Receptor-mediated endocytosis for targeted internalization and degradation of immune-related membrane proteins

Abstract

Disclosed are fusion proteins (and homodimers and heterodimers thereof). Fusion proteins can bind to a protein of interest and to an internalizing receptor (transferrin receptor) on a cell surface. Once bound, the protein of interest can be internalized and / or degraded inside a cell.

Description

DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 RECEPTOR-MEDIATED ENDOCYTOSIS FOR TARGETED INTERNALIZATION AND DEGRADATION OF IMMUNE-RELATED MEMBRANE PROTEINS

[0001] This application is an International Application, which claims the benefit of priority from U.S. provisional patent application no.63 / 566,046, filed on March 15, 2024, U.S. provisional patent application no.63 / 566,069, filed on March 15, 2024, and U.S. provisional patent application no.63 / 566,076, filed on March 15, 2024, the entire contents of each which are incorporated herein by reference in their entireties.

[0002] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

[0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records but otherwise reserves any and all copyright rights. FIELD

[0004] Aspects of the invention are drawn to compositions and methods for modulating molecules on the cell surface of immune system related cells, including immune cell receptors and coreceptors in immune cells to reversibly control immune cell activity and to treat immune related diseases. SEQUENCE LISTING

[0005] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on [ ], is named [ ] and is [ ] bytes in size.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 BACKGROUND

[0006] Traditional small molecule inhibitor-based therapies have certain disadvantages, such as toxicity and limited efficacy. Examples of inhibitor features that contribute to their disadvantages include a binding affinity that is the determinant of inhibitor potency; a therapeutic response that depends on sustained target binding; a limited functionality on the target protein; and subverted efficacy through target protein overexpression, native ligand competition, and development of target protein mutations that limit binding or facilitate resistance. Thus, a desirable therapeutic modality exhibits low toxicity and high efficacy. For example, a desirable therapeutic modality includes a variety of features that contribute to overall potency; a therapeutic response that does not entirely or mostly depend on sustained target binding; the ability to completely or substantially limit functionality of the target protein; and limited or no ability of a target cell to subvert efficacy, such as through target protein overexpression, native ligand competition, and / or development of target protein mutations that limit binding or facilitate resistance.

[0007] Membrane proteins are central to a myriad of cellular functions and serve as targets for over half of all drugs. Therefore, developing strategies to degrade membrane proteins is of exceptional interest for both basic research and therapeutic intervention purposes.

[0008] Targeted protein degradation (TPD) is a rapidly growing field in drug discovery and pharmacology. Complementing traditional drug modalities, TPD molecules offer a novel therapeutic mechanism to tackle challenging targets or increase the therapeutic potential of currently used drugs.

[0009] Eukaryotic cells use proteosomes to degrade proteins via the ubiquitin-proteosome pathway (UPP), and lysosomes degrade protein aggregates and whole organelles through endocytosis / phagocytosis. They also use lysosomes to degrade proteins and organelles through endocytosis, phagocytosis, and autophagy. A further component of this pathway is the E3 enzyme which recognizes the targeted protein. This interacts with a 26S proteosome which degrades the protein. Further, TPD has a role in immunology as it protects mechanisms when pathogens, cancers, and other diseases target the mechanisms that protect and regulate key functions.

[0010] Proof-of-concept strategies for membrane receptor degradation have been described. These strategies use heterobifunctional biologics that recruit a specific “effector” protein such asDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 a membrane E3 ligase (Cotton, A. D., Nguyen, D. P., Gramespacher, J. A., Seiple, I. B. & Wells, J. A. Development of Antibody-Based PROTACs for the Degradation of the Cell-Surface Immune Checkpoint Protein PD-L1. J Am Chem Soc 143, 593-598 (2021)) or a lysosome shuttling receptor (Ahn, G. et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol 17, 937-946 (2021)) to the protein of interest (POI) to induce lysosome-mediated protein degradation. However, the effectiveness of these biological effectors is often limited by their tissue-specific expression patterns. GalNAc-LYTAC, for instance, targets the hepatocyte-specific receptor asialoglycoprotein receptor (ASGPR), making it only suitable for treating liver disease or clearing circulating targets (Ahn, G. et al. Nat Chem Biol 17, 937-946 (2021); Zhou, Y., Teng, P., Montgomery, N. T., Li, X. & Tang, W. Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins. ACS Cent Sci 7, 499-506 (2021)), while RNF43- or ZNRF3-based methods are more effective for treating Wnt-signaling upregulated disorders where RNF43 and ZNRF3 are expressed at high levels.

[0011] Current technologies are therefore not able to cover the full spectrum of diseases, and developing alternative effectors overexpressed in different diseases and tissues would greatly expand the range of cell surface targets that can be regulated and also increase the targeting specificity. In particular, the use of TBD for treating immune related diseases is an area that is yet needed to be explored and developed.

[0012] Accordingly, there is a need to improve targeted protein degradation, particularly of membrane proteins to treat an array of diseases, such as diseases of the immune system. SUMMARY

[0013] Disclosed here are new reagents (bispecific modulators, also called fusion proteins) and methods for regulating molecules on the surface of cells (e.g., proteins of interest). In some embodiments, the reagents and methods are used to control the levels of cell-surface molecules on cells related to the immune system. In some embodiments, the reagents and methods are used to reversibly activate or inactivate an immune cell. In some embodiments, immune cell activation is modulated in vivo. In some embodiments, the reagents and methods are used to control the levels of receptors and / or co-receptors on the surface of immune cells (e.g., epidermal growth factor receptor or CCR6, CD19, CD20, programmed death-ligand 1 (PD-L1), epidermalDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 growth factor (EGFR), CD8, CD3 or a T cell receptor (TCR) and the like) to inhibit and / or modulate immune responses.

[0014] In some embodiments, the reagents and methods can be used to control the levels of molecules like chemokine receptor 6 (CCR6), chemokine receptor type 2 (CCR2), cluster of differentiation 19 (CD19), cluster of differentiation 20 (CD20), cluster of differentiation 22 (CD22), cluster of differentiation 38 (CD38), B-cell activating factor receptor (BAFF R), tachykinin precursor 1 (TAC1), B-cell maturation antigen (BCMA, C5a receptor 1 (C5aR1), major histocompatibility complex (MHC), cluster of differentiation 3 (CD3), cluster of differentiation (CD4), cluster of differentiation (CD8), cluster of differentiation (CD25), B cell receptor (BCR), interleukin-7 receptor α-chain (IL7Ra), interleukin-15 receptor α-chain (IL15Ra), ORAI1-3, voltage-gated potassium channel KV1.3 (Kv1.3), (Fc receptor) FcRs, prostaglandin receptor D2 (PGD2R), chemoattractant receptor homologous molecule expressed on Th2 lymphocytes (CRTH2), GPR44, high-affinity IgE receptor (FceR1, also known as FcεRI or Fc epsilon RI), Interleukin CXCR1 / 2, Interleukin CXCR1 / 2, Interferon receptors (IFN Receptors), Glycoprotein 130 (gp130), Interleukin-23 receptor (IL23R), P2X purinoceptor 7 (p2X7 receptor, and S1P-R.

[0015] In some embodiments, disclosed are bispecific modulators as described herein (also called fusion proteins, fusion protein homodimers, fusion protein heterodimers). In some embodiments, a protein complex (e.g., an antigen or autoantigen and, optionally a MHC molecule) to which a cell-surface molecule (e.g. a TCR receptor in an immune cell) can bind or an antibody or antibody fragment that can bind to the cell-surface molecule is fused to a ligand for an internalizing receptor or an antibody or antibody fragment that can bind to the internalizing receptor or membrane protein. In embodiments, after binding, the fusion protein can cause the cell-surface molecule (e.g., proteins of interest) to be internalized by the immune cell and, in some embodiments, the internalized cell-surface molecule can be degraded. In various embodiments, the fusion proteins can target single-pass or multi-pass membrane proteins.

[0016] In some embodiments, monomers and dimers of the fusion proteins are described herein. In particular embodiments, the fusion proteins are monomers. In particular embodiments, the fusion proteins are dimers. In particular embodiments, the fusion proteins are homodimers. In particular embodiments, the fusion proteins are heterodimers. In particular embodiments, theDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 fusion proteins have a means for dimerizing the fusion proteins. In some embodiments, the means for dimerizing can be one or more disulfide bonds between cysteine amino acid residues of separate fusion protein molecules.

[0017] Disclosed are fusion proteins of Formula I, R1-R2-R3 (I), wherein R1 is a protein of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI) for binding CCR6, CD19, CD20, a programmed death-ligand (PD-L1), an epidermal growth factor receptor (EGFR), CD8, CD3 or a T cell receptor (TCR). R2 is a linker of the formula R4-R5 or R5-R4, wherein, R4 is IgG Fc region, and R5 is an optional protease-sensitive linking means (also known as a means for linking), and R3 is a TR binding means (also known as a means for binding TR), wherein the TR binding means (also known as a means for binding TR) is non- competitive with endogenous transferrin for binding to the TR, and optionally, comprising a glycine-rich linker between R2 and R3.

