] The model was developed by connecting a two-compartment pharmacokinetic model representing the clearance and distribution of AZD2936 in the central and peripheral compartments, a tumor compartment, and two independent target-mediated drug disposition modules (TMDs) in the central and tumor compartments to capture drug concentration and receptor binding dynamics. The tumor compartment was considered an effect compartment, which assumes that the distribution of AZD2936 in the tumor does not affect its concentration in the blood. The overall scheme of the PK / PD model is shown in FIG. 1. The model was then used to predict the occupancy of PD-1 and TIGIT receptors in both blood and tumor following intravenous administration of AZD2936 at various dose levels.

[00159] PD1 and TIGIT expressions were measured in peripheral blood mononuclear cells (PBMCs). The concentrations of the four receptor types were estimated from PBMC data. First, concentrations of T cells, NK cells, and other PBMCs of PD1+TIGIT+ / PD1+TIGIT / PD1-TIGIT+ receptor expression types were calculated. Analysis of TIGIT PD1 in PBMCs in combination with previous results suggests that a similar number of PD1 or TIGIT receptors are expressed in cells that co-express the same receptors (see Johnston et al., Cancer Cell, 26(6):923-937, 2014). The ratios of initial PD1 and TIGIT concentrations in PD1+TIGIT+ cells Petition 870250088197, dated 09 / 29 / 2025, page 62 / 166 55 / 103 (designated as RAo and RBo), PD1 in cells PD1+TIGIT- (RCo) and TIGIT in cells PD1-TIGIT+ (RDo) were calculated as being 1:1:2:3.

[00160] The receptor concentrations (RAo, RBo, RCo, RDo) in the central compartment were calculated by multiplying the concentrations of PD1+TIGIT+ / PD1+TIGIT- / PD1-TIGIT+ T cells, NK cells, and other PBMCs by the number of receptors per cell, which is assumed to be between 10,000 and 1,000,000. The resulting receptor concentration for PD1 in PD1+TIGIT RA0 cells is 0.001 to 0.1 nM. The other receptor concentrations (RBo, RCo, RDo) were calculated using the aforementioned 1:1:2:3 ratio.

[00161] From the analysis of PBMCs, it can be concluded that approximately 78% of T cells are PD1-TIGIT- in blood PBMCs. Assuming that (i) this percentage is lower in the tumor microenvironment (TME) due to the induction of PD1 / TIGIT expression, (ii) more PD1 receptors per cell are induced in the TME compared to those in blood (M. Mkrtichyan et al., J. Immunol., 189(5): 2338-2347, 2012), and (iii) the ratio of PD1+TIGIT+, PD1+TIGIT-, and PD1-TIGIT+ T cells remains the same as in blood, the percentages of these cell types can be calculated. Total tumor T-cell volume densities can be calculated from area densities (which can be measured through digital pathology from patient tumor samples) using the stereology formula of J.-P. Royet, Progress in Neurobiology, 37(5):433-474, 1991.

[00162] In the analysis dataset for AZD2936, there were 72 patients who received 70 mg, 210 mg, 750 mg, or 1500 mg Q3W. The pharmacokinetics of AZD2936 were reasonably described using a 2-compartment model with first-order elimination. Body weight was applied to pharmacokinetics using an approach of Petition 870250088197, dated 09 / 29 / 2025, page 63 / 166 56 / 103 allometric scale (0.75 in elimination clearance (CL) and intercompartmental clearance (Q); 1 in central distribution volume (CV) and peripheral distribution volume (PV)). Intersubject variability was estimated for CL, CV, and PV. Parameter estimates were CL, 0.392 L / day; CV, 3.63 L; PV, 2.94 L; Q, 0.935 L / day, additive error of 2.11 μg / mL and proportional error of 29.05%.

[00163] AZD2936 dosing was scheduled to be administered as an intravenous infusion every three weeks. Dose levels for simulations were set at 70, 210, 500, 750, and 1500 mg. For each of the four combinations of partition coefficient (PC) and receptor concentration (RC), 1000 virtual patients were simulated.

[00164] Among the 1000 virtual patients, five parameters were sampled using a Latin hypercube sampling (LHS) scheme: RAo,vc, RAo,vt, KintpDi, Keq,AZD2936, and Ql. The parameters were sampled from a lognormal distribution with 95% of values ​​between 1 / 2 and 2 times their respective mean values. In addition to, and independently of, five parameters, VC, VP, and CL were sampled based on estimated intersubject variability (BSV).

[00165] The model was developed in Matlab Simbiology (version 2021b). The simulations were performed on the SCP cluster using Matlab (version 2019b). Results

[00166] Sensitivity analysis was performed to evaluate the relative impact of key parameters on predicting tumor receptor occupancy. From this analysis, in the dose ranges most likely to achieve full receptor occupancy (750 and 1500 mg), the predicted tumor receptor occupancy of PD-1 and TIGIT is more sensitive to the tumor partition coefficient (TPC), which determines the amount Petition 870250088197, dated 09 / 29 / 2025, page 64 / 166 57 / 103 of the drug that can penetrate tumor tissue (i.e., tumor penetration) and the initial receptor (CR) concentration in the tumor microenvironment. They are also sensitive to internalization rates and the equilibrium rate constant.

[00167] In these four parameters, PC and RC are highly variable among the patient population, while internalization rates and the equilibrium rate constant are informed by internal knowledge and the literature with some level of uncertainty. Without sufficient information to assign a probability distribution for PC and RC in patients, four groups were examined, consisting of combinations using high and low PC and RC values. For kint,PD1 and keq,AZD2936, the groups sampled them from a distribution as described in section 2.5 to reflect the best knowledge while considering uncertainty in the values.

[00168] Virtual patients were divided into 4 subgroups, high PC, low CR, high PC, high CR, low PC, low CR and low PC, high CR when predicting receptor occupancy, based on their tumor penetration (PC = 5% or 50%) and tumor CR (3 nM or 30 nM for PD-1; 4 nM or 40 nM for TIGIT, which can be calculated using RAo,vt = 1 or 10 nM, ψBA = 1, ψCA = 2, ψDA = 3). High / low tumor PD-1 / TIGIT receptor concentrations were calculated based on the assumption that the number of receptors per cell is 100,000, the T cell area density in the tumor varies from 400 to 4,000 cells / mm2, and that the ratio between PD-1+TIGIT+ / PD-1+TIGIT- / PD-1-TIGIT+ cells remains the same between peripheral and tumor cells. 50% in the high PC group were supported by experimental investigations using radiolabeled mAbs that measured tumor uptake.Since these data lack sufficient granularity to quantitatively describe the spatial heterogeneity of mAb concentrations within a tumor lesion, a study... Petition 870250088197, dated 09 / 29 / 2025, pp. 65 / 166 A conservative approach of 58 / 103 was applied to approximate the scenario in the low PC group and resulted in ~5% tumor concentration relative to blood (TR, Li et al., Clinical Pharmacology & Therapeutics, 110(1):200-209, 2021). High / low tumor PD-1 / TIGIT receptor concentrations were calculated based on the assumption that the number of receptors per cell is 100,000, the density of T cells in the tumor varies from 500 to 5,000 cells / mm2, and that the ratio of PD-1+TIGIT+ / PD-1+TIGIT- / PD-1-TIGIT+ cells remains the same between peripheral and tumor cells.

[00169] The model predicts receptor occupancy > 90% for both PD-1 and TIGIT in blood throughout the dosing range in > 90% of patients starting with a 70 mg dose, regardless of patient subgroups. The predicted PD-1 and TIGIT receptor occupancy in the tumor microenvironment following intravenous administration of AZD2936 at 70, 210, 750, and 1500 mg Q3W is shown in FIG. 1 and Table 2. Doses of 70 and 210 mg Q3W are likely to show suboptimal receptor occupancy (particularly PD-1) in patients with low tumor partition coefficient (i.e., low drug penetration into the tumor). The 750 mg Q3W dose level is predicted to achieve intratumoral receptor occupancy of > 90% in most patients across a broad spectrum of conditions. The 1500 mg Q3W dose level is predicted to achieve better receptor occupancy than 750 mg Q3W, especially in the low CP, high RC group. Table 2. Results of Receptor Occupancy Modeling Dose de AZD2936 A1 70 mg A2 210 mg A3 750 mg A4 1500 mg PC alta, RC baixa PD-1 % RO > 90% > 90% > 90% > 90% > 90% TIGIT % RO > 90% > 90% > 90% > 90% > 90% PC alta, RC alta Petição 870250088197, de 29 / 09 / 2025, pág. 66 / 166 59 / 103 Dose de AZD2936 A1 70 mg A2 210 mg A3 750 mg A4 1500 mg PD-1 % RO > 90% 74,2% > 90% > 90% > 90% TIGIT % RO > 90% > 90% > 90% > 90% > 90% PC baixa, RC baixa PD-1 % RO > 90% < 1% 49.5% > 90% > 90% TIGIT % RO > 90% 86,6% > 90% > 90% > 90% PC baixa, RC alta PD-1 % RO > 90% < 1% 9,7% 78,5% > 90% TIGIT % RO > 90% 8,2% 54,1% > 90% > 90%

[00170] The predicted RO for PD-1 in the tumor from different dose levels of AZD2936 was compared with that of other anti-PD-1 drugs (i.e., nivolumab and pembrolizumab). The comparison was performed under the same four PC / RC combination scenarios. Binding affinity and population pharmacokinetic parameters for nivolumab and pembrolizumab were obtained from the literature and regulatory reports listed below, while the remaining parameters and system variabilities remained the same as in the simulations with AZD2936.

[00171] Using 240 mg Q2W for nivolumab and 200 mg Q3W for pembrolizumab, the simulation shows that the PD-1 tumor RO is maintained above 90% at the minimum concentration in all four patient groups. With AZD2936, the 210 mg Q3W dose is predicted to have suboptimal receptor occupancy in patients with low tumor partition coefficient compared to nivolumab and pembrolizumab in the same virtual patient group. SUMMARY

[00172] TIGIT and PD1 receptor occupancy in blood and tumor was predicted when virtual patients were treated with AZD2936. The conclusions of this analysis are: Petition 870250088197, dated 09 / 29 / 2025, page 67 / 166 60 / 103 • The model predicts receptor occupancy > 90% for both PD-1 and TIGIT in blood throughout the dosing range in > 90% of patients starting with a 70 mg dose, regardless of patient subgroups. • Sensitivity analysis shows that tumor OR is significantly affected by tumor penetration and receptor concentration, which are highly variable in different patients. Due to a lack of data on the probability distribution of these two parameters among patients, tumor OR under different dose levels in each subgroup was evaluated. • Doses of 70 and 210 mg Q3W predict suboptimal PD-1 receptor occupancy in patients with low tumor penetration. The 750 mg Q3W dose level is predicted to achieve >90% intratumoral receptor occupancy in most patients across a broad spectrum of conditions. The 1500 mg Q3W dose level is predicted to achieve better receptor occupancy than 750 mg Q3W, especially in patients with low tumor penetration and high receptor concentration. Example 2: Study Design and Definitions

[00173] Multiple malignant solid tumors, including NSCLC, are considered sensitive to immune checkpoint blockade. However, subjects who initially respond to immuno-oncology (IO) therapy may experience disease progression due to primary or secondary resistance mediated by multiple mechanisms such as T-cell exhaustion, insufficient T-cell initiation, and abnormal antigen presentation, and TIGIT has been identified as a key inhibitor of antitumor responses that can hinder multiple steps of the cancer immunity cycle. In vitro and in vivo studies have demonstrated the ability of AZD2936 to inhibit the binding of TIGIT and PD-1 to their primary ligands (CD155 and PD-L1, respectively), thus Petition 870250088197, dated 09 / 29 / 2025, pp. 68 / 166 61 / 103 promoting better immune-mediated antitumor responses compared to targeting PD-1 alone. Therefore, targeting both PD-1 and TIGIT with AZD2936 provides clinical benefit to subjects with advanced or metastatic NSCLC.