[0018] The disclosed fusion proteins (or homodimers and heterodimers thereof) can have a TR binding means (also known as a means for binding TR) that is VHHA-12 (SEQ ID NO: 154), VHHA (SEQ ID NO: 146), VHHA-5 (SEQ ID NO: 155), VHHA-7 (SEQ ID NO: 156), or VHHB (SEQ ID NO: 148). The disclosed fusion proteins can have a protease-sensitive linking means (also known as a means for linking) that is a cathepsin-cleavable peptide. The cathepsin- cleavable peptide linker can be FK, VA, VK, SEQ ID NO: 7, 8, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144 and 145.

[0019] The disclosed fusion proteins can be homodimers. The TR binding means (also known as a means for binding TR) within the homodimer can have a binding affinity to TB (Kd) of about 0.001-50 nM.

[0020] The disclosed fusion proteins (e.g., R1-R2-R3 (I)) can be heterodimers linked to a fusion protein of Formula II, R4’-R3’ (II), wherein R4’ is IgG Fc region, and R3’ is a TR binding means (also known as a means for binding TR), and optionally, wherein a linkage between R3’ and R4’ is a protease-sensitive linking means (also known as a means for linking). The TR binding means (also known as a means for binding TR) within the heterodimer can have a binding affinity to TB (Kd) of about 0.1-200 nM.

[0021] The disclosed fusion proteins can have a TR binding means (also known as a means for binding TR) that is an antibody or polypeptide. The TR binding means (also known as aDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 means for binding TR) can be an antibody fragment having a heavy chain variable region. The TR binding means (also known as a means for binding TR) can have: (a) a VH CDR1 having the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 having the amino acid sequence of ITATGNT (SEQ ID NO: 176), and a VH CDR3 having the amino acid sequence of YMLDK (SEQ ID NO: 177); (b) a VH CDR1 having the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 having the amino acid sequence of FTATGNT (SEQ ID NO: 179), and a VH CDR3 having the amino acid sequence of AMLDK (SEQ ID NO: 180); or (c) a VH CDR1 having the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 having the amino acid sequence of FTATGNT (SEQ ID NO: 179), and a VH CDR3 having the amino acid sequence of YMADK (SEQ ID NO: 183).

[0022] The disclosed fusion proteins can have a POIB or POI binding means (also known as a means for binding POI) that is an antibody. The antibody can bind to an extracellular domain of a transmembrane protein. The POIB or POI binding means (also known as a means for binding POI) can bind to an extracellular domain of CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or TCR.

[0023] The POIB or POI binding means (also known as a means for binding POI) of the disclosed fusion proteins can bind CCR6 and can have a VH CDR1 that has the amino acid sequence of GFSFSDY (SEQ ID NO: 200), a VH CDR2 that has the amino acid sequence of TTGGR (SEQ ID NO: 201), a VH CDR3 that has the amino acid sequence of PLRGAWFAY (SEQ ID NO: 202), a VL CDR1 that has the amino acid sequence of RSSQSIVHSNANTYLE (SEQ ID NO: 203), a VL CDR2 that has the amino acid sequence of KVSNRF (SEQ ID NO: 204), and a VL CDR3 that has the amino acid sequence of FQGTYLPLT (SEQ ID NO: 205). The POIB or POI binding means (also known as a means for binding POI) can bind CD8 and can have a VH CDR1 comprising the amino acid sequence of GFTFDDY (SEQ ID NO: 206), a VH CDR2 that has the amino acid sequence of RIFDRH (SEQ ID NO: 207), a VH CDR3 that has the amino acid sequence of GSFWACTRPEGAMDY (SEQ ID NO: 208). The POIB or POI binding means (also known as a means for binding POI) can bind CD8 and can have a VH CDR1 that has the amino acid sequence of GFSLISD (SEQ ID NO: 209), a VH CDR2 that has the amino acid sequence of WADGS (SEQ ID NO: 210), a VH CDR3 that has the amino acid sequence of NRESYYFDY (SEQ ID NO: 211), a VL CDR1 that has the amino acid sequence of QASQNIDKYIA (SEQ ID NO: 212), a VL CDR2 that has the amino acid sequence ofDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 YTSTLVS (SEQ ID NO: 213), a VL CDR3 that has the amino acid sequence of LQYDTLYT (SEQ ID NO: 214).

[0024] The disclosed fusion proteins can have a glycine-rich linker that is SEQ ID NO: 9, 10, 11, 12, 13, 14, 15 or 16.

[0025] Disclosed are homodimers of a fusion protein of Formula I, R1-R2-R3 (I), wherein R1 is a of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI) for binding CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or a TCR, R2 is a linker of the formula R4-R5 or R5-R4, wherein R4 is IgG Fc region, and R5 is an optional protease-sensitive linking means (also known as a means for linking), and R3 is a TR binding means (also known as a means for binding TR), wherein the TR binding means (also known as a means for binding TR) is non-competitive with endogenous transferrin for binding to the TR, and optionally, the homodimer of the fusion protein has a glycine-rich linker between R2 and R3. In the homodimer of a fusion protein TR binder or TR binding means can be VHHA-5 (SEQ ID NO: 155), VHHA (SEQ ID NO: 146), VHHA-7 (SEQ ID NO: 156), VHHA-12 (SEQ ID NO: 154) or VHHB (SEQ ID NO: 148). The homodimer of a fusion protein can have a disulfide bond between cysteine amino acids in R4 of separate fusion proteins.

[0026] Disclosed are homodimers of a fusion protein of Formula III, R1-R6-R3 (III), wherein R1 is a protein of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI) for binding CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or a TCR, R6 is a dimerization means (also known as a means for dimerizing), and R3 is a TR binder or TR binding means (also known as a means for binding TR), wherein the TR binder or TR binding means (also known as a means for binding TR) is non-competitive with endogenous transferrin for binding to the TR, and wherein the homodimer optionally has a protease-sensitive linking means (also known as a means for linking) between R1 and R6.

[0027] Disclosed are heterodimer of fusion proteins of Formula IV and V (R1-R2 (IV); R3- R2’ (V)) wherein R1 is at least one protein of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI) for binding CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or a TCR, R2 and R2’ are linkers of the formula R4 or optionally R4-R5, wherein R4 is an IgG Fc region, R5 is an optional protease-sensitive linking means (also known as a means for linking), and R3 is at least one TR binding means (also known as a means for binding TR) wherein the TR binding means (also known as a means for binding TR) is non-competitive withDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 endogenous transferrin for binding to the TR. The R4 of separate fusion proteins in the heterodimer can have complementary knob and hole structures.

[0028] Disclosed are heterodimers of fusion proteins of Formula I and VI (R1-R2-R3 (I); R2’ (VI)), wherein R1 is a protein of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI) for binding TCR, CD3, CD8, EGFR, PD-L1, CD20 or CCR6, R2 is a linker of the formula R4-R5 or R5-R4, wherein R4 is an IgG Fc region, R5 is an optional protease-sensitive linking means (also known as a means for linking), R3 is at least one TR binder or TR binding means (also known as a means for binding TR), wherein the TR binder or TR binding means (also known as a means for binding TR) is non-competitive with endogenous transferrin for binding to the TR, and R2’ is a linker of the formula R4 or optionally R4-R5.

[0029] Disclosed are fusion proteins of Formula I, R1-R2-R3 (I), wherein R1 is a protein of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI) for binding CD8. R2 is a linker of the formula R4-R5 or R5-R4, wherein, R4 is IgG Fc region, and R5 is an optional protease-sensitive linking means (also known as a means for linking), and R3 is a TR binding means (also known as a means for binding TR), wherein the TR binding means (also known as a means for binding TR) is non-competitive with endogenous transferrin for binding to the TR, and optionally, comprising a glycine-rich linker between R2 and R3.

[0030] Disclosed are nucleic acid sequences encoding the fusion proteins and homodimers and heterodimers thereof disclosed herein.

[0031] Disclosed are methods for treating a subject that has an immune related disease, the method being administering the disclosed fusion proteins / homodimers / heterodimers to the subject. The subject can have type 2 diabetes mellitus, Alzheimer’s disease, obesity or depression. The disclosed fusion proteins can be for use in treating an immune related disease in a patient. Disclosed are uses of the disclosed fusion proteins for treating a subject having an immune related disease.

[0032] Disclosed are pharmaceutical compositions of any of the fusion proteins, and homodimers or heterodimers thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Certain illustrations, charts, or flow charts are provided to allow for a better understanding for the present invention. It is to be noted, however, that the drawings illustrateDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 only selected embodiments of the inventions and are therefore not to be considered limiting of scope. Additional and equally effective embodiments and applications of the present invention exist.

[0034] FIGS.1 A, 1B-C, 1D illustrate PD-L1 degradation in an embodiment using Immune TransTACs (fusion proteins, fusion protein homodimers, fusion protein heterodimers) variants with various geometries. FIG.1A illustrates PD-L1 Immune TransTAC variants. FIG.1B shows results of an SDS-PAGE showing protein expression of the Immune TransTAC variants. FIG. 1C illustrates results of Western Blot showing PD-L1 degradation for each of the Immune TransTAC variants. FIG.1D shows PD-L1 dose curve degradation for variants v1.4 (top) and V1.2 (bottom).

[0035] FIG.2 illustrates PD-L1 degradation in an embodiment using VHHA or VHHB as TfR1 binders (transferrin receptor binders or TRBs).

[0036] FIGS.3A, 3B shows an embodiment of amino acid sequences corresponding to Immune TransTAC variants v1.2 (FIG.3A and SEQ ID NO 150-151) and v1.4 (FIG.3B, SEQ ID NO: 152-153). In the sequences, yellow is POIB (R1), blue is R4 (IgG Fc region), green is TRB (R3). Unshaded regions are either leader sequences or GS linkages. The “TS” amino acids at the N-terminus of some of the sequences were added for convenience in constructing plasmids.

[0037] FIGS.4A, 4B. FIG.4A shows IC50 values for PD-L1 degradation by Immune TransTAC variants that include H7, VHHA or VHHB as second motif binders (e.g. TRBs) in an embodiment. FIG.4B shows IC50 for VHHA Immune TransTAC variant in an embodiment.

[0038] FIGS.5A-D. illustrates pharmacokinetics of Immune TransTACs in an embodiment. FIG.5A shows a schematic of the experimental design used to assess the in vivo half-life and safety of EGFR-Immune TransTACs. FIG.5B shows weight over time of mice treated as described in FIG.5A. N=3 per treatment group. FIG.5C shows mice erythrocyte cell counts and other relevant properties measured at day 5 of the experimental designed described in FIG.5A. N=3 per treatment group. RBC: Red blood cell counts; Hb: Hemoglobin levels; HCT: Hematocrit counts; MCV: Mean corpuscular volume, which refers to the average size and volume of a red blood cell; MCH: Mean corpuscular hemoglobin, which indicates the amount of hemoglobin per red blood cell; CHC: Cell hemoglobin concentration; RDW: Red cell distribution width. Results in b and c indicated no observable toxic effects from the injectedDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 proteins. The error bars represent the standard deviation. FIG.5D shows Western blot and quantification of plasma levels of the proteins injected in mice according to the different treatments described in FIG.5A. N = 3 per treatment group. The error bars represent standard deviation. i.p.: intraperitoneal injection.

[0039] FIG.6 illustrates an example approach for controlling T cell activation using targeted CD19 binding receptor internalization and / or degradation (fusion proteins, including TransTAC molecules) (TransTAC is Transferrin receptor-mediated TArgeting Chimera), as disclosed herein.

[0040] FIG.7 illustrates an example schematic of TransTAC technology. When applied to cells of the immune system is called Immune TransTAC (TransTAC is Transferrin receptor- mediated TArgeting Chimera, e.g., a type of fusion protein). Extracellular proteins (e.g., target membrane proteins with extracellular domains present in the surface of immune cells) can be selectively internalized and degraded by tethering, for example, an antibody to (or a ligand of) the target membrane protein to a transferrin receptor with a fusion protein, shown as a membrane protein-specific antibody-transferrin fusion protein.

[0041] FIG.8A-B illustrates the characterization of EGFR-Immune TransTAC cleavage in HEK cells expressing EGFR only, TfR1 only, or both EGFR and TfR1. Western blot (FIG.8A) and quantification of FIG.8A (FIG.8B). Recombinant Immune TransTAC - / + cathepsin B was used as a control. Cells were treated with TransTACs for 24 hours. N = 2-3 biologically independent experiments.

[0042] FIGS.9A-B, 9C, 9D, 9E show Immune TransTAC degraders for various proteins (proteins of interest or POIs) in an embodiment. FIG.9A shows a schematic of membrane proteins targeted by TransTACs. These targets are either synthetic, or native, single- or multi- pass proteins expressed on immune cells surfaces. FIG.9B shows PD-L1 degradation by Immune TransTACs in MDA-MB-231 cells analyzed by Western blot. A scFv format of atezolizumab is used as the PD-L1 binding moiety. FIG.9C shows EGFR degradation by Immune TransTAC in A549 cells. An affibody is used as the EGFR binding moiety. FIG.9D shows CD20 degradation by Immune TransTAC. A Fab format of rituximab is used as the CD20 binding moiety. FIG.9E shows CD19 binding receptor degradation by an Immune TransTAC. An engineered CD19 ectodomain is used as the CAR binding moiety. All cells were incubated with TransTACs for 12-18 hours. Data are representative of 3 independent experiments.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 Controls without the TfR1 binding domain or the cathepsin cleavable linker showed no or little cleavage. Error bars represent standard deviations. P values were determined by unpaired two- tailed t tests. ns, not significant; * P ≤0.05; **P ≤0.01; ***P ≤0.001.

[0043] FIG.10 illustrates results showing expression of an anti-EGFR affibody-Fc-Tr Immune TransTAC molecule (Left) and the effect on EGFR levels of incubating the Immune TransTAC molecule with a MCF10A EGFR expressing cell line (Right) in an embodiment.

[0044] FIGS.11A-B illustrates results in an embodiment showing the effect on EGFR levels of incubating an Immune TransTAC molecule with A549 cells (A) and killing of MCF10A EGFR cells (B).

[0045] FIG.12 illustrates results in an embodiment showing that Immune TransTAC targeting effectively internalized the receptor.

[0046] FIG.13 illustrates example results showing expression of various Immune TransTAC proteins in cultured cells.

[0047] FIG.14 illustrates results in an embodiment showing Immune TransTAC targeting of T cells expressing a CD19 binding receptor (CD19 binding T cells) effectively decreased levels of the CD19 binding receptor (e.g., internalized the CD19 binding receptor).

[0048] FIG.15 illustrates example results showing that Immune TransTAC targeting of a CD19 binding T cell effectively internalized the CD19 binding receptor.

[0049] FIG.16 illustrates example results showing that Immune TransTAC targeting of a CD19 binding receptor on Jurkat cells, in the presence of K562 cells, inhibited activation of the Jurkat cells.

[0050] FIG.17 illustrates example results showing Immune TransTAC targeting of a CD19 binding receptor internalized the CD19 binding receptor. inhibited T cell activation.

[0051] FIG.18 illustrates results in an embodiment showing that an Immune TransTAC molecule specific for CD19 blocks the activation of CD19 binding T cells in presence of K562 cells and also shows that the Immune TransTAC molecule had minimal effect on the Jurkat cells in absence of the K562 cells.

[0052] FIGS.19A-B, 19C illustrates a schematic diagram in an embodiment of an Immune TransTAC molecule that can bind a CD19 binding receptor and an internalizing receptor, and a dimer of a Immune TransTAC molecule that can bind a T cell receptor and an internalizingDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 receptor (A), and results of using the molecules on cells expressing the CD19 binding receptor on the levels of the CD19 binding receptor (B). FIG.19C illustrates fluorescence microscopy of the targeted CD19 binding receptors on the cells in FIG.19B.

[0053] FIGS.20A-B, 20C, 20D-E, 20F-G, 20H and 20I illustrate an embodiment where an internalized CD19 binding receptor is not degraded, but linker engineering (here, incorporating a cathepsin-sensitive linker) resulted in degradation of the CD19 binding receptor. (A) shows schematic diagrams of various molecules used in this study. GFLG indicates a Gly-Phe-Leu-Gly peptide linker which is sensitive to lysosomal cathepsin proteases. (B) shows Western blots of the targeted CD19 binding receptor (Anti-CD3z) and actin control (β-Actin) when various of the molecules in (A) were used. (C) shows a graph of the data from (B), where CD19 binding receptor levels are normalized to β-Actin levels. (D) shows Western blots as above, using other of the molecules in (A). (E) shows a graph of the normalized data from (D). (F) shows a schematic of a dimer of an Immune TransTAC molecule that can bind a CD19 binding receptor and an internalizing receptor, which also contains GFLG linkers. (G) shows Western blots using the molecule shown in (F). (H) shows a graph of the normalized data from (F). (I) shows results from screening additional cathepsin-sensitive Immune TransTAC molecules that have improved inhibition potency.

[0054] FIGS.21A-B shows results in an embodiment demonstrating Immune TransTAC inhibition of T cell activity is more potent than inhibition by ImmuneTrap (domain to which CD19 binding receptor can bind fused to an Fc region) in Jurkat cells (A) and in primary T cells (B).

[0055] FIGS.22A, 22B show results in an embodiment illustrating that CD19 binding receptor Immune TransTAC that binds to CD19 receptor turns off A375 cell killing of the T cells expressing a CD19 binding receptor, and that A375 cell killing of the -T cells resumes when the Immune TransTAC molecule is removed.