[00174] FIG. 2 shows a study flowchart of the study described in the Examples below. The study is a first-time human (FTIH), open-label, multicenter, multipart, dose-escalation and expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of AZD2936 in adult subjects with unresectable stage III or stage IV NSCLC.

[00175] Each of Parts A through D of the study includes a screening period, which runs from Day -28 to Day -1. Screening includes a consultation with a medical professional, i.e., V1. During the screening period, subjects are assessed, which may include recording medical history, performing a physical examination, blood and urine tests for safety, biomarker assessment, and tumor tissue collection.

[00176] As shown in the diagram in FIG. 2, Part A through Part D is a sequential treatment study with 4 parts, without masking.

[00177] Part A evaluates dose escalation of AZD2936 in subjects who have already received second-line or higher (2L+) checkpoint inhibitors (CPIs) with unresectable stage III or stage IV NSCLC whose tumors express TPS PD-L1 > 1% and with primary or secondary resistance to a regimen including CPIs in order to determine a maximum tolerated dose (MTD), an optimal biological dose (OBD) or a maximum viable dose (MFD), and a recommended Phase II dose (RP2D). Dose escalation follows the modified toxicity likelihood range-2 (mTPI-2) algorithm consisting of up to 12 subjects per dose level. Intermediate dose levels Petition 870250088197, dated 09 / 29 / 2025, p. 69 / 166 62 / 103 rivers are explored if justified by emerging safety, pharmacokinetic (PK), pharmacodynamic, biomarker, and response data. Subjects are assessed for dose-limiting toxicities (DLTs) during a 21-day DLT assessment period.

[00178] Parts BD are initiated once MTD, OBD, or MFD and a RP2D are established in Part A (dose escalation). Parts B and C evaluate the safety, tolerability, and antitumor activity of AZD2936 at the RP2D determined during Part A (dose escalation) in 2 cohorts.

[00179] Part B (dose expansion) is performed in subjects who have already received 2L+ CPI with unresectable stage III or stage IV NSCLC whose tumors express TPS PD-L1 > 1%. The subject criteria are the same as in Part A (dose escalation), including both subjects who have already received primary and secondary CPI.

[00180] Part C (dose expansion) is performed in subjects who have never received IPC with stage IV NSCLC, whose tumors express TPS PD-L1 > 1%.

[00181] Part D incorporates a randomized design that evaluates the safety, tolerability, and antitumor activity of AZD2936 at 750 mg and 1500 mg Q3W. Part D is designed to assess whether a dose efficacy plateau is achieved at 750 mg Q3W and to allow selection of the optimal dose for exploration in future studies. Part D is run in parallel with Part C, where that cohort is already open, or Part D replaces Part C, where that cohort is not yet open. Part D (dose expansion) is performed in subjects who have never received CPI with stage IV NSCLC whose tumors express TPS PD-L1 > 50%. Subjects are randomized 1:1 to AZD2936 750 mg Q3W (RP2D) or AZD2936 1500 mg Q3W. Petition 870250088197, dated 09 / 29 / 2025, p. 70 / 166 63 / 103

[00182] Definitions - The terms that follow are used in the study described in the Examples below.

[00183] Dose-Limiting Toxicity (DLT). DLTs will be assessed during Part A (dose escalation). The DLT assessment period will be 21 days from the first dose of AZD2936 on Day 1 of Cycle 1. A DLT will be defined during Part A (dose escalation) as any toxicity > Grade 3 that occurs during the DLT assessment period, with modifications or exceptions. Toxicity that is clearly attributable to the primary disease, other concomitant medications, processes related to the disease under investigation, or other etiology unrelated to the drug (not related to study intervention treatment) is excluded from this definition. All DLTs must be documented as adverse events. All adverse events will be classified according to NCI CTCAE v5.0.

[00184] Maximum Tolerated Dose (MTD). The MTD will be selected from all tested dose levels that have not been previously declared unsafe with a DU (current dose is unacceptably toxic) decision, according to the mTPI-2 algorithm. With this restriction, the MTD will be determined as the dose level with the DLT estimate closest to the target toxicity level of 30%.

[00185] In the case of dose levels with estimated toxicity equidistant (tied dose levels) from the target toxicity of 30%, the following approach will be used (Ji, Y. et al., A modified toxicity probability interval method for dose-finding trials, Clin Trials, 2010, 7(6):653-63): among all tied dose levels, the highest dose level with target toxicity < 30% will be selected, unless all tied dose levels have estimated toxicity > 30%, in which case the lowest dose level will be selected.

[00186] Efficacy Assessments. Tumor response will be evaluated. Petition 870250088197, dated 09 / 29 / 2025, page 71 / 166 64 / 103 by RECIST v1.1 (Eisenhauer et al., 2009) according to the schedule (Q9W [± 7 days] for 54 weeks, then Q18W [± 14 days] relative to the date of the first dose [Cycle 1 Day 1] until disease progression or initiation of other anticancer therapy).

[00187] Tumor Assessment. Tumor assessments will include physical examination and cross-sectional imaging using computed tomography (preferred) or magnetic resonance imaging. Chest computed tomography and computed tomography or magnetic resonance imaging of the abdomen and pelvis will be performed at screening (with contrast unless the subject has documented intolerance). The preferred method for assessing systemic disease is contrast-enhanced CT; if contrast-enhanced CT is contraindicated, non-contrast CT is preferred over MRI. The preferred method for brain imaging is MRI rather than CT (with contrast unless the subject has documented intolerance). The preferred method for bone imaging is bone scintigraphy. At screening, bone imaging is applicable only to subjects who have a clinical suspicion of or confirmed bone metastases.Follow-up brain and bone imaging is necessary as clinically indicated if there is no metastasis at baseline, and with each restaging if brain or bone metastases at baseline are present. The same method should be used for all subsequent tumor assessments. Pre-baseline tumor assessments may also be requested, if available, provided these examinations were performed 6 months prior to the start of treatment. Circulating tumor deoxyribonucleic acid (ctDNA) and tumor antigen markers will be used, when available, as exploratory markers in assessing disease response.

[00188] Performance Status of the Eastern Cooperative Oncology Group. The ECOG's performance status will be assessed at specific times. Petition 870250088197, dated 09 / 29 / 2025, page 72 / 166 65 / 103

[00189] Adverse Events. An adverse event (AE) is the development of any undesirable medical occurrence in a patient or clinical study subject who has been administered a medication and which does not necessarily have a causal relationship with that treatment. An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom (e.g., nausea, chest pain) or illness temporarily associated with the use of a medication, whether or not it is considered related to the medication.

[00190] The term AE is used to include both serious and non-serious AEs and may include the deterioration of a pre-existing medical condition. An AE can occur at any time, including adaptation or clearance periods, even if no Study treatment has been administered.

[00191] Serious Adverse Events. A serious adverse event (SAE) is an AE that occurs during any phase of the study (i.e., fitting, treatment, clearance, follow-up phase) and that meets one or more of the following criteria: (1) Results in death; (2) Is immediately life-threatening; (3) Requires hospitalization of the subject or prolongation of existing hospitalization; (4) Results in persistent or significant disability or incapacity; (5) Is a congenital anomaly or birth defect; (6) Is a major medical event that may put the subject at risk or may require medical treatment to prevent one of the outcomes listed above.

[00192] Disease Progression. Disease progression can be considered as a worsening of a subject's condition attributable to the disease for which the experimental product is being studied. It may be an increase in the severity of the disease under study and / or an increase in the symptoms of the disease. The development of new metastases or progression of existing metastases to the primary cancer under study. Petition 870250088197, dated 09 / 29 / 2025, page 73 / 166 66 / 103 should be considered as disease progression and not an adverse event (AE). Events that are unequivocally due to disease progression should not be reported as AEs during the study.

[00193] New Cancers. The development of a new cancer should be considered an SAE. New primary cancers are those that are not the primary reason for administering the study intervention and were identified after the subject's inclusion in this study. They do not include metastases from the original cancer. Example 3: Formulation and administration of AZD2936

[00194] This example shows the formulation and administration of AZD2936. AZD2936 is supplied in Parts A - Part D as a lyophilized or liquid product.

[00195] Lyophilized AZD2936 is supplied in glass vials as a sterile, white to off-white lyophilized product with a nominal fill volume of 5.0 mL for infusion after reconstitution. Each vial contains 250 mg (nominal) of new active agent. Following reconstitution with 5.0 mL of sterile water for injection (sWFI), each vial contains 50 mg / mL of AZD2936. The reconstituted solution should be clear to opalescent, colorless to slightly yellow, and free from visible particles. After reconstitution with sWFI, AZD2936 is further diluted in 0.9% (w / v) saline solution.

[00196] AZD2936 liquid is supplied in glass vials as a sterile solution with a nominal fill volume of 15.0 mL for infusion. Each vial contains 750 mg (nominal) of the novel active agent.

[00197] AZD2936 product vials are stored in a way that prevents exposure to light. Experimental product vials are stored at 2°C to 8°C (36°F to 46°F) until ready for use. Petition 870250088197, dated 09 / 29 / 2025, page 74 / 166 67 / 103

[00198] AZD2936 is administered via intravenous infusion.

[00199] The dose of AZD2936 for administration is prepared using aseptic technique. The total time from needle puncture of the AZD2936 vial to the start of administration should not exceed 24 hours between 2°C and 8°C (36°F and 46°F) or should not exceed 4 hours at room temperature up to 25°C (77°F). The standard infusion time for AZD2936 is over 1 hour (up to a total of 90 minutes); however, if there are interruptions during the infusion, the total permitted infusion time should not exceed 4 hours at room temperature. No other medication is co-administered through the same infusion line. If the preparation time or infusion time exceeds the time limits, a new dose is prepared from new vials. AZD2936 contains no preservatives.

[00200] Doses administered using intravenous bags are prepared as follows: AZD2936 doses between 70 mg and 1500 mg are administered using an intravenous bag containing 0.9% (w / v) saline solution, with a final AZD2936 concentration ranging from 1 to 24 mg / mL, and administered through an intravenous administration set with a 0.2 or 0.22 µm filter. The required volume of AZD2936 (in mL) added to the intravenous bag for each dose level is calculated as follows: Nominal dose (mg) Drug Product Volume (mL) =----------—:--'}50 mg / mL where 50 mg / mL is the nominal drug concentration of AZD2936. Example 4: Initial risk / benefit assessment

[00201] Studies are conducted to evaluate the risk of administering AD2936 and to provide the appropriate dose of AZD2936 for Parts A through D.