[0056] FIGS.23A-B shows schematic diagrams of molecules used in the study in an embodiment, including affibody-based EGFR Immune TransTAC molecules (A). (B) shows results of removing EGFR from the surface of A549 cells using the molecules shown in (A). The data show that use of the affibody-based Immune TransTAC molecule produces good results (approximately 10-50-fold improvement in IC50).DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0057] FIGS.23C-D shows results of inhibition of cell proliferation by the molecules in an embodiment shown in (A), as measured using the MTT cellular proliferation assay. The data show that use of the affibody-based Immune TransTAC molecule produces good results (approximately 10-50-fold improvement in IC50).

[0058] FIGS.24A-B, 24C. (A) shows a schematic of molecules used in this study in an embodiment (B) and western blot results measuring internalization and degradation of the molecules (C). FIG.24C shows a graph of the normalized data from FIG.24(B) in an embodiment.

[0059] FIGS.25A-B illustrate example data demonstrating protein internalization by Immune TransTAC and reversibility of the internalization.

[0060] FIG.26 shows example data demonstrating Immune TransTAC can interfere with IFNγ production.

[0061] FIGS.27A and 27B show example data of transferrin receptor expression on various cells.

[0062] FIGS.28 A-B illustrates CD20 degradation kinetics in an embodiment. FIG.28A shows time-course measurement of whole-cell CD20 levels in Raji B cells treated with 25 nM CD20-Immune TransTAC. FIG.28B shows reversibility of degradation. Cells were treated with TransTAC for 12-16 hours before washout.

[0063] FIGS.29A and 29B show example data demonstrating that Immune TransTACs can degrade EGFR in cells and the underlying cellular machinery that mediates the degradation.

[0064] FIGS.30A and 30B-C show EGFR internalization using with Immune TransTACs in an embodiment.

[0065] FIG.31 shows example data demonstrating that Immune TransTACs with the linker variants can degrade receptors in Jurkat cells.

[0066] FIGS.32A and 32B shows example data demonstrating that Immune TransTACs can degrade PD-L1.

[0067] FIG.33 shows example data demonstrating that Immune TransTAC can degrade CD20.

[0068] FIGS.34A-D show example Immune TransTAC molecules that include protease- sensitive linkers and example data obtained with the molecules.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0069] FIG.35 shows example data obtained with Immune TransTAC molecules containing various protease-sensitive linkers.

[0070] FIGS.36A-C show example Immune TransTAC molecules that include an antibody fragment specific for transferrin binding and example data obtained with the molecules.

[0071] FIGS.37A-B show examples of Immune TransTAC molecules and example data obtained with the molecules. These molecules target a chimeric antigen receptor (CAR). The TRBs in these molecules are H7.

[0072] FIGS.38A-E and 38F-H show an example overview of the Immune TransTAC technology and TfR expression analysis. (A) Schematic of the example Immune TransTAC technology. Immune TransTAC induces close proximity of TfR and POI at the cell surface, leading to co-internalization of the complex to early endosomes (EE), where a cathepsin enzyme cleaves Immune TransTAC and separates the POI from the TfR. The POI then traffics to late endosomes (LE) / lysosomes for degradation, while TfR is recycled back to the cell surface. (B) Illustration of an example Immune TransTAC protein. Some example designs to make Immune TransTACs efficient degraders include: (1) containing two anti-TfR binders for binding and priming a TfR dimer for endocytosis, (2) having a cathepsin B-sensitive linker between the anti- POI binder and the Fc for endosomal cleavage to separate the POI from the recycling TfRs, and (3) using an antibody binder instead of a native TF ligand to reduce trafficking to the recycling endosomes (REs). (C) Relative cell surface TfR expression levels across various cell lines characterized by flow cytometry. Data are representative of 3 independent experiments. (D) Relative TFRC RNA expression levels in diverse tissues based on the MERAV database. (E) Relative TFRC RNA expression levels in native T cells. TfR is upregulated by approximately 6- fold in activated CD4 and CD8 T cells compared to inactivated T cells with statistical significance (p=1.25e-68 for CD4 T cells and 4.81e-68 for CD8 T cells, FIG.38H).

[0073] FIGS.39A-H, I-L show example Immune TransTAC degrader engineering. (A) Schematic of example CD19 binding receptor-Immune TransTACs and control. Immune TransTACv0.1 has a single CD19NT.1 domain, a single TF, and a knob-in-hole (KIH) Fc, v0.2 has two CD19NT.1s, two TFs, and a homodimeric Fc that connects the binders, v0.4 contains a cathepsin-sensitive linker between CD19NT.1 and Fc, v0.5 contains a H7 scFv for TfR binding, v1.0 contains both the H7 and the cathepsin sensitive linker. (B) Schematic of a myc-tagged anti- CD19 receptor. (C) Flow cytometry measurements of cell-surface CD19 binding receptorDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 expression levels in -Jurkats treated with Immune TransTACv0.1, v0.2, and control. Immune TransTACv0.2 results in higher CD19 binding receptor clearance from cell surface than v0.1 and no hook effect. Data are representative of 2 independent experiments. (D) Characterization of whole-cell CD19 binding receptor levels by Western blot in Jurkat cells expressing the CD19 binding receptor and treated with Immune TransTACs. Immune TransTACv1.0 degrades approximately 80% of CD19 binding receptor; v0.2 didn’t result in significant CD19 binding receptor degradation. (E-H) Schematics showing different Immune TransTACs alter intracellular trafficking of the POI. Cleavage of the cathepsin sensitive-linker in v0.4 and v1.0 leads to separation of POI from TfR, hence enhanced LE / lysosomal trafficking of the POI and degradation; the H7 scFv in v0.5 and v1.0 reduces trafficking of the complex to the REs, hence increases the proportion of POI in EEs and subsequent proteolytic processing, when a cleavage linker is present. (I, J) Representative fluorescence images of Hela cells co-expressing CD19 binding receptor-GFP (green) and endosomal / lysosomal markers-mCherry (red) treated with various Immune TransTAC molecules. Cell nucleus is stained with Hoechst (blue). Untreated (UT) or control-treated cells had CD19 binding receptor-GFP localized at the cell membrane. v0.5 and v1.0 led to efficient degradation of CD19 binding receptor-GFP, manifested by the significantly lower GFP signals. v0.2-treated cells predominantly trafficked CD19 binding receptor to the REs, showing co-localization of CD19 binding receptor -GFP with mCherry- Rab11 (white arrows). v0.5-treated cells trafficked CD19 binding receptor to the EEs, showing co-localization of CD19 binding receptor -GFP with mCherry-Rab5 (white arrows). (K) Pearson correlation analysis of CD19 binding receptor -GFP colocalization with the Rab5 (EE), EEA1 (EE), and Rab11 (RE) markers. T-tests show Rab5, EEA1, Rab11 colocalization with CD19 binding receptor are statistically different for cells treated with v0.2 vs. v0.5. (L) Pearson correlation analysis of CD19 binding receptor -GFP colocalization with the Rab7 (LE) and Lamp1 (lysosome) markers. T-tests show Rab7 and Lamp1 colocalization with CD19 binding receptor are statistically significant for v0.2 vs. v0.4, and v0.5 vs. v1.0. For k and l, number of cells used for each analysis are as follows: For v0.2, N=12, N=12, and N=13 for the EEA1, Rab5 and Rab11 markers, respectively. For v0.5, N=10, N=22, and N=15 for the EEA1, Rab5 and Rab11 markers respectively. For v0.2, v0.4, v0.5, and v1.0 with the Lamp1 marker N=16, N=21, N=13, and N=13, respectively.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0074] FIGS.40A-D shows examples of Developing Immune TransTACs degraders for various membrane targets. (A) Schematic of membrane proteins targeted by Immune TransTACs in the present study. These targets are either synthetic, or native, single- or multi-pass proteins expressed on cell surface. (B) PD-L1 degradation by Immune TransTACs in MDA-MB-231 cells analyzed by Western blot. A scFv or Fab format of atezolizumab is used as the PDL1 binding moiety. (C) EGFR degradation by Immune TransTAC in A549 cells. An affibody is used as the EGFR binding moiety. (D) CD20 degradation by Immune TransTAC. A Fab format of rituximab is used as the CD20 binding moiety.

[0075] FIGS.41A-H and 41I show example structure-activity relationship (SAR) studies of Immune TransTACs, mechanisms, and in vivo characterizations. (A) Time-course measurement of cell surface CD19 binding receptor levels in CD19 binding receptor -Jurkat cells treated with Immune TransTACs, revealing the fast kinetics of Immune TransTAC-mediated CD19 binding receptor internalization. (B) Schematics of Immune TransTAC variants consisting of one or two copies of anti-POI and anti-TfR binders in different protein geometries. (C) Cell surface CD19 binding receptor level measurements in CAR-Jurkats treated with Immune TransTAC variants outlined in (B). The results highlight the impacts of having two vs. one TfR binders (v0.5 vs v0.7) and geometry (v0.8 vs. v0.9) in modulating protein internalization. Data are representative of 3 independent measurements. (D) Competition assay with a H7-Fc fusion protein. Concentration-dependent reduction of receptor internalization is observed with H7-Fc, proving internalization is mediated through TfR. Data are representative of 3 independent measurements. (E) Study of underlying degradation pathways with Immune TransTACs. Intact lysosomal function is critical for degradation, as degradation is fully inhibited by bafilomycin in A549 cells treated with EGFR-Immune TransTACs. (F) Whole-cell TfR level measurement with Immune TransTAC treatment. TfR level stays consistent while PD-L1 is degraded in MDA-MB-231 cells treated with PDL1 Immune TransTAC. (G) Schematic of mouse experiments to assess Immune TransTAC safety and serum half-life via IP injection. (H) Weight monitoring of mice over time after Immune TransTAC or control IgG injection. Results reveal no observable effects on mouse weight over time, showing molecules are well tolerated. N=2 per treatment group. (I) Western blot quantification of plasma levels of CD20-Immune TransTAC and IgG control over time. N=2 per treatment group.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0076] FIGS.42A-C illustrates dependency of Immune TransTACs on TfR1 for target degradation. FIG.42A shows cell-surface levels of TfR1 in siTfR-1 and siTfR-2 siRNAs treated cells. FIG.42B shows EGFR degradation in siTfR-1 or 2 transfected PC9 Del19 cells. Cells were treated with TransTACs for 18-24 hours. FIG.42C shows EGFR degradation in A549 cells treated with bafilomycin and chloroquine (CQ) with EGFR-Immune TransTACs, but not with MG132.10 µM MG132 conditions were not quantified due to observed cytotoxicity effects in the cells. Cells were treated with TransTACs for 12-16 hours and inhibitors were added 1 hour before TransTAC treatment.

[0077] FIGS.43A-B shows example characterization of Fc fusions of wildtype (WT) CD19 ectodomain and the variants. CD19ecto-WT-Fc shows aggregations in SDS-PAGE gel while the variants derived from yeast display do not. Among the four variants, CD19NT.1 is selected for Immune TransTAC engineering given its high expression level.

[0078] FIGS.44A-E shows example different CAR degradation efficiencies mediated by Immune TransTAC variants. (A) Schematics of different generations of CAR-Immune TransTACs and the CD19NT.1-Fc control. (B) Western blots showing neither the control nor v0.2 leads to CAR degradation. (C) Western blots showing v0.4-GFLG, which contains a cathepsin sensitive GFLG linker between the CD19NT.1 and Fc domains, leads to approximately 40-50% of CAR degradation. v0.3-GFLG, which contains the cleavable linker between the Fc and the TF domains, doesn’t lead to significant receptor degradation, possibly due to Fc mediated receptor recycling. (D) Western blots showing different linker variants of v0.4 lead to varying receptor degradation efficiencies. (E) Western blots showing different linker variants of v1.0 lead to varying receptor degradation efficiencies. Among all variants, linker GFLG-VR and VR show highest degradation.

[0079] FIGS.45A-B, 45C-D, and 45E-F show example colocalization analysis of internalized receptors with various endosomal / lysosomal markers. (A-C) Representative fluorescence images of Hela cells co-expressing Receptor-GFP (green) and endosomal / lysosomal markers-mCherry (red), treated with various Immune TransTACs or controls. EEA1: EE marker, Rab7: LE marker, Lamp1: lysosomal marker. Cell nucleus is stained with Hoechst (blue). (D) Pearson correlation analysis of Receptor-GFP colocalization with the five endosomal / lysosomal markers. T-tests show Rab5, EEA1, Rab11 colocalization with CAR are statistically different for cells treated with v0.2 vs. v0.5, and Rab7 and Lamp1 colocalizationDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 with CAR are statistically significant for v0.2 vs. v0.4, and v0.5 vs. v1.0. Cell numbers used for the analysis are as follows: For the control, UT, v0.2, v0.4, v0.5, and v1.0, N=5, N=4, N=12, N=15, N=10, and N=11, respectively for the EEA1 marker. For the control, UT, v0.2, v0.4, v0.5, and v1.0, N=12, N=11, N=12, N=15, N=22, and N=17, respectively for the Rab5 marker. For the control, UT, v0.2, v0.4, v0.5, and v1.0, N=9, N=7, N=8, N=12, N=26, and N=11, respectively for the Rab7 marker. For the control, UT, v0.2, v0.4, v0.5, and v1.0, N=9, N=6, N=13, N=13, N=15, and N=22, respectively for the Rab11 marker. For the control, UT, v0.2, v0.4, v0.5, and v1.0, N=17, N=12, N=16, N=21, N=13, and N=13, respectively for the Lamp1marker. (E-F) Incorporating a cathepsin sensitive linker into Immune TransTAC enhances LE / lysosomal trafficking. Representative fluorescence images of Hela cells co-expressing Receptor-GFP (green) and mCherry-Rab7 or Lamp1-mCherry (red), treated with Immune TransTACv0.2 vs v0.4. Cell nucleus is stained with Hoechst (blue). The v0.4 GFP images were collected with 1000x more exposure than the v0.2 images to get sufficient GFP signals for the Pearson coefficient analysis in Fig.2i. v0.4-treated cells show colocalization of the internalized Receptor- GFP with mCherry-Rab7 and Lamp1 (white arrows).

[0080] FIGS.46A-C shows example characterizing Immune TransTAC degraders for various membrane proteins. Different linkers and geometry designs lead to varied degradation efficiencies. (A) Western blots showing controls or v0.2 and v0.4 PDL1 Immune TransTAC variants do not lead to much target degradation in MDA-MB-231 cells. (B) Western blots showing EGFR Immune TransTACv0.2 does not cause much target degradation in A549 cells, whereas v0.4 or v1.0 with different linkers cause varying degrees of degradation, with v1.0-EVR and GFLG-VR giving the highest degradation efficiency. (C) Western blots showing a rituximab-scFv-Fc control does not lead to significant CD20 degradation in Raji cells.

[0081] FIGS.47A-E shows examples of Immune TransTAC regulating primary T cell activities. (A) Schematic of using -Immune TransTAC to reversibly control T cells. Immune TransTAC-mediated removal of CD19 binding receptor from cell surface prevents T cells from engaging with CD19+ cells, hence inhibits cytokine release and cytotoxicity. (B) Schematic of the setup of a primary T cell co-culture assay. Secreted IFN-^^ levels are measured to determine T cell activation levels in the presence if CD19+ A375 cells and Immune TransTACs; live cell fluorescence microscopy is used to cell killing. (C) Measurement of human primary CD19 binding receptor T cell IFN-^^ release in the co-culture assay described in (b) with an IFN^^ split-DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 luciferase assay (Promega). IFN-^^ secretion is inhibited by Immune TransTACv0.4 in a dose- dependent manner. Immune TransTAC shows an IC500f approximately 0.4 nM. Data are representative of 2 independent experiments. (D) Fluorescence microscopy of mCherry-labeled A375 cells showing T cell-mediated A375 killing reversibly controlled with CD19 binding receptor-Immune TransTACv4. (E) Overlay of bright field and mCherry channel images showing T cell-mediated A375 killing activity was resumed after Immune TransTAC washout over time.

[0082] FIGS.48A-B. FIG.48A illustrates PD-L1 degradation in MDA-MB-231 cells treated with bafilomycin and chloroquine (CQ), or MG132, and with PD-L1-Immune TransTACs. Cells were treated with Immune TransTACs for 12-16 hours and inhibitors were added 1 hour before TransTAC treatment. FIG.48B shows CD20 degradation in bafilomycin treated Raji B cells. Cells were treated with Immune TransTACs for 12-16 hours and inhibitors were added 1 hour before TransTAC treatment.

[0083] FIGS.49A, 49B shows an embodiment of (A) Cleavage of the indicated linkers on yeast at pH 4.4 by recombinant cathepsin B as compared to cleavage of GFLGGVR (SEQ ID NO: 144). (B) Cleavage of the indicated linkers on yeast at pH 6.4 by recombinant cathepsin B as compared to GFLGGVR (SEQ ID NO: 144).

[0084] FIG.50 shows amino acid sequences encoding TfR binders (VHHA and VHHB) and nucleotide sequences encoding the amino acid sequences in an embodiment.

[0085] FIG.51A shows PD-L1 degradation by binder and linker Immune TransTACs variants. FIG.51B provides more information on the homodimeric molecules in FIG.51A, which have different TfR binders.

[0086] FIG.52 provides a western blot assay showing CCR6 is degraded by DJ1 heterodimeric fusion proteins (shown in inset) in doxycycline inducible CCR6-expressing Jurkat cells.

[0087] FIG.53 provides a western blot assay showing degradation of CCR6 by a CCR6 homodimeric fusion protein LS28 (VHH-A homodimer; shown in inset) in doxycycline inducible CCR6-expressing Jurkat cells.

[0088] FIG.54 provides a western blot assay showing no degradation of CCR6 by DJ2 control fusion protein (shown in inset) in doxycycline inducible CCR6-expressing Jurkat cells.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0089] FIG.55 is a western blot assay showing degradation of CCR6 and prevention of TfR1 co-degradation by CCR6 heterodimeric fusion protein LS13 (VHHA-12 monomer; shown in inset) in doxycycline inducible CCR6-expressing Jurkat cells.