[00202] First, an initial dose of FTIH based on the no-observed-adverse-effect level (NOAEL) was identified as 70 mg for a human based on a toxicological study by Boas Petition 870250088197, dated 09 / 29 / 2025, page 75 / 166 68 / 103 Laboratory practices in cynomolgus monkeys.

[00203] An initial risk assessment was then conducted based on the identified starting dose of 70 mg with dose escalation. A total of 64 2L+ subjects with NSCLC received AZD2936 therapy in 5 dose cohorts: Cohort A1, 70 mg (4 subjects), Cohort A2, 210 mg (11 subjects), Cohort A3, 750 mg (13 subjects), Cohort A4, 1500 mg (7 subjects), and Cohort B, 750 mg (29 subjects).

[00204] The results of this initial evaluation show that AZD2936 was well tolerated at all doses evaluated (up to and including 1500 mg Q3W). The safety profile of AZD2936 is similar at all dose levels and no DLTs were reported up to and including the 1500 mg Q3W regimen, and therefore the MTD has not yet been reached during dose escalation. Additional safety evaluations were performed and are described below.

[00205] Preliminary signs of efficacy were observed in initial cohorts of 46 2L+ subjects with NSCLC, with 2 subjects achieving a partial response (one subject [9.1%] in Cohort A2 and one subject [8.3%] in Cohort A3). A total of 16 subjects achieved stable disease at > 8 weeks; of these, 9 subjects (75%) were from Cohort A3 and treated with AZD2936 750 mg Q3W.

[00206] Preliminary pharmacokinetic data were evaluated using non-compartmental analysis in 32 subjects who received AZD2936 monotherapy at doses of 70, 210, 750, and 1500 mg Q3W in the dose-escalation portion of this study. Systemic exposure to AZD2936 above 70 to 1500 mg increases in a nearly dose-proportional manner. No target-mediated drug disposition was observed at dose levels of 70, 210, 750, and 1500 mg Q3W. Following a single IV dose administration, AZD2936 levels declined in a biphasic manner with a mean terminal elimination half-life (t1 / 2) of approximately 8 to 9 days. The state of Petition 870250088197, dated 09 / 29 / 2025, page 76 / 166 Equilibrium is reached approximately in cycle 3, with minimal AZD2936 accumulation observed following repeated doses, with the average accumulation ratio ranging from 1.14 to 1.3 for Cmax.

[00207] Based on the clinical samples analyzed in this study, AZD2936 achieves > 90% PD-1 and RO TIGIT in peripheral T cells at all dose levels up to and including 1500 mg and predicted PK / PD shaping doses > 750 mg to achieve optimal intratumoral RO PD-1 and TIGIT (> 90%). Example 5: study subjects

[00208] This Example provides criteria for selecting subjects for the study of Part A through Part D.

[00209] Inclusion criteria for Part A-Part D: 1. Be 18 years of age or older when enrolled in the study. 2. Histologically or cytologically documented squamous / non-squamous NSCLC not amenable to curative surgery or radiation as defined below (according to the 8th edition of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology): Part A and Part B: Unresectable stage III and squamous / non-squamous stage IV NSCLC. Part C and Part D: only squamous / non-squamous NSCLC stage IV. 3. PD-L1 documented by IHC PD-L1 meeting the criteria below: Part A: PD-L1 TPS > 1% per local report. Part B: PD-L1 TPS > 1% per local report. Part C: PD-L1 TPS > 1% per local report. Part D: PD-L1 TPS > 50% per local report. Part C: must meet one of the definitions below: (i) No prior treatment for NSCLC, eligible Petition 870250088197, dated 09 / 29 / 2025, p. 77 / 166 70 / 103 for monotherapy with PPC due to high PD-L1 expression (TPS > 50%) and no need for rapid disease control through a chemotherapy-containing regimen, or (ii) No prior treatment for NSCLC and ineligible for or not consenting to a platinum-based chemotherapy or combination regimen, or (iii) Prior treatment for NSCLC with a chemotherapy-only regimen. Part D: must meet one of the definitions below: (iv) No prior treatment for NSCLC and not requiring rapid disease control through a chemotherapy-containing regimen, or (v) Prior treatment for NSCLC with a chemotherapy-only regimen. 5. Body mass index > 17. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of registration. 7. Projected life expectancy of > 12 weeks. 8. Must have at least one measurable lesion according to RECIST v1.1. (a) For subjects who underwent biopsies during screening and / or treatment, the lesion that was biopsied must be different from any lesion used in the RECIST v1.1 assessment. 9. Adequate organ and bone marrow function measured in the 28 days prior to the first dose. Details of the criteria are shown in Table 3. Petition 870250088197, dated 09 / 29 / 2025, page 78 / 166 71 / 103 Table 3. Criteria for Adequate Organ and Bone Marrow Function Type Parameter Value Hematological Hemoglobin > 9.0 g / dL (5.59 mmol / L) without any blood transfusions (red blood cell concentrate) within 28 days before the first dose Absolute neutrophil count > 1.5 x 10⁹ / L (1,500 per mm³) Platelet count > 100 x 10⁹ / L (100,000 per mm³) without any platelet transfusions within 28 days before the first dose Hepatic Total bilirubin < 1.5 x ULN in the absence of Gilbert's syndrome < 3 x ULN if the participant has Gilbert's syndrome Alanine transaminase and aspartate transaminase < 3 x ULN < 5 x ULN in the case of metastasis to the liver Renal Creatinine clearance calculated by modified Cockcroft-Gault (Rostoker et al., 2007) > 45 mL / minute Example 6: Dose escalation of Part A

[00210] This Example describes the dose escalation study of Part A to determine the AZD2936 dosage for Parts B and C.

[00211] The main objectives of the Part A dose escalation include evaluating safety and tolerability, characterizing DLTs, and determining the MTD, OBD or MFD, and RP2D of AZD2936 in subjects who have already received 2L+ CPI with unresectable stage III / IV NSCLC with Petition 870250088197, dated 09 / 29 / 2025, page 79 / 166 72 / 103 PD-L1 (TPS > 1% using an immunohistochemistry (IHC) assay for PD-L1). Outcomes include the percentage of subjects with adverse events (AEs) and immune-mediated AEs (iAEs), serious AEs (SAEs), DLTs, abnormal vital signs and laboratory parameters; and the discontinuation rate of AZD2936 due to toxicity.

[00212] Secondary endpoints of Part A dose escalation include determining the preliminary antitumor activity of AZD2936 in subjects who have already received 2L+ CPI with unresectable stage III / IV NSCLC with PD-L1 TPS > 1%. Outcomes include, according to RECIST v1.1: ORR, disease control rate (DCR), duration of response (DoR), and durable response rate (DRR).

[00213] The secondary objectives of the Part A dose escalation also include assessing the target engagement of AZD2936 in peripheral blood. Outcomes include measuring the TIGIT and PD-1 receptor (RO) occupancy in peripheral blood T cells.

[00214] For all Part A - Part D, secondary objectives include evaluating the compatibility of the pharmacokinetic (PK) profile of AZD2936 with Q3W dosing in subjects who received 2L+ CPI and subjects who never received CPI with unresectable stage III / IV NSCLC. Outcomes include serum concentrations and PK parameters (when applicable) of AZD2936; PK parameters to be evaluated include, but are not limited to, maximum observed concentration (Cmax), area under the concentration-time curve (AUC), clearance, and terminal elimination half-life (t1 / 2).

[00215] For all Part A - Part D, secondary objectives also include assessment of the immunogenicity of AZD2936. Outcomes include the incidence of antidrug antibodies (ADAs) against AZD2936 in serum.

[00216] Following an mTPI-2 dose escalation design up to 6 dose levels, subjects were enrolled in Part A. Petition 870250088197, dated 09 / 29 / 2025, page 80 / 166Dose escalation to the next dose level is conducted using the mTPI-2 algorithm with a target DLT rate of 30% and an equivalence interval (25%, 35%). A minimum of 3 subjects had to complete the DLT assessment period before making an escalation decision. Dose escalation consists of at least 3 planned dose levels of AZD2936. Intermediate dose levels may be explored if justified by emerging safety, pharmacokinetic, pharmacodynamic, biomarker, and efficacy data. Dose escalation and reduction recommendations followed the mTPI-2 algorithm. The mTPI-2 algorithm employs a simple beta-binomial Bayesian model. The prior distribution for all dose levels is Beta(1,1). The posterior density of toxicity probability is divided into multiple intervals of equal length. These intervals are categorized as underdosing, adequate dosing, and overdosing in terms of toxicity.The underdosing interval corresponds to a dose escalation, overdosing corresponds to a dose reduction, and the appropriate dosage corresponds to maintaining the current dose. Given an interval and a probability distribution, the unit probability mass of that interval is defined as the probability of the interval divided by the interval duration. The design for the dose escalation phase of the study uses a target DLT rate of 30% and an equivalence interval (25%, 35%) for dose escalation / reduction decisions, as well as for MTD determination. A dose level will be considered unsafe, with no additional subjects enrolled at that dose level, if it has an estimated probability of 95% or greater of exceeding the target DLT rate of 30% (i.e., Probability [DLT > 30% of data] > 95%) with at least 3 subjects treated and evaluated at that dose level.

[00217] In Part A, four dose levels of 70 mg, 210 mg, 750 mg and 1500 mg were used. Petition 870250088197, dated 09 / 29 / 2025, page 81 / 166 74 / 103

[00218] After an initial screening period of up to 28 days, the Part A intervention period was scheduled. The Part A intervention period includes a maximum of 35 cycles, with each cycle lasting 21 days, and AZD2936 is administered every three weeks (Q3W), i.e., once every 21-day cycle.

[00219] Eligible subjects receive AZD2936 Q3W administered by intravenous (IV) infusion at the selected dose starting on Day 1 of Cycle 1 for a maximum of 35 cycles. Subjects are treated with the study intervention until disease progression, unacceptable toxicity, investigator decision, completion of the maximum 35 treatment cycles, or withdrawal of consent. All subjects are followed for survival until the end of the study. No dose reductions of AZD2936 are permitted at any time.

[00220] After the invention period, subjects are further assessed for disease progression, final treatment status and follow-up status.

[00221] Current data obtained during Part A show that preliminary pharmacokinetics were nearly dose-proportional (70, 210, 750, and 1500 mg Q3W), with limited ADA impact. While in peripheral blood all tested doses of AZD2936 achieved >90% RI for PD-1 and TIGIT. Of the doses tested in dose escalation, 750 mg Q3W was estimated to be the lowest dose to achieve >90% intratumoral receptor occupancy for PD-1 and TIGIT in most subjects across a broad spectrum of conditions. Based on PK / PD modeling analysis and the emerging safety profile of AZD2936, 750 mg Q3W was identified as the RP2D for further evaluation in the expansion phase of this study (Parts B and C). Example 7: Dose expansion of part B

[00222] The study phase of Part B in this Example was conducted using a 750 mg dose of AZD2936 to study the expansion Petition 870250088197, dated 09 / 29 / 2025, page 82 / 166 75 / 103 dose.

[00223] The BD Parts (dose expansion) are initiated after the establishment of the MTD, OBD or MFD and the RP2D in Part A (dose escalation).