[0090] FIG.56 provides a heterodimeric fusion protein design for autoimmune targets. (A) An illustration of a construct for autoimmune targets. (B) An amino acid sequence encoding pLS23-VHHA12-Hole is shown. In B, green is R3 (TRB) and underlined amino acids are CDRs. Blue is R4 (IgG Fc region). Unshaded regions are either leader sequences or linkages.

[0091] FIG.57 provides example protein of interest binder (POIB) sequences for CCR6. (A) Amino acid sequence for pLS15 Anti-CCR6_B368-G29A_HC-Knob_Fc-His is shown. (B) Amino acid sequence for pLS16-Anti-CCR6_B3G8-G29A_LC is shown. In the sequences, yellow is R1 (POIB) and underlined amino acids are CDRs. Blue is R4 (IgG Fc region).

[0092] FIG.58 provides example POIB sequences for CD8. (A) The CD8 (human) amino acid sequence for Anti-CD8 VHH_B368-G29A_HC-Knob_Fc-His is shown. (B) The CD8 (mouse) amino acid sequences for Anti-CD8-Fab-HC_B368-G29A_HC-Knob_Fc-His and Anti- CD8 Ab-LC_B3G8-G29A_LC are shown. In the sequence, yellow is R1 (POIB) and underlined amino acids are CDRs. Blue is R4 (IgG Fc region).

[0093] FIG.59 provides a CCK8 assay showing cytotoxicity of fusion protein treatment in MDA-MB-231 cells. The star-shaped indicator represents CAX20 (VHH-A-Fc). The triangle- shaped indicator represents Ate-FC (PD-L1 antibody control). The asterisk-shaped indicator represents DP219 (H7-Fc).

[0094] FIG.60 provides an assay showing intracellular iron measurement in MDA-MB-231 cells. VHH-A fusion proteins include JD31 (pH-sensitive binder + VHH-A (non-competitive)), AD4 (Ate-scFv + VHH-A (non-competitive)), and CAX20 (VHH-A control). H7 TransTACs include DP186 (Ate-scFv + H7 (competitive)) and DP219 (H7 control). Ate-FC is a PD-L1 antibody control. DETAILED DESCRIPTION

[0095] Targeted protein degradation (TPD) is a rapidly growing field in drug discovery and pharmacology. Complementing traditional drug modalities, TPD molecules offer a novel therapeutic mechanism to tackle challenging targets, increase the therapeutic potential of currently used drugs, and the like. While many efforts in this field have focused on smallDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 molecules for intracellular targets, inducing targeted degradation of extracellular proteins is a new opportunity. Developing strategies to degrade extracellular proteins is of exceptional interest for both basic research and therapeutic intervention purposes.

[0096] Iron is an essential element for cells, and its transportation is facilitated by transferrin receptor (TfR). TfR undergoes rapid endocytosis as a recycling receptor, with an average internalization rate of 500 molecules per cell per second, making it one of the fastest internalizing receptors known. Furthermore, TfR is upregulated in cells that have a high demand for iron. This includes rapidly dividing cancer cells and activated T cells. TfR expression in these cells are higher than in non- or slowly- dividing normal tissues. TfR can be expressed on non- cancer cells at sufficient levels where the reagents and methods described herein can be used.

[0097] Herein, these features of TfR are leveraged and protein engineering is used to develop a new technology for degrading membrane proteins. Herein, this technology is called receptor- mediated Targeting Chimeras (Immune TransTACs; also herein called fusion proteins, homodimers or heterodimers of fusion proteins). In some embodiments, Immune TransTACs are heterobispecific antibodies that bring a protein of interest (POI) and TfR in close proximity at the cell surface and induce endocytosis of the POI / TfR complex and subsequent lysosomal-mediated POI degradation. Immune TransTACs are effective in degrading various types of membrane proteins, including single-pass, multi-pass, native, and synthetic receptors, showing a degradation efficiency of over 80% for targets in various cellular systems. A notable characteristic of Immune TransTACs is its fast kinetics of targeted internalization, occurring on a timescale of minutes, making it a valuable molecular tool for rapidly knocking down cell-surface expression, offering temporal specificity for cell signaling studies that is not possible with genetic approaches. Moreover, Immune TransTAC molecules are fully recombinant and modular. These properties make Immune TransTACs a versatile technology for manipulating cell surface targets in disease-specific manners.

[0098] Immune TransTAC can have broad applicability in both basic research and translational applications. Herein is demonstrated non-limiting applications of Immune TransTACs in immune related disorders. Immune Trans TACs represent a new molecular archetype to control cell surface proteins.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0099] Immune TransTAC is the first fusion protein technology that repurposes a recycling ligand / receptor interaction for targeted protein internalization and degradation, which can significantly expand the scope of effectors at the cell surface amenable for such purposes.

[0100] Herein are disclosed new, modular, and reversible strategies for modulating immune cells activities (e.g., T cell activities). Generally, the methods do not require additional genetic engineering of T cells. In some embodiments, these strategies are based on reversible internalization of cell surface molecules present in cells related to the immune system.

[0101] In some embodiments, a bispecific modulator (fusion protein), including for example a transferrin receptor-mediated targeting chimera or Immune TransTAC molecule, can colocalize a receptor to an internalizing cell surface protein. In some embodiments, fusion proteins can downregulate cell surface levels of said receptor. In some embodiments, the fusion proteins can inhibit T cell activation and / or function.

[0102] In embodiments, the fusion proteins can have a first portion or moiety (R1) that is an antibody, antibody fragment that specifically binds to a target molecule on a cell (e.g., proteins of interest including, but not limited to EGFR, CD3, CD8, TCR, CD20, PDL1, CD19, and the like), and a second portion or moiety (R3) (e.g., transferrin or an antibody or antibody fragment) that can bind to an internalizing molecule on the cell surface (e.g., transferrin receptor). In embodiments, the fusion proteins can have a first portion that is an antigen, or autoantigen, or ligand, or autoantigen-MHC complex, for a target protein on a cell (e.g., TCR that recognizes an autoantigen in the context of an MHC complex, or a CD19 antigen or its variants for a CD19- specific receptor). In embodiments, the fusion proteins can have a first portion that is an antibody or antibody fragment that can specifically bind a target molecule (e.g., protein of interest) on a cell. The fusion proteins can have a second portion that binds to an internalizing protein on the cell surface (e.g., transferrin receptor). Binding of a fusion protein to the target molecule and to the internalizing protein results in internalization of the target molecule.

[0103] In some embodiments, the fusion proteins do not require engineering of the target molecule or the immune cells and can be applied to immune diseases related therapies that are already approved or in clinical development.

[0104] In other embodiments, the fusion proteins can be reversible. Reversibility can provide for fine tuning of immune cell activities, for example for autoimmune related activities management and / or to activate / inactivate the immune cells for treatment. In some embodiments,DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 CD20 degradation by an Immune TransTAC can be reversible. In some embodiments, CD20 degradation by an Immune TransTAC including a first moiety that binds to CD20 can be reversed by stopping binding of the Immune TransTAC to CD20. In some embodiments, after reversing CD20 degradation, CD20 can be expressed de novo in the cell surface of the targeted cell. In some embodiments, fusion proteins can be tailored to immune cells that target different autoantigens, for example, by replacing the components used in the designs.

[0105] In some embodiments, reversibility can provide for fine tuning of CAR-T cell activities, for example for toxicity management and / or to rejuvenate the cells for continued treatment. In some embodiments, fusion proteins can be tailored to CAR-T cells that target different tumor antigens, for example, by replacing the components used in the designs (i.e., the traps and / or modulators can be modular).

[0106] Also disclosed are approaches for enhancing immune efficacy for controlling and / or treating immune related diseases. In some embodiments, by alternating immune cells status between an “active” and a “resting” state, the disclosed reversible modulators can control / treat immune related diseases.

[0107] Also disclosed are approaches for enhancing CAR-T efficacy. Temporal “rest” of CAR-T cells can reverse CAR-T exhaustion. In some embodiments, by alternating CAR-T cells between an “active” and a “resting” state, the disclosed reversible CAR modulators can increase efficacy of CAR-T cells.

[0108] Disclosed are development of Immune TransTAC degraders to target immune related diseases. Herein is shown that Immune TransTAC can (1) effectively degrade immune related proteins and hence treat immune related disorders, (2) Immune TransTAC can specifically target immune cells that react to a specific autoantigen while sparing immune cells that do not react to that specific autoantigen, and (3) that the geometry of TransTAC molecules can influence TransTAC target degrading activities. The reagents and methods disclosed herein can be used on cells that are not immune cells.

[0109] Detailed descriptions of one or more embodiments are provided herein. It is to be understood, however, that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in any appropriate manner.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0110] The singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0111] Wherever any of the phrases “for example,” “such as,” “including” and the like are used herein, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. Similarly, “an example,” “exemplary” and the like are understood to be nonlimiting.

[0112] The term “substantially” allows for deviations from the descriptor that do not negatively impact the intended purpose. Descriptive terms are understood to be modified by the term “substantially” even if the word “substantially” is not explicitly recited.