[00224] The primary objectives of the Part B dose expansion phase include evaluating the safety and tolerability of AZD2936 in RP2D in subjects who have previously received 2L+ CPI with unresectable stage III / IV NSCLC with PD-L1 TPS > 1%. Outcomes include the percentage of subjects with adverse events and AEMIs, SAEs, DLT-like events, abnormal vital signs and laboratory parameters; and the AZD2936 discontinuation rate due to toxicity.

[00225] The primary objectives of the Part B dose expansion also include determining the preliminary antitumor activity of AZD2936 in RP2D in subjects who have already received 2L+ CPI with unresectable stage III / IV NSCLC with PD-L1 (TPS > 1% using the PD-L1 IHC assay). Outcomes include the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

[00226] Secondary objectives of the Part B dose expansion include determining the preliminary antitumor activity of non-RP2D AZD2936 in subjects who have already received 2L+ CPI with unresectable stage III / IV NSCLC with PD-L1 TPS > 1%. Outcomes include, according to RECIST v1.1: DCR, DoR, DRR, and progression-free survival (PFS).

[00227] The secondary objectives of Part B also include evaluating the target engagement of AZD2936 in RP2D in peripheral blood. Outcomes include measuring the RO of TIGIT and PD-1 in peripheral blood T cells.

[00228] A sample size of at least 30 subjects was required. Petition 870250088197, dated 09 / 29 / 2025, page 83 / 166 76 / 103 were collected to obtain a preliminary ORR with a standard error (SE) of no more than 0.1. Two-sided 80% confidence intervals (CIs) are provided below using the Clopper-Pearson method for a range of possible response rates in 30 subjects: TRO of 3% (1 / 30 responses); CI of 80% [0.4%, 12%], TRO of 7% (2 / 30 responses); CI of 80% [2%, 17%], TRO of 10% (3 / 30 responses); CI of 80% [4%, 21%], TRO of 13% (4 / 30 responses); CI of 80% [6%, 25%], ORR of 20% (6 / 30 responses); CI of 80% [11%, 32%].

[00229] Based on a decision framework (Frewer, P. et al., Decision-making in early clinical drug development, Pharm. Stat., 2016, 15(3):255-63) with a target value (TV) of 15% in ORR, it is concluded that there is no evidence of target activity if an objective RECIST response < 1 (confirmed complete response [CR] or partial response [PR]) is observed (observed ORR < 3%). If the actual response rate is 15%, the chance of observing < 1 response in 30 evaluable subjects is < 10%.

[00230] Based on PK / PD modeling analysis and the emerging safety profile of AZD2936, 750 mg Q3W was identified as the RP2D for further evaluation in the Part B and Part C expansion phase.

[00231] After the screening period of up to 28 days, the Part B intervention period was scheduled. The Part B intervention period includes a maximum of 35 cycles, each cycle includes 21 days, and AZD2936 is administered every three weeks (Q3W), i.e., once every 21-day cycle.

[00232] In particular, eligible subjects receive AZD2936 Q3W administered by intravenous (IV) infusion in RP2D (750 mg Q3W) starting on Day 1 of Cycle 1 for a maximum of 35 cycles. Subjects are treated with study intervention until disease progression, toxicity Petition 870250088197, dated 09 / 29 / 2025, p. 84 / 166 77 / 103 unacceptable risk, researcher's decision, completion of the maximum of 35 treatment cycles or withdrawal of consent.

[00233] After the intervention period, subjects are further assessed regarding disease progression, treatment completion status, and follow-up status. Example 8: Preliminary results for Part A and Part B

[00234] Eighty-three subjects were evaluated in Part E and Part B of the study described in the Examples above.

[00235] Table 4 shows the demographic data of the subjects evaluated in Part A and Part B. Table 5 shows the disease status of the 83 subjects evaluated in Part A and Part B. As shown in Table 5, most subjects have metastatic disease and non-squamous histology.

[00236] Adverse events occurring in more than 5% of subjects in a preliminary analysis are graphically represented in FIG. 3. Adverse events related to AZD2936 are shown on the right side of the graph. Adverse events occurring in more than 5% of subjects who received 750 mg of AZD2936 in a preliminary analysis are graphically represented in FIG. 4. Adverse events occurring in more than 10% of subjects treated with AZD2936 750 mg Q3W are graphically represented in FIG. 10. Adverse events related to AZD2936 are shown on the right side of the graph.Nine serious adverse events (SAEs) were observed, possibly related to AZD2936: an increase in alanine aminotransferase (occurring in Part A4-JPN), an increase in aspartate aminotransferase (occurring in Part A4-JPN), colitis (occurring in Part A4), diarrhea (occurring in Part A4), pneumonitis (occurring in Part B), a skin rash (occurring in Part B), and a suspected immune system disorder (occurring in Part A3); one case of acute hepatitis and one case of fatigue (both occurring in Part B). Petition 870250088197, dated 09 / 29 / 2025, page 85 / 166 Table 4. Demographic Data of Evaluated Subjects A1 70 mg N = 4 Dose Escalation A2 A3 A3-JPN1 A3+2 210 mg 750 mg 750 mg 750 mg N = 11 N = 12 N = 6 N = 4 A4 1500 mg N = 11 A4-JPN 1500 mg N = 3 Expansion B 750 mg N = 32 All Patients A + BA + B 750 mg all doses N = 54 N = 83 Age, mean 70.5 63.0 68.0 60.5 58 65.0 53.0 63.0 63.0 63.0 Sex, n (%) Female Male 4 (100) 0 3 (27.3) 8 (72.7) 5 (41.7) 7 (58.3) 1 (16,7) 5 (83,3) 1 (25,0) 3 (75,0) 7 (63,6) 4 (36,4) 0 3 (100) 9 (28,1) 23 (71,9) 16 (29,6) 38 (70,4) 30 (36,1) 50 (63,9) 78 / 103 Petition 870250088197, dated 09 / 29 / 2025, page 86 / 166 Table 5. Disease Status of Evaluated Subjects Dose Escalation A1 A2 A3 A3-JPN1 A3+2 A4 A4-JPN 70 mg 210 mg 750 mg 750 mg 750 mg 1500 mg 1500 mg N = 4 N = 11 N = 12 N = 6 N = 4 N = 11 N = 3 Expansion B 750 mg N = 32 All Patients A + BA + B 750 mg all doses N = 54 N = 83 AJCC Staging at study entry, n (%) Stage I Stage IA Stage IB Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV Stage IVA Stage IVB 0 0 0 0 1 (25.0) 0 0 0 0 0 0 0 0 1 (33.3) 0 0 0 0 0 0 0 0 1 (9,1) 0 0 0 1 (9,1) 1 (33,3) 1 (25,0) 2 (18,2) 4 (33,3) 1 (16,7) 0 1 (9,1) 0 1 (25,0) 2 (18,2) 1 (8,3) 1 (16,7) 0 1 ( 9,1) 0 1 (25,0) 0 0 0 1 (25,0) 2 (18,2) 0 0 1(9,1) 0 0 1 (25,0) 0 0 1 (25,0) 4 (36,4) 3 (25,0) 2 (33,3) 1 (25,0) 1 (9,1) 0 0 1 (9,1) 4 (33,3) 2 (33,3) 0 5 ( 45.5) 1 (33.3) 0 0 1 (1.2) 1(1.2) 4 (12.5) 3(9.4) 2 (6.3) 1 (3.1) 9 (28.1) 11 (34.4) 1 (1.9) 1 (1.2) 0 1 (1.2) 1 (1.9) 1 (1.2) 1 (1.9) 4 (4.8) 9 (16.7) 13 (15.7) 5 (9.3) 9 (10.8) 3 (5.6) 6 (7.2) 2 (3.7) 3 (3.6) 15 (27.8) 21 (25.3) 17 (31.5) 24 (28.9) 79 / 103 Petition 870250088197, dated 09 / 29 / 2025, page 87 / 166 Dose Escalation A1 70 mg N = 4 A2 210 mg N = 11 A3 750 mg N = 12 A3-JPN1 750 mg N = 6 A3+2 750 mg N = 4 Type of histology, n (%) Squamous cell carcinoma 1 (25.0) 5 (45.5) 4 (33.3) 0 1 (25.0) Cell carcinoma small 0 0 0 0 0 Large cell carcinoma 0 0 0 0 0 Adenocarcinoma 3 (75.0) 6 (54.5) 7 (58.3) 5 (83.3) 2 (50.0) Adenosquamous 0 0 0 0 0 Other 0 0 1 (8.3) 1 (16.7) 1 (25.0) Absent 0 0 0 0 0 AJCC = American Joint Committee on Cancer Petition 870250088197, dated 09 / 29 / 2025, page 88 / 166 Expansion All Patients A4 A4-JPN BA + BA + B 1500 mg 1500 mg 750 mg 750 mg all doses N = 11 N = 3 N = 32 N = 54 N = 83 2 (18.2) 0 6 (18.8) 11 (20.4) 19 (22.9) 0 0 0 0 0 0 1 (33.3) 0 0 1 (1.2) 9 (81.8) 2 (66.7) 26 (81.3) 40 (74.1) 60 (72.3) 0 0 0 0 0 0 0 0 3 (5.6) 3 (3.6) 0 0 0 0 0 80 / 103 Efficacy results are given in Table 6: Table 6. Initial Effectiveness Results for Studies Subjects evaluable by provisional response* Dose Escalation A4-JPN 1500 mg N = 3 Expansion B 750 mg N = 32 All Patients A1 70 mg N = 4 A2 210 mg N = 11 A3 750 mg N = 12 A3-JPN 750 mg N = 6 A3+ 750 mg N = 4 A4 1500 mg N = 11 A + B 750 mg N = 54 A + B all doses N = 83 Overall response rate, confirmed, % 1 (25.0) 1 (9.1) 1 (8.3) 1 (16.7) 0 0 0 1 (3.1) 3 (5.6) 5 (6.0) Complete response (CR), confirmed, n (%) 0 0 0 0 0 0 0 0 0 0 Response Partial (PR), confirmed, n (%) 1 (25.0) 1 (9.1) 1 (8.3) 1 (16.7) 0 0 0 1 (3.1) 3 (5.6) 5 (6.0) CR or PR, not confirmed, n (%) 0 0 1 (8.3) 0 0 0 1 (33.3) 0 2 (3.7) 3 (3.6) Stable disease (> 8 weeks), n (%) 2 (50.0) 1 (9.1) 9 (75.0) 3 (50.0) 0 5 (45.5) 1 (33.3) 12 (37.5) 24 (44.4) 33 (39.8) Progression 1 (25.0) 9 (81.8) 2 (16.7) 2 (33.3) 3 (75.0) 5 (45.5) 2 (66.7) 19 (59.4) 24 (44.4) 43 (51.8) 81 / 103 Petition 870250088197, dated 09 / 29 / 2025, page 89 / 166 Subjects evaluable by provisional response* A1 70 mg N = 4 A2 210 mg N = 11 Dose Escalation Expansion B 750 mg N = 32 All Patients A3 750 mg N = 12 A3-JPN 750 mg N = 6 A3+ 750 mg N = 4 A4 1500 mg N = 11 A4-JPN 1500 mg N = 3 A + B 750 mg N = 54 A + B all doses N = 83 Not evaluable*, n (%) 0 0 0 0 1 (25.0) 1 (9.1) 0 0 1 (1.9) 2 (2.4) Disease control rate (DCR), % 75.0 18.2 83.3 66.7 0 45.5 33.3 40.6 50.0 45.8 + All subjects who have measurable disease at baseline and who have their first dose at least 9 weeks prior to data extraction (where 9 weeks is the protocol time between tests) * No disease assessment at the time of DCO 82 / 103 Petition 870250088197, dated 09 / 29 / 2025, page 90 / 166 83 / 103 Table 7. Summary of Results AZD2936 (all doses) AZD2936 (750 mg q3w) Efficacy Response (confirmed), n (%) N = 83 N = 54 Complete response (CR) 0 0 Partial response (PR) 5 (6.0) 3 (5.6) Overall response rate, % Non-response, n (%) 6.0 5.6 Stable disease 33 (39.8) 24 (44.4) Progression 43 (51.8) 24 (44.4) Disease control rate (DCR), % 45.8 50 Progression-free survival, month, mean (95% CI) 2.1 (2.0, 4.0) 3.8 (2.0, 4.2) 6-month progression-free survival, % 30.5 31.5 Safety N=83 N = 54 Any TEAEs, n (%) 75 (90.4) 51 (94.4) possibly related to study treatment 45 (54.2) 33 (61.1) Any TEAE > Grade 3, n 28 (33.7) 17 (31.5) (%) possibly related to study treatment 6 (7.2) 4 (7.4) Any AE leading to discontinuation, n (%) 3 (3.6) 2 (2.4) ECOG performance status, ECOG 0, n (%) / ECOG 1 n, (%) 26 (31.3) / 57 (68.7) 17(31.5) / 37(68.5)