[0113] The terms “comprising” and “including” and “having” and “involving” (and similarly “comprises”, “includes,” “has,” and “involves”) and the like are used interchangeably and have the same meaning. Specifically, each of the terms is defined consistent with the common United States patent law definition of “comprising” and is therefore interpreted to be an open term meaning “at least the following,” and is also interpreted not to exclude additional features, limitations, aspects, etc. Thus, for example, “a process involving steps a, b, and c” means that the process includes at least steps a, b and c. Wherever the terms “a” or “an” are used, “one or more” is understood, unless such interpretation is nonsensical in context.

[0114] As used herein, the term “about” can refer to approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. The term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower). Immune System and Immune Related Diseases

[0115] A feature of the immune system is its ability to distinguish self-antigens from non-self- antigens. This ability is essential to prevent infections and colonization by foreign pathogens, but also to prevent autoimmune diseases caused by chronic immune responses against self-antigens. In autoimmune diseases, the tolerance to self-antigens is perturbed, leading to inappropriate activation of the immune system and subsequent attack and destruction of tissues and organs.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0116] In some embodiments, the strategies disclosed herein can be used for regulating the immune system, treating immune system related diseases, and / or treating autoimmune diseases. In some embodiments, the strategies disclosed herein can be used for regulating a molecule on the cell surface of a cell involved in the immune system (e.g., proteins of interest) and / or the regulatory activity of such molecules using the fusion protein approaches described herein.

[0117] The cells of the immune system can originate and / or mature in the bone marrow. All white blood cells of the immune system, derive from the same progenitor, the hematopoietic stem cells, pluripotent hematopoietic stem cells in the bone marrow that can give rise to stem cells of more limited potential, which are the immediate progenitors of red blood cells, platelets, and the two main categories of white blood cells (Chaplin, D. J. Allergy Clin Immunol.2010 Feb; 125(2 Suppl 2): S3–23).

[0118] In some embodiments, the immune cells described herein can be derived from a common lymphoid progenitor and / or from a myeloid progenitor. In some embodiments, the immune cell can be a T cell. In some embodiments the immune cell can be a B cell. In some embodiments, the immune cell can be a CD4+ T cell, or CD4 lymphocyte. In some embodiments, the immune cell can be a CD8+ T cell, or CD8 lymphocyte. In embodiments, the immune cell can be any cell originated and / or matured in the bone marrow. In some embodiments, the immune cell can be a naïve cell. In some embodiments, the immune cell is not activated. In some embodiments, the immune cell is activated.

[0119] In some embodiments, the immune system cells include, but are not limited to T cells, B cells, natural killers (NK cell), dendritic cells (DC), NKT cells, mast cells, monocytes, macrophages, basophils, eosinophils, or neutrophils. In some embodiments, the immune system cells include cells of the adaptive immune system. In some embodiments, the immune system cells include cells of the innate immune system. Typical cells of the innate immune system include, but are not limited to, congenital lymphoid cells (ILC1, ILC2, ILC3), basophils, eosinophils, mast cells, NK cells, neutrophils, and monocytes. In some embodiments, the immune system cells include memory cells. In some embodiments, the immune system cells include human primary T cell. In some embodiments, the immune cell is a mouse, dog, cat, horse, rat, goat, monkey, or rabbit cell. In some embodiments, the cell is a human cell. In some embodiments, the cell suspension comprises non-mammalian animal cells. In some embodiments, the cell is a chicken, frog, insect, or nematode cell.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0120] In some embodiments, a cell of the immune system includes cells in dormant state. In some examples, a cell of the immune system includes cells an active state.

[0121] The fusion proteins of the immune system described herein can be used for the treatment of autoimmune diseases including, but not limited to, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, polychondritis, psoriatic arthritis, psoriasis, dermatitis, polymyositis / dermatomyositis, inclusion body myositis, inflammatory myositis, toxic epidermal necrolysis, systemic scleroderma and sclerosis, CREST syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, adult respiratory distress syndrome (ARDS), meningitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus, discoid lupus, lupus myelitis, lupus cerebritis, juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis, neuromyelitis optica, rheumatic fever, Sydenham's chorea, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis including Wegener's granulomatosis and Churg-Strauss disease, agranulocytosis, vasculitis (including hypersensitivity vasculitis / angiitis, ANCA and rheumatoid vasculitis), aplastic anemia, Diamond Blackfan anemia, immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia, pure red cell aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases involving leukocyte diapedesis, central nervous system (CNS) inflammatory disorders, multiple organ injury syndrome, myasthenia gravis, antigen-antibody complex mediated diseases, anti- glomerular basement membrane disease, anti-phospholipid antibody syndrome, allergic neuritis, Behcet disease, Castleman's syndrome, Goodpasture's syndrome, Lambert-Eaton Myasthenic Syndrome, Reynaud's syndrome, Sjorgen's syndrome, Stevens-Johnson syndrome, solid organ transplant rejection, graft versus host disease (GVHD), bullous pemphigoid, pemphigus, autoimmune polyendocrinopathies, seronegative spondyloarthropathies, Reiter's disease, stiff- man syndrome, giant cell arteritis, immune complex nephritis, IgA nephropathy, IgM polyneuropathies or IgM mediated neuropathy, idiopathic thrombocytopenic purpura (ITP), thrombotic throbocytopenic purpura (TTP), Henoch-Schonlein purpura, autoimmune thrombocytopenia, autoimmune disease of the testis and ovary including autoimmune orchitisDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 and oophoritis, primary hypothyroidism; autoimmune endocrine diseases including autoimmune thyroiditis, chronic thyroiditis (Hashimoto's Thyroiditis), subacute thyroiditis, idiopathic hypothyroidism, Addison's disease, Grave's disease, autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), Type I diabetes also referred to as insulin-dependent diabetes mellitus (IDDM) and Sheehan's syndrome; autoimmune hepatitis, lymphoid interstitial pneumonitis (HIV), bronchiolitis obliterans (non-transplant), non-specific interstitial pneumonia (NSIP), Guillain-BarréSyndrome, large vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu's) arteritis), medium vessel vasculitis (including Kawasaki's disease and polyarteritis nodosa), polyarteritis nodosa (PAN) ankylosing spondylitis, Berger's disease (IgA nephropathy), rapidly progressive glomerulonephritis, primary biliary cirrhosis, Celiac sprue (gluten enteropathy), cryoglobulinemia, cryoglobulinemia associated with hepatitis, amyotrophic lateral sclerosis (ALS), coronary artery disease, familial Mediterranean fever, microscopic polyangiitis, Cogan's syndrome, Whiskott-Aldrich syndrome and thromboangitis obliterans.

[0122] The fusion proteins disclosed herein can include an autoantigen, or self-antigen, which is the target of one's own immune system. Autoantigens include any self-antigen that the host or patient immune system recognizes and responds against as foreign including, e.g., self-antigens associated with an autoimmune disorder including, e.g., myelin basic protein (MBP), proteolipid protein PLP-1, myelin oligodendrocyte glycoprotein, pro-insulin / insulin, glutamic acid decarboxylase (GAD), matrix metalloproteinase (MMP-1), type II collagen, thyroglobulin, and the like. For more examples of autoantigens see, e.g., Hirsch et al., ImmunoTargets and Therapy 2015:41–11, and WO2006012416, Wang et al., J Intern Med; 2015; 278: 369–395, the disclosures of which are incorporated by reference herein.

[0123] The fusion proteins disclosed herein can bind, target, and / or interact with molecules involved in the immune system including, but not limited to, T cell receptor (TCR), programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR), chemokine receptor 6 (CCR6), chemokine receptor type 2 (CCR2), cluster of differentiation 19 (CD19), cluster of differentiation 20 (CD20), cluster of differentiation 22 (CD22), cluster of differentiation 38 (CD38), B-cell activating factor receptor (BAFF R), tachykinin precursor 1 (TAC1), B-cell maturation antigen (BCMA, C5a receptor 1 (C5aR1), major histocompatibility complex (MHC), cluster of differentiation 3 (CD3), cluster of differentiation (CD4), cluster of differentiation (CD8), cluster of differentiation (CD25), B cell receptor (BCR), T cell receptor (TCR),DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 interleukin-7 receptor α-chain (IL7Ra), interleukin-15 receptor α-chain (IL15Ra), ORAI1-3, voltage-gated potassium channel KV1.3 (Kv1.3), (Fc receptor) FcRs, prostaglandin receptor D2 (PGD2R), chemoattractant receptor homologous molecule expressed on Th2 lymphocytes (CRTH2), GPR44, high-affinity IgE receptor (FceR1, also known as FcεRI or Fc epsilon RI), Interleukin CXCR1 / 2, Interleukin CXCR1 / 2, Interferon receptors (IFN Receptors), Glycoprotein 130 (gp130), Interleukin-23 receptor (IL23R), P2X purinoceptor 7 (p2X7 receptor, and S1P-R.