[00237] As can be seen in Table 6, at the 750 mg Q3W dosage, the overall response rate (ORR) was 5.6%, with 24 subjects having stable disease for a DCR of 50.0%. The difference in DCR Petition 870250088197, dated 09 / 29 / 2025, page 91 / 166 The difference of 84 / 103 at a dose of 750 mg between Part A and Part B is likely explained by a heterogeneous patient population with an enrichment of patients with adverse disease features in Part B.

[00238] Tables 6 and 7 show a summary of the initial results obtained in Part A and Part B in participants who had previously received second-line or higher (2L+) checkpoint inhibitors (CPIs). 83 subjects with pre-treated NSCLC were treated as described above. AZD2936 continues to show a favorable safety profile, and this safety profile may evolve further with longer follow-up and transition to subjects who have never received CPIs. Example 9: Dose Expansion of Part C

[00239] This Example describes the use of a 750 mg dose of AZD2936 for an additional dose expansion study.

[00240] The primary objectives of Part C include evaluating the safety and tolerability of AZD2936 in RP2D in subjects who have never received IPC with stage IV NSCLC with PD-L1 (TPS > 1% using the PD-L1 IHC assay). Outcomes include the percentage of subjects with AEs and imAEs, SAEs, DLT-like events, abnormal vital signs and laboratory parameters; and the AZD2936 discontinuation rate due to toxicity.

[00241] The primary objectives of Part C also include determining the preliminary antitumor activity of AZD2936 in RP2D in subjects who have never received IPC with stage IV NSCLC with PDL1 TPS > 1%. Outcomes include ORR, according to RECIST v1.1.

[00242] Secondary objectives of Part C include further characterization of the preliminary antitumor activity of AZD2936 in RP2D in subjects who have never received IPC with stage IV NSCLC with Petition 870250088197, dated 09 / 29 / 2025, page 92 / 166 85 / 103 TPS PD-L1 > 1%. Outcomes include, according to RECIST v1.1: DCR, DoR, DRR, and PFS.

[00243] A sample size of at least 30 subjects would yield a preliminary ORR with an SE of no more than 0.1. Two-sided 80% confidence intervals are provided below using the Clopper-Pearson method for a range of possible response rates from 30 subjects: ORR of 20% (6 / 30 responses); CI of 80% [11%, 32%], ORR of 30% (9 / 30 responses); CI of 80% [19%, 43%], ORR of 40% (12 / 30 responses); CI of 80% [28%, 53%], ORR of 47% (14 / 30 responses); CI of 80% [34%, 60%], ORR of 60% (18 / 30 responses); CI of 80% [47%, 72%].

[00244] Based on a decision framework (Frewer et al., 2016) with a 40% TV in ORR, it is concluded that no evidence of targeted activity is obtained if < 8 objective RECIST responses (confirmed CR or PR) are observed (observed ORR < 27%). If the actual response rate is 40%, the chance of observing < 8 responses in 30 evaluable subjects is < 10%.

[00245] During the execution of Part C, the occurrence of toxicities that are not clearly attributable to the primary disease, other concomitant medications, processes related to the disease under investigation, or other etiology unrelated to the medication (unrelated to the study intervention treatment) will trigger automatic interruption rules. In this scenario, enrollment of new participants in the study will be immediately interrupted until the Safety Review Committee assesses the benefit / risk of AZD2936, if one of the following conditions occurs: 1. A Grade 5 related toxicity event at any time during the execution of Part C; 2. Two Grade 4 related toxicities in two different participants at any time during the execution of Part C; Petition 870250088197, dated 09 / 29 / 2025, page 93 / 166 86 / 103 3. The occurrence of > 4 events in different subjects (i.e., > 2 events occurring in the same subject will be counted only once) described as a serious adverse drug reaction (SAR) in the first 10 subjects enrolled, or the occurrence of > 7 SARs in the first 20 subjects.

[00246] Subjects are enrolled in Part C. Following an initial screening period of up to 28 days, eligible subjects receive AZD2936 Q3W administered by intravenous (IV) infusion at RP2D (750 mg Q3W) starting on Day 1 of Cycle 1 for a maximum of 35 cycles. Subjects are treated with the study intervention until disease progression, unacceptable toxicity, investigator decision, completion of the maximum 35 treatment cycles, or withdrawal of consent. All subjects are followed for survival until the end of the study. Dose reductions of AZD2936 are not permitted at any time.

[00247] After the screening period, the Part C intervention period is scheduled. The Part C intervention period includes a maximum of 35 cycles, each cycle includes 21 days, and AZD2936 is administered every three weeks (Q3W), i.e., once every 21-day cycle.

[00248] In particular, eligible subjects receive AZD2936 Q3W administered by intravenous (IV) infusion at RP2D (750 mg Q3W) starting on Day 1 of Cycle 1 for a maximum of 35 cycles. Subjects are treated with the study intervention until disease progression, unacceptable toxicity, investigator decision, completion of the maximum 35 treatment cycles, or withdrawal of consent. All subjects are followed for survival until the end of the study. Dose reductions of AZD2936 are not permitted at any time.

[00249] After the invention period, the subjects are evaluated adiPetition 870250088197, dated 09 / 29 / 2025, page 94 / 166 87 / 103 nationally regarding disease progression, treatment completion status, and follow-up status. Example 10: Part D dose expansion

[00250] This Example describes the use of the 750 mg dose (Part D1) and the 1500 mg dose (Part D2) of AZD2936 for a dose expansion study.

[00251] The primary objectives of Part D include evaluating the safety and tolerability of AZD2936 at doses of 750 mg and 1500 mg every 3 weeks (Q3W) in subjects who have never received IPC with stage IV NSCLC with PD-L1 TPS > 50%. Outcomes include the percentage of subjects at each dose level with AEs and AEims, SAEs, DLT-like events, abnormal vital signs and laboratory parameters; and the discontinuation rate of AZD2936 due to toxicity at each dose level.

[00252] The primary objectives of Part D also include assessment of the preliminary antitumor activity of AZD2936 at 750 mg and 1500 mg Q3W in subjects who have never received IPC with stage IV NSCLC with PD-L1 TPS > 50%. Outcomes include ORR at each dose level according to RECIST v1.1.

[00253] Secondary objectives of Part D include further description of the preliminary antitumor activity of AZD2936 at 750 mg and 1500 mg Q3W in treatment-naïve subjects with stage IV NSCLC and PD-L1 (TPS > 50% using the PD-L1 IHC assay). Outcomes include, at each dose level, according to RECIST v1.1: DCR, DoR, DRR, and PFS.

[00254] Subjects are enrolled for the primary analysis in Part D, with subjects randomized 1:1 to AZD2936 750 mg Q3W (RP2D; n = 30) or AZD2936 1500 mg Q3W (n = 30). A sample size of at least 30 subjects at each dose level would yield a preliminary ORR with an SE of no more than 0.1. Cis values ​​are provided below. Petition 870250088197, dated 09 / 29 / 2025, page 95 / 166 88 / 103 80% bilateral using the Clopper-Pearson method for a range of possible response rates in 30 subjects: 20% ORR (6 / 30 responses); 80% CI [11%, 32%], 30% ORR (9 / 30 responses); 80% CI [19%, 43%], 40% ORR (12 / 30 responses); 80% CI [28%, 53%], 47% ORR (14 / 30 responses); 80% CI [34%, 60%], 60% ORR (18 / 30 responses); 80% CI [47%, 72%].

[00255] Based on a decision framework (Frewer et al., 2016) with a TV of 45% in the ORR, a conclusion of no evidence of targeted activity would be reached if < 9 objective RECIST responses (CR or PR confirmed) were observed (observed ORR < 30%). If the actual response rate is 45%, the chance of observing < 9 responses in 30 evaluable subjects is < 10%.

[00256] During the execution of Part D, the occurrence of toxicities that are not clearly attributable to the primary disease, other concomitant medications, processes related to the disease under investigation, or other non-drug related etiology (unrelated to the study intervention treatment) will trigger automatic interruption rules (hereinafter defined as interruption rules). In this scenario, enrollment of new subjects in the study will be immediately interrupted until the Safety Review Committee assesses the benefit / risk of AZD2936, if one of the following conditions occurs: 1. A Grade 5 related toxicity event at any time during the execution of Part D; 2. Two Grade 4 related toxicities in two different subjects at the same dose level at any time during the execution of Part D; 3. The occurrence of > 4 events in different subjects (i.e., > 2 events occurring in the same subject will be counted only once) Petition 870250088197, dated 09 / 29 / 2025, pp. 96 / 166 89 / 103 in one dose) described as SADRs in the first 10 subjects enrolled or the occurrence of > 7 SADRs in the first 20 subjects at each dose.

[00257] After the screening period, the Part D intervention period is scheduled. The Part D intervention period includes a maximum of 35 cycles, each cycle includes 21 days, and AZD2936 is administered every three weeks (Q3W), i.e., once every 21-day cycle.

[00258] In particular, eligible subjects will receive AZD2936 Q3W administered via intravenous (IV) infusion at a dose of 750 mg or 1500 mg Q3W (randomization 1:1) starting on Day 1 of Cycle 1 for a maximum of 35 cycles. Subjects are treated with the study intervention until disease progression, unacceptable toxicity, investigator decision, completion of the maximum 35 treatment cycles, or withdrawal of consent. All subjects are followed for survival until the end of the study. After the intervention period, subjects are further assessed for disease progression, end-of-treatment status, and follow-up status.

[00259] As described in Part A above, 750 mg Q3W of AZD2936 was identified as the RP2D for further evaluation in the expansion phase of Part D. Additionally, a higher dose of 1500 mg Q3W of AZD2936 is evaluated along with the 750 mg Q3W PR2D. The 1500 mg dose was declared safe and tolerable by SRC.The 1500 mg dose was chosen based on emerging data showing a similar target engagement in peripheral blood of >90% RO with 750 mg in the preliminary analysis and predicted to achieve >90% intratumoral RO for both PD-1 and TIGIT. In contrast, as shown in Example 1 above, a lower dose of 210 mg is predicted to achieve suboptimal intratumoral RO compared to 750 mg and 1500 mg. By exploring the 1500 mg dose level, Part D assesses whether a dose plateau is established. Petition 870250088197, dated 09 / 29 / 2025, page 97 / 166 90 / 103 efficacy is achieved at 750 mg Q3W and allows for the selection of the ideal dose for exploration in future studies.

[00260] In Part D, potential bias is reduced by the following steps: all subjects are assigned to a randomized study intervention using an Interactive Response Technology (IRT) / Randomization and Trial Supply Management (RTSM). Example 11: Expanded results from the dose escalation study of Part A and Part B

[00261] The Part A dose-escalation and Part B dose-expansion study of AZD2936 described above was continued. Inclusion criteria for subjects in Part A and Part B were as given in Example 5 above and included: (i) must have received both prior CPI and prior platinum-based chemotherapy (combined or separate treatment lines); (ii) must have confirmed progression during treatment with a CPI-containing regimen; (iii) must not have epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, or other known genomic alteration with an approved first-line targeted therapy; and (iv) must not have any prior CPI treatment discontinuation due to toxicity. Abbreviations are as defined in Example 2 above. 83 subjects were enrolled and treated: 51 in Part A and 32 in Part B.The subjects had unresectable stage III NSCLC or stage IV NSCLC previously treated with a CPI, with TPS PD-L1 > 1%.

[00262] AZD2936 was administered intravenously once every three weeks (Q3W). Subject demographics are given in Table 8. Petition 870250088197, dated 09 / 29 / 2025, p. 98 / 166 91 / 103 Table 8. Demographic Data and Baseline Disease Characteristics Dose Escalation (Part A) Dose Expansion (Part B) 70-1500 mg Q3W (N=51) 750 mg Q3W (N=32) Mean Age (range), years 65.0 (39-83) 63.0 (41-85) Male / Female, n (%) 30 (58.8) / 21 (41.2) 23 (71.9) / 9 (28.1) White / Asian / Other, n (%) 27 (52.9) / 22 (43.1) / 2 (3.9) 20 (62.5) / 12 (37.5) / 0 ECOG PS 0 / 1, n (%) 20 (39.2) / 31 (60.8) 6 (18.8) / 26 (81.3) Histology, n (%) Adenocarcinoma 34 (66.7) 26 (81.3) Squamous 13 (25.5) 6 (18.8) PD-L1 TPS 1-49% / >50%, n (%) 28 (54.9) / 23 (45.1) 16 (50.0) / 16 (50.0) Current or past smoker / never smoked, n (%) 41 (80.4) / 10 (19.6) 26 (81.3) / 6 (18.8) Primary / secondary resistance* to previous CPI treatment, n (%) 19 (37.3) / 32 (62.7) 12 (37.5) / 20 (62.5) Liver metastasis / brain metastasis, n(%) 4 (7.8) / 5 (9.8) 6 (18.8) / 13 (40.6)

[00263] Primary resistance is defined as resistance with exposure to CPI therapy < 6 months, and secondary resistance is defined as resistance with exposure to CPI therapy > 6 months. ECOG PS stands for Eastern Cooperative Oncology Group Performance Status. As can be seen in Table 8, most subjects had acquired resistance to prior CPI treatment.

[00264] The median duration of treatment was 14 weeks (inter Petition 870250088197, dated 09 / 29 / 2025, page 99 / 166 92 / 103 (range: 1.7-95.6) for Part A and 10.7 weeks (range: 5.9-60.7) for Part B at the time of data collection. No dose-limiting toxicities (TLDs) were observed during dose escalation (Part A). OA RP2D was 750 mg based on Part A data and supported by predicted intratumoral receptor occupancy modeling analysis. A safety summary of the study is given in Table 9. Treatment-emergent adverse events (TEAEs) occurred in 90.4% of subjects and were grade 3 or higher in 33.7% for the 70-1500 mg dose, and occurred in 94.4% of subjects and were grade 3 or higher in 31.5% for the 750 mg dose. Treatment-related adverse events (TRAEs) occurred in 53.0% of subjects and were grade 3 or higher in 8.4% for the 70-1500 mg range, and occurred in 59.3% of subjects and were grade 3 or higher in 9.3% for the 750 mg range. Table 9. Safety Summary Event, n (%) Dose Escalation (Part A) Dose Expansion (Part B) Total (Parts A and B) 70 mg (n=4) 210 mg (n=11) 750 mg (n=22) 1500 mg (n=14) 70-1500 mg (n=51) 750 mg (n=32) 750 mg (n=54) 70-1500 mg (n=83) Any TEAE 3 (75.0) 9 (81.8) 20 (90.9) 12 (85.7) 44 (86.3) 31 (96.9) 51 (94.4) 75 (90.4) Any TRAE* 1 (25.0) 4 (36.4) 14 (63.6) 7 (50.0) 26 (51.0) 18 (56.3) 32 (59.3) 44 (53.0) Any TEAE Grade >3 1 (25.0) 3 (27.3) 6 (27.3) 7 (50.0) 17 (33.3) 11 (34.4) 17 (31.5) 28 (33.7) Any TRAE Grade >3* 0 0 2 (9.1) 2 (14.3) 4 (7.8) 3 (9.4) 5 (9.3) 7 (8.4) Any treatment-emergent SAE 1 (25.0) 3 (27.3) 7 (27.3) 6 (42.9) 17 (33.3) 11 (34.4) 18 (33.3) 28 (33.7) Any treatment-related SAE* 0 0 1 (4,5) 2 (14,3) 3 (5,9) 3 (9,4) 4 (7,4) 6 (7,2) Petition 870250088197, dated 09 / 29 / 2025, pp. 100 / 166 93 / 103 Event, n (%) Dose Escalation (Part A) Dose Expansion (Part B) Total (Parts A and B) 70 mg (n=4) 210 mg (n=11) 750 mg (n=22) 1500 mg (n=14) 70-1500 mg (n=51) 750 mg (n=32) 750 mg (n=54) 70-1500 mg (n=83) Any treatment-emergent adverse event leading to death 1 (25.0) 0 1 (4.5) 2 (14.3) 4 (7.8) 0 1 (1.9) 4 (4.8) Any treatment-related adverse event leading to death* 0 0 0 0 0 0 0 0 Any treatment-related adverse event leading to discontinuation 0 0 1 (4.5) 0 1 (2.0) 2 (6,3) 3 (5,6) 3 (3,6) Any imAEf 1 (25,0) 2 (18,2) 3 (13,6) 3 (21,4) 9 (17,6) 5 (15,6) 8 (14,8) 16,9) *Possibly related to AZD2936 as assessed by the investigator. fImmune-mediated as assessed by the investigator. AE, adverse event; AESI, adverse event of special interest; imAE, immune-mediated adverse event; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event

[00265] FIG. 5 summarizes the TEAEs and TRAEs that occurred in >5% of the 83 subjects treated with AZD2936 (20 - 1,500 mg Q3W). FIG. 6 summarizes the TEAEs and TRAEs that occurred in >5% of the subset of 54 patients treated with AZD2936 at the recommended phase 2 dose (750 mg Q3W). As shown by the graphs in FIG. 5 and FIG. 6, there were no Grade 4 or 5 TRAEs. Thirteen (15.7%) patients received steroids to treat TRAEs. Three (3.6%) patients, all receiving 750 mg, discontinued AZD2936 due to AEs. These AEs were considered treatment-related in two patients, both of whom recovered with steroids: myocarditis (Grade 1) and acute hepatitis (Grade 3). Four (4.8%) patients Petition 870250088197, dated 09 / 29 / 2025, pp. 101 / 166 94 / 103 presented with AEs that led to death, all in Part A: ileal volvulus (n=2), pneumonia (n=1), and respiratory failure (n=1). None were considered related to AZD2936.

[00266] The efficacy of AZD2936 was analyzed by measuring the change in target lesion size. FIG. 7 is a cascade graph of the best percent change from baseline in target lesion size for all doses in 82 subjects analyzed. Table 10 shows a summary of antitumor activity in all 83 subjects. Overall, mediated PFS is 2.1 months and the RRO is 6.0%. Table 10: Antitumor activity in subjects with CPI-resistant NSCLC Dose Escalation (Part A) Dose Expansion (Part B) Total (Parts A and B) 70 - 1500 mg (n=51) 750 mg (n=32) 750 mg (n=54) 70 - 1500 mg (N=83) ORR, % (95% CI) 7.8 (2.2, 18.9) 3.1 (0.1, 16.2) 5.6 (1.2, 15.4) 6.0 (2.0, 13.5) Complete Response, n (%) 0 0 0 0 Partial Response, n (%) 4 (7.8) 1 (3.1) 3 (5.6) 5 (6.0) Median DoR (range), months* 14.5 (4.8-14.5) 4.1 (NC) 14.5 (4.1- 14.5) 14.5 (4.1-14.5) Durable response at 6 months, n (%) 3 (5.9) 0 2 (3.7) 3 (3.6) Stable disease, n (%) 21 (41.2) 12 (37.5) 24 (44.4) 33 (39.8) Unconfirmed response, complete or partial, n (%) 2 (3.9) 1 (3.1) 2 (3.7) 3 (3.6) Petition 870250088197, dated 09 / 29 / 2025, pp. 102 / 166 95 / 103 Dose Escalation (Part A) Dose Expansion (Part B) Total (Parts A and B) 70 - 1500 mg (n=51) 750 mg (n=32) 750 mg (n=54) 70 - 1500 mg (N=83) Disease control rate, % (95% CI) 31.4 (19.1-45.9) 28.1 (13.8-46.8) 31.5 (19.5-45.6) 30.1 (20.5-41.2) Median PFS (95% CI), months 3.1 (2.0, 4.1) 2.1 (2.0, 5.2) 3.8 (2.0, 4.2) 2.1 (2.0, 4.0) Mean duration of follow-up (range), months 9.1 (0.4-21.3) 10.1 (1.6-13.7) 9.9 (0.8-17.9) 9.7 (0.4-21.3) *DoR is calculated based on the Kaplan-Meier technique; Disease control = complete response + partial response + stable disease at or after 182 days; CI, confidence interval; DoR, duration of response; NC, not calculable; ORR, objective response rate; PFS, progression-free survival.

[00267] FIG. 8 shows the percent change from baseline in target lesion size over time in the subset of 54 subjects treated with the recommended phase 2 dose (750 mg Q3W, Parts A and B), as summarized in column 3 of Table 10. The median PFS is 3.8 months and ORR is 5.6%. Responses and stable disease were generally durable at this dose.

[00268] Based on the efficacy results as described above, twenty patients had stable disease lasting at least 6 months, most of whom (n=18) received doses of 750 mg or 1500 mg; they had PD-L1 TPS 1-49% (n=10) or >50% (n=10).

[00269] Pharmacodynamics were measured for two subjects. FIG. 9A and FIG. 9B each show a subject treated with the recommended phase 2 dose who had a confirmed radiographic response. Petition 870250088197, dated 09 / 29 / 2025, pp. 103 / 166 96 / 103 in 9 weeks. Patient 1 (FIG. 9A) is a 59-year-old woman with adenocarcinoma, PD-L1 >50%, with primary resistance, and 2 prior lines of treatment. Patient 2 (FIG. 9B) is a 53-year-old man with adenocarcinoma, PD-L1 >50%, with secondary resistance, and 8 prior lines of treatment. FIG. 9C shows that both subjects had a corresponding 100% reduction in ctDNA at 6 weeks. Common characteristics of these patients include PR lasting > 6 months, PD-L1 TPS > 50%, and ECOG PS 0.

[00270] In conclusion, this study demonstrated that: • AZD2936 was safe at all doses tested. No DLTs were observed during dose escalation and no MTD was reached. • Antitumor activity was observed in heavily pre-treated patients with advanced / metastatic IPC-resistant NSCLC treated with AZD2936, including at the recommended phase 2 dose. • The preliminary safety and efficacy observed in pre-treated patients provide a rationale for further testing with AZD2936 in NSCLC patients who have never received IPC. Example 12: Preliminary Part C results

[00271] Nineteen subjects were evaluated in Part C of the study described in the Examples above.

[00272] Table 11 shows the available demographic data for seven subjects evaluated in Part C. Table 12 shows the available disease status for seven subjects evaluated in Part C. As shown in Table 12, most subjects have metastatic disease and squamous histology. Adverse events occurring in more than 10% of subjects in Part C are graphically represented in FIG. 11. Adverse events related to AZD2936 are shown on the right side of the graph. One SAE was observed, possibly related to AZD2936: immune-mediated hepatitis. Petition 870250088197, dated 09 / 29 / 2025, pp. 104 / 166 97 / 103 Table 11. Demographic Data of Subjects Evaluated in Part C Part C 750mg N = 7 Age, median 65.0 Sex, n (%) Female Male 1 (14.3) 6 (85.7) Table 12. Disease Status of Subjects Evaluated in Part C Part C 750 mg N = 7 AJCC Staging at study entry, n (%) Stage I 0 Stage IA 0 Stage IB 0 Stage IIB 0 Stage IIIA 0 Stage IIIB 0 Stage IIIC 0 Stage IV 0 Stage IVA 6 (85.7) Stage IVB 1 (14.3) Histology type, n (%) 5 (71.4) Squamous cell carcinoma Small cell carcinoma 0 Large cell carcinoma 0 Adenocarcinoma 2 (28.6) Adenosquamous 0 Other 0 Absent 0 AJCC = American Joint Committee on Cancer Petition 870250088197, dated 09 / 29 / 2025, pp. 105 / 166 98 / 103

[00273] The efficacy results are given in Table 13. Table 13. Initial Effectiveness Results for Studies in Part C Part C Subjects evaluable by provisional response + 750 mg N=7 Overall response rate, confirmed, % 4 (57.1) Complete response (CR), confirmed, n (%) 0 Partial response (PR), confirmed, n (%) 4 (57.1) CR or PR, not confirmed, n (%) 1 (14.3) Stable disease (> 8 weeks), n (%) 3 (42.9) Progression 0 Not evaluable*, n (%) 0 Disease control rate (DCR), % 100 +All subjects who had measurable disease at baseline and who had their first dose at least 9 weeks prior to data extraction (where 9 weeks is the protocol time between tests) *No disease assessment at the time of DCO Table 14. Summary of results Part C Effectiveness N = 7 Response (confirmed), n (%) Complete response (CR) Partial response (PR) 0 4 (57.1) Overall response rate, % 57.1 Petition 870250088197, dated 09 / 29 / 2025, pp. 106 / 166 99 / 103 Part C Non-response, n (%) Stable disease Progression 3 (42.9) 0 Disease control rate (DCR), % 100 Progression-free survival, month, median (95% CI) - 6-month progression-free survival, % - Safety N = 19 No TEAEs, n (%) possibly related to study treatment 17 (89.5) 11 (57.9) No TEAEs > Grade 3, n (%) possibly related to study treatment 4 (21.1) 1 (5.3) No AEs leading to discontinuation, n (%) 1 (5.3)

[00274] As can be seen in Table 13, at the 750 mg Q3W dosage, the overall response rate (ORR) was 57.1% with 3 subjects having stable disease for a DCR of 100.0%.

[00275] Tables 13 and 14 show a summary of the initial results obtained in Part C in subjects who had never received CPI. Nineteen subjects with NSCLC were treated as described above, with 7 eligible for efficacy assessment. The preliminary safety profile of AZD2936 remains favorable and the initial efficacy is encouraging. Example 13: Preliminary results from Part D

[00276] Twenty-seven subjects were evaluated in Part D of the study described in the Examples above. This includes fourteen patients in D1 (750 mg Q3W) and thirteen patients in D2 (1500 mg Q3W).

[00277] Table 15 shows the available demographic data for Petition 870250088197, dated 09 / 29 / 2025, pp. 107 / 166 100 / 103 eleven subjects evaluated in Part D. Table 16 shows the disease status available for eleven subjects evaluated in Part D. As shown in Table 16, most subjects present with metastatic disease, with squamous cell carcinoma and adenocarcinoma as the most common histologies. Adverse events occurring in more than 10% of subjects dosed with AZD2936 1500 mg Q3W are graphically represented in FIG. 12. Adverse events occurring in more than 10% of subjects dosed with AZD2936 750 mg Q3W are graphically represented in FIG. 13. Adverse events related to AZD2936 are shown on the right side of both graphs. One SAE was observed, which was possibly related to AZD2936: increased alanine aminotransferase (occurring in Part D2 15000 mg Q3W). Table 15. Demographic Data of the Subjects Evaluated in Part D Part D1 Part D2 750 mg N = 6 1500 mg N = 5 Age, median 72.5 68.0 Sex, n (%) Female Male 0 6 (100) 4 (80.0) 1 (20.0) Table 16. Disease Status of Subjects Evaluated in Part D Part D1 Part D2 750 mg 1500 mg N = 6 N = 5 AJCC Staging at study entry, n (%) Stage I Stage IA 0 0 Stage IB 0 0 Stage IIB 0 0 Stage IIIA 0 0 Petition 870250088197, dated 09 / 29 / 2025, pp. 108 / 166 101 / 103 Part D1 Part D2 Stage IIIB 1 (16.7) 0 Stage IIIC 0 0 Stage IV 0 0 Stage IVA 0 2 (40.0) Stage IVB 2 (33.3) 2 (40.0) Absent 2 (33.3) 1 (20.0) 1 (16.7) 0 Histology type, n (%) 1 (16.7) 3 (60.0) Squamous cell carcinoma 0 0 Small cell carcinoma 0 0 Large cell carcinoma 4 (66.7) 2 (40.0) Adenocarcinoma 0 0 Adenosquamous 0 0 Other 1 (16.7) 0 Absent AJCC = American Joint Committee on Cancer

[00278] Efficacy results are given in Table 17. Table 17. Initial Effectiveness Results for Studies Part D1 Part D2 Subjects evaluable by provisional response + 750 mg N=7 1500 mg N=5 Overall response rate, confirmed, % 2 (28.6) 1 (20.0) Complete response (CR), confirmed, n (%) 0 0 Partial response (PR), confirmed, n (%) 2 (28.6) 1 (20.0) CR or PR, not confirmed, n (%) 1 (14.3) 2 (40.0) Stable disease (> 8 weeks), n (%) 5 (71.4) 2 (40.0) Progression 0 2 (40.0) Not evaluable*, n (%) 0 0 Petition 870250088197, dated 09 / 29 / 2025, pp. 109 / 166 102 / 103 Part D1 Part D2 Disease control rate (DCR), % 100 60.0 +All subjects who had measurable disease at baseline and who had their first dose at least 9 weeks prior to data extraction (where 9 weeks is the protocol time between tests) *No disease assessment at the time of DCO Table 18. Summary of Results Part D1 750mg Q3W Part D2 1500mg Q3W Efficacy N = 7 N = 5 Response (confirmed), n (%) Complete response (CR) Partial response (PR) 0 2 (28.6) 0 1 (20.0) Overall response rate, % 28.6 20.0 Non-response, n (%) Stable disease Progression 5 (71.4) 0 2 (40.0) 2 (40.0) Disease control rate (DCR), % 100 60 Progression-free survival, month, median (95% CI) - - 6-month progression-free survival, % - - Safety N = 14 N = 13 Any TEAEs, n (%) possibly related to study treatment 8 (57.1) 7 (50.0) 10 (76.9) 7 (53.8) Any TEAE > Grade 3, n (%) possibly related to study treatment 3 (21.4) 0 3 (23.1) 0 Petition 870250088197, dated 09 / 29 / 2025, pp. 110 / 166 103 / 103 Part D1 750mg Q3W Part D2 1500mg Q3W Any AE leading to discontinuation, n (%) 0 0

[00279] As can be seen in Table 17, at the 750 mg Q3W dosage, the ORR was 28.6% with 5 subjects having stable disease for a DCR of 100.0% and at the 1500 mg Q3W dosage, the ORR was 20% with 2 subjects having stable disease for a DCR of 60%.

[00280] Tables 17 and 18 show a summary of the initial results obtained in Part D in subjects who had never received CPI. Twenty-seven subjects with NSCLC were treated as described above, with 12 being evaluable for efficacy. The differences in ORR observed between cohorts in Parts C and D are likely a reflection of sample size and will evolve over time.

[00281] The best percent change from baseline in target lesion size in all 19 NSCLC subjects who had never received CPI dosed with AZD2936 750 mg and 1500 mg Q3W from Parts C and D is shown in FIG. 14. Changes in target lesion size over time in 19 NSCLC subjects who had never received CPI dosed with AZD2936 750 mg and 1500 mg Q3W from Parts C and D are shown in FIG. 15. The preliminary safety profile of AZD2936 remains favorable and the initial efficacy is encouraging. Petition 870250088197, dated 09 / 29 / 2025, pp. 111 / 166

Claims

1 / 12 CLAIMS 1. A method for treating cancer in a subject, characterized in that it comprises administering to the subject a bispecific binding protein that specifically binds to Programmed Death-1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) in an amount of about 70 mg to about 1500 mg, the bispecific binding protein comprising: a) a first binding domain that specifically binds to PD-1, wherein the first binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 1, an HCDR2 having the amino acid sequence of SEQ ID NO: 2 and an HCDR3 having the amino acid sequence of SEQ ID NO: 3, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 4, an LCDR2 having the amino acid sequence of SEQ ID NO: 5 and an LCDR3 having the amino acid sequence of SEQ ID NO: 6;(b) a second binding domain that specifically binds to TIGIT, wherein the second binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 11, an HCDR2 having the amino acid sequence of SEQ ID NO: 12 and an HCDR3 having the amino acid sequence of SEQ ID NO: 13, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 14, an LCDR2 having the amino acid sequence of SEQ ID NO: 15 and an LCDR3 having the amino acid sequence of SEQ ID NO:

16.

2. Method according to claim 1, characterized in that the amount of bispecific binding protein administered is about 70 mg, about 150 mg, about 210 mg, about 450 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1250 mg or about 1500 mg.

3. Method according to claim 2, characterized in that the amount of bispecific binding protein administered is approximately 750 mg.

4. Method according to claim 2, characterized in that the amount of bispecific binding protein administered is about 1500 mg.

5. A method, according to any of the preceding claims, characterized in that the bispecific binding protein is administered once per treatment cycle.

6. Method according to claim 5, characterized in that the treatment cycle is about 7 days, about 14 days, about 21 days, about 28 days or about 35 days.

7. Method according to claim 5, characterized in that the treatment cycle is approximately 7 days.

8. Method, according to any one of claims 5 to 7, characterized in that the treatment cycle is repeated for up to 35 cycles.

9. A method, according to any of the preceding claims, characterized in that the bispecific binding protein is administered to the subject as monotherapy.

10. A method, according to any of the preceding claims, characterized in that the bispecific binding protein is administered via intravenous (IV) infusion.

11. A method, according to any of the preceding claims, characterized by the fact that the subject has not received a prior line of systemic therapy.

12. Method, according to any of the claims Petition 870250088197, dated 09 / 29 / 2025, page 145 / 166 3 / 12 tions 1 to 10, characterized by the fact that the subject has previously received chemotherapy.

13. A method, according to any of the preceding claims, characterized in that the cancer comprises a cancer cell expressing PD-L1.

14. Method, according to any one of claims 1 to 13, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having the amino acid sequence of SEQ ID NO:

9.

15. Method, according to any one of claims 1 to 13, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

9.

16. Method, according to any one of claims 1 to 13, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having the amino acid sequence of SEQ ID NO:8 and a light chain having the amino acid sequence of SEQ ID NO:

10.

17. Method, according to any one of claims 1 to 13, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:8 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

10.

18. Method, according to any one of claims 1 to 17, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having the amino acid sequence of SEQ ID NO:

19.

19. Method, according to any one of claims 1 to 17, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

19.

20. Method, according to any one of claims 1 to 17, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having the amino acid sequence of SEQ ID NO:18 and a light chain having the amino acid sequence of SEQ ID NO:

20.

21. Method, according to any one of claims 1 to 17, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:18 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

20.

22. A method, according to any of the preceding claims, characterized in that the bispecific binding protein is a human or humanized bispecific antibody or antigen-binding fragment thereof.

23. A method, according to any of the preceding claims, characterized in that the bispecific binding protein comprises a variant Fc region.

24. Method according to claim 23, characterized in that the variant Fc region of the bispecific binding protein comprises at least one substitution selected from 221K, 221Y, 225E, 225K, 225W, 228P, 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235E, 235F, 236E, 237L, 237M, 237P, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 243W, 243L 243Y, 243R, 243Q, 244H, 245A, 247L, 247V, 247G, 250E, 250Q, 251F, 252L, 252Y, 254S, 254T, 255L, 256E, 256F, 256M, 257C, 257M, 257N, 262I, 262A, 262T, 262E, 263I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265A, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266I, 266A, 266T, 266M, 267Q, 267L, 268E, 269H, 269Y, 269F, 269R, 270E, 280A, 284M, 292P, 292L, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 296G, 297S, 297D, 297E, 298A, 298H,298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 305I, 308F, 313F, 316D, 318A, 318S, 320A, 320S, 322A, 322S, 325Q, 325L, 3251, 325D, 325E, 325A, 325T, 325V, 325H, 326A, 326D, 326E, 326G, 326M, 326V, 327G, 327W, 327N, 327L, 328S 328M, 328D, 328E, 328N, 328Q, 328F, 3281, 328V, 328T, 328H, 328A, 329F, 329H, 329Q, 330K, 330G, 330T, 330C, 330L, 330Y, 330V, 3301, 330F, 330R, 330H, 331G, 331A, price 870250088197, on 09 / 29 / 2025, page. 148 / 166 6 / 12 331L, 331M, 331F, 331W, 331K, 331Q, 331E, 331S, 331V, 3311, 331C, 331Y, 331H, 331R, 331N, 331D, 331T, 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y, 332A, 333A, 333D, 333G, 333Q, 333S, 333V, 334A, 334E, 334H, 334L 334M,334Q, 334V, 334Y, 339T, 370E, 370N, 378D, 392T, 396L, 416G, 419H, 421K, 428L, 428F, 433K, 433L, 434A, 434W, 434Y, 436H, 440Y and 443W conform to the number in the EU and most of the time., 25. Method according to claim 23, characterized in that the variant Fc region of the bispecific binding protein comprises one or more amino acid substitutions at selected positions 428 and 434 as numbered by the EU index as shown in Kabat.

26. Method, according to any one of claims 23 to 25, characterized in that the variant Fc region of the bispecific binding protein comprises one or more amino acid substitutions selected from 428L, 428F, 434A, 424F, 434W and 434Y.

27. A method according to any one of claims 23 to 26, characterized in that the variant Fc region of the bispecific binding protein comprises a YTE mutation.

28. Method according to claim 23 or 24, characterized in that the variant Fc region of the bispecific binding protein comprises a triple mutation (TM) L234F / L235E / P331S.

29. A method according to any one of claims 23 to 28, characterized in that the Fc region of the bispecific binding protein is aglycosylated.

30. Method, according to any one of claims 23 to 28, characterized in that the Fc region of the bispecific binding protein is deglycosylated. Petition 870250088197, dated 09 / 29 / 2025, pp. 149 / 166 7 / 12 31. A method according to any one of claims 23 to 28, characterized in that the Fc region of the bispecific binding protein has reduced fucosylation or is afucosylated.

32. A method, according to any of the preceding claims, characterized in that the bispecific binding protein comprises a constant region of the kappa light chain.

33. A method according to any one of claims 1 to 32, characterized in that the bispecific binding protein comprises a constant region of the lambda light chain.

34. A method, according to any of the preceding claims, characterized in that the bispecific binding protein is an antibody.

35. Method according to claim 34, characterized in that the antibody is an IgG antibody.

36. Method according to claim 35, characterized in that the antibody is an IgG1 antibody.

37. Method, according to any one of claims 34 to 36, characterized in that the antibody is humanized.

38. A method, according to any of the preceding claims, characterized in that the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma, and lung cancer.

39. Method according to claim 38, characterized in that the cancer is non-small cell lung cancer (NSCLC).

40. Method according to claim 39, characterized in that the NSCLC is advanced or metastatic. Petition 870250088197, dated 09 / 29 / 2025, pp. 150 / 166 8 / 12 41. Method, according to claim 39, characterized in that the subject has a PD-L1 tumor proportion score greater than or equal to 1%.

42. Method, according to claim 39, characterized in that the subject has a PD-L1 tumor proportion score greater than or equal to 50%.

43. A method according to any one of claims 39 to 42, characterized in that the subject never received a checkpoint inhibitor (CPI).

44. Pharmaceutical composition, characterized in that it comprises a bispecific binding protein that binds specifically to PD-1 and TIGIT in an amount of about 70 mg to about 1500 mg, the bispecific binding protein comprising: a) a first binding domain that binds specifically to PD-1, wherein the first binding domain comprises a variable heavy chain domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 1, an HCDR2 having the amino acid sequence of SEQ ID NO: 2 and an HCDR3 having the amino acid sequence of SEQ ID NO: 3, and a variable light chain domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 4, an LCDR2 having the amino acid sequence of SEQ ID NO: 5 and an LCDR3 having the amino acid sequence of SEQ ID NO: 6;(b) a second binding domain that binds specifically to TIGIT, wherein the second binding domain comprises a heavy chain variable domain comprising an HCDR1 having the amino acid sequence of SEQ ID NO: 11, an HCDR2 having the amino acid sequence of SEQ ID NO: 12 and an HCDR3 having the amino acid sequence of SEQ ID NO: 13, and a light chain variable domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 14, an LCDR2 having the amino acid sequence of SEQ ID NO: 15 and an LCDR3 having the amino acid sequence of SEQ ID NO: 16.; 45. Pharmaceutical composition, according to claim 44, characterized in that the pharmaceutical composition comprises about 70 mg, about 150 mg, about 210 mg, about 450 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1250 mg or about 1500 mg of bispecific binding protein.

46. ​​Pharmaceutical composition according to claim 44, characterized in that the pharmaceutical composition comprises approximately 750 mg of bispecific binding protein.

47. Pharmaceutical composition, according to claim 44, characterized in that the pharmaceutical composition comprises about 1500 mg of bispecific binding protein.

48. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having the amino acid sequence of SEQ ID NO:

9.

49. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:7 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

9.

50. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having the amino acid sequence of SEQ ID NO:8 and a light chain having the amino acid sequence of SEQ ID NO:

10.

51. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the first binding domain of the bispecific binding protein that specifically binds to PD-1 comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:8 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

10.

52. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having the amino acid sequence of SEQ ID NO:

19.

53. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a variable heavy chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:17 and a variable light chain domain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

19.

54. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having the amino acid sequence of SEQ ID NO:18 and a light chain having the amino acid sequence of SEQ ID NO:

20.

55. Pharmaceutical composition, according to any one of claims 44 to 47, characterized in that the second binding domain of the bispecific binding protein that specifically binds to TIGIT comprises a heavy chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:18 and a light chain having an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO:

20.

56. Kit, characterized in that it comprises the pharmaceutical composition as defined in any one of claims 44 to 55.

57. Kit, according to claim 56, characterized in that it further includes instructions for administering the pharmaceutical composition.

58. Pharmaceutical composition, according to any one of claims 44 to 55, characterized in that it is for use in the treatment of cancer.

59. Pharmaceutical composition for use, according to claim 58, characterized in that the cancer is one or more of ovarian cancer, breast cancer, colorectal cancer, prostate cancer, cervical cancer, uterine cancer, testicular cancer, bladder cancer, head and neck cancer, melanoma, pancreatic cancer, renal cell carcinoma and lung cancer.

60. Pharmaceutical composition for use, according to claim 59, characterized in that the cancer is non-small cell lung cancer (NSCLC).

61. Pharmaceutical composition for use according to claim 60, characterized in that the NSCLC is advanced or metastatic.

62. Pharmaceutical composition for use, according to claim 60 or 61, characterized in that the cancer has a PD-L1 tumor ratio score greater than or equal to 1%.

63. Pharmaceutical composition for use, according to claim 60 or 61, characterized in that the cancer has a PD-L1 tumor proportion score greater than or equal to 50%.

64. Pharmaceutical composition for use, according to any one of claims 60 to 63, characterized in that the cancer has not been previously treated with a checkpoint inhibitor.

65. Use of a bispecific binding protein that binds specifically to Programmed Death-1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), characterized by the fact that it is for the manufacture of a drug for use in therapy.

66. Use of a composition as defined in any one of claims 44 to 55, characterized in that it is for the manufacture of a medicament for use in therapy. Petition 870250088197, dated 09 / 29 / 2025, pp. 155 / 166

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