[0124] In some embodiments, the first moiety of an immune TransTAC can bind to ORAI 1. Store-operated Ca2+entry (SOCE) through Ca2+release–activated Ca2+channels is a signaling pathway involved in autoimmune diseases. Ca2+release–activated Ca2+channels can be formed by ORAI1, ORAI2, and ORAI3 proteins. Orai1 gene deletion in T cells can ameliorate the severity of autoimmune diseases including, but not limited to, experimental autoimmune encephalomyelitis EAE.

[0125] In some embodiments, the first moiety (POIB or a POI binding means (also known as a means for binding POI)) of an immune TransTAC can bind to KV1.3 channel. Voltage-gated potassium channel Kv1.3 is a membrane protein that can be activated upon a change of membrane potential. KV1.3 channels can participate in regulation of Ca2+signaling to induce T- cell proliferation and activation, and cytokine production. Blocking of KV1.3 channels from in vitro and in vivo studies with animal models of autoimmune diseases showed attenuation of autoimmune disease manifestations.

[0126] In some embodiments, the first moiety of an immune TransTAC can bind to a Fc receptor (FcRs). The receptors for the Fc portion of immunoglobulin, Fc receptors (FcRs), are important initiators of antibody mediated defense against harmful pathogens and are also key players in both the pathogenesis and severity of immune complex (IC) mediated autoimmune diseases.

[0127] In some embodiments, the first moiety of an immune TransTAC can bind to a prostaglandin (PG) D2 receptor (PGD2, also known as CRTH2 and DP2). PGD2 can be involved in immunomodulating effects, including induction of migration, activation, and cytokine release of leukocytes and has emerged as a target for the treatment of immune related disease including, but not limited to, allergies and asthma.

[0128] In some embodiments, the first moiety of an immune TransTAC can bind to a high- affinity IgE receptor (FcεRI, FcERI or Fc epsilon RI). FcεRI is the high-affinity receptor for theDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 Fc region of immunoglobulin E (IgE), an antibody isotype involved in allergy disorders and parasite immunity. During autoimmune diseases including, but not limited to, rheumatoid arthritis, lupus or immune thrombocytopenia, autoantibodies and immune complexes lead to inflammation through FcR aggregation.

[0129] In some embodiments, the first moiety of an immune TransTACs include can bind to an Interferon type I (IFN 1). IFN 1 binds to a specific cell surface receptor complex known as the IFN-α / β receptor (IFNAR) that can include IFNAR1 and IFNAR2 chains.. IFN 1 system is our main defense against viral infections and consists of a large number of sensors of nucleic acid that can trigger the production of more than 15 different proteins with antiviral and immunostimulatory capacity. There are several observations suggesting an important role for this system in the etiopathogenesis of immune diseases including, but not limited to, systemic lupus erythematosus (SLE), multiple sclerosis, and other autoimmune diseases.

[0130] The chemokine receptors CXCR1 / 2 have been identified as key players in many inflammatory disorders. Therapeutic inhibition of CXCR1 / 2 (or its ligands including CXCL8) can help reduce neutrophil recruitment in disorders with unwanted neutrophil recruitment including, but not limited to, inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis. CXCR1 and CXCR2 are closely related receptors that recognize CXC chemokines that possess an E-L-R amino acid motif immediately adjacent to their CXC motif. CXCL8 (otherwise known as interleukin-8) and CXCL6 can both bind CXCR1 in humans, while all other ELR- positive chemokines, such as CXCL1 to CXCL7 bind only CXCR2. They are both expressed on the surface of neutrophils in mammals.

[0131] In some embodiments, the first moiety of an immune TransTAC can bind to an interleukin 8 receptor alpha (IL8RA, also named C-X-C motif chemokine receptor 1 or CXCR1, also named CD181 or cluster of differentiation 181). CXCR1 can be a receptor for interleukin 8 (IL8). CXCR1 can be cleaved and inactivated by Neutrophil Derived Serine Proteases (NSPs), leading to neutrophil dysfunction and impaired bacterial killing in cystic fibrosis lung disease. CXCL1 was identified as a possible marker for β-cell destructive autoimmune activity in the pancreas during onset of type 1 diabetes. In some embodiments, the first motif of an immune TransTACs includes interleukin 8 receptor beta (IL8RB, also known as CXCR2).

[0132] In some embodiments, the first moiety of an immune TransTAC can bind to a Glycoprotein 130 (also known as gp130, IL6ST, IL6R-beta or CD130). Gp130 is aDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 transmembrane protein and the founding member of the class of tall cytokine receptors. Gp130 can form one subunit of the type I cytokine receptor within the IL-6 receptor family. Constitutive activation of the cytokine receptor subunit gp130 in T cells developed fatal, multi-organ inflammation with changes in T cell profiles. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis.

[0133] In some embodiments, the first moiety of an immune TransTAC can bind to an IL23R. The interleukin-23 receptor is a type I cytokine receptor that binds to IL-23, a heterodimeric pro- inflammatory cytokine secreted by dendritic cells and macrophages that belongs to the IL-12 family. IL-23R is involved in various autoimmune diseases including psoriasis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA).

[0134] In some embodiments, the first moiety of an immune TransTACs can bind to a P2X7 receptor (P2X7R). P2X7R is a member of purinergic type 2 receptor family with ubiquitous expression in human body. P2X7R can meditate responses involved in the development of autoimmunity including the assembly of nucleotide-binding domain (NOD) like receptor protein 3 (NLRP3) inflammasome, non-classical secretion of IL-1β, modulation of cytokine-independent pathways in inflammation such as P2X7R- transglutaminase-2 (TG2) and P2X7R-cathepsin pathway, activation and regulation of T cells, etc. P2X7R can be involved in the pathogenesis of autoimmune diseases including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS), etc.

[0135] In some embodiments, the first moiety of an immune TransTAC can bind to a Chemokine receptor 6 (CCR6). CCR6 can be expressed in a variety of immune cell types and can bind to molecules including CCL20, human beta-defensins (hBDs)-1 and -2, and a group of anti-bacterial peptides. CCR6 can affect signaling pathways implicated in autoimmune diseases including, but not limited to, psoriasis, multiple sclerosis, and rheumatoid arthritis.

[0136] In some embodiments, the first moiety of an immune TransTAC can bind to a Chemokine receptor 2 (CCR2, also known as CD192 or cluster of differentiation 192). CCR2 is encoded by the CCR2 gene in humans and can be expressed by monocytes, activated T cells, B cells and natural killer cells. CCR2 has been implicated in the pathogenesis in autoimmune diseases, including, but not limited to, multiple sclerosis, rheumatoid arthritis and atherosclerosis.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0137] In some embodiments, the first moiety of an immune TransTAC can bind to a Cluster of Differentiation 22 (CD22). CD22 is a member of the Siglec family of cell surface proteins that can be expressed by B-cell lineages. CD22 can be a co-receptor of the B-cell receptor (BCR) and can contribute to B-cell responses to antigens through activation of signaling molecules such as phosphatases. Loss of CD22 function could contribute to the pathogenesis of autoimmune diseases including, but not limited to, systemic lupus erythematosus (SLE).

[0138] In some embodiments, the first moiety of an immune TransTACs can bind to a Cluster of Differentiation 38 (CD38, also known as cyclic ADP ribose hydrolase). CD38 is a glycoprotein that can be found on the surface of many immune cells including, but not limited to, CD4+, CD8+, B lymphocytes and natural killer cells. CD38 can be involved in cell adhesion, signal transduction and calcium signaling. CD38 has been implicated in the pathogenesis of autoimmune diseases, including, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes (T1D) and inflammatory bowel disease.

[0139] In some embodiments, the first moiety of an immune TransTAC can bind to a B-cell activating factor receptor (BAFF-R, also known as tumor necrosis factor receptor superfamily member 13C (TNFRSF13C) and BLyS receptor 3 (BR3). BAFF-R is a membrane protein of the TNF receptor superfamily which recognizes BAFF. BAFF provides an important homeostatic signal for B cell survival and selection, and it can be expressed at high levels in the serum and in the target organs of individuals with established autoimmune diseases including, but limited to, rheumatoid arthritis (RA), Multiple sclerosis (MS) and Sjögren's syndrome.

[0140] In some embodiments, the first moiety of an immune TransTACs can bind to a Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI, also known as tumor necrosis factor receptor superfamily member 13B (TNFRSF13B)). TACI is a transmembrane protein of the TNF receptor superfamily found predominantly on the surface of B cells that can recognizes three ligands: APRIL, BAFF and CAML.

[0141] In some embodiments, the first moiety of an immune TransTACs can bind to a B-cell maturation antigen (BCMA or BCM, also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17, or CDD269)). Mature B cells and their differentiated progeny can be identified by the presence in their surface of molecules including B cell maturation antigenDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 (BCMA). BCMA has been implicated in autoimmune diseases including, but not limited to, systemic lupus erythematosus.

[0142] In some embodiments, the first moiety of an immune TransTAC can bind to a C5a receptor 1 (C5aR1, also known as complement component 5a receptor 1 (C5AR1) or CD88 (Cluster of Differentiation 88)). C5aR1 functions as a complement receptor and it is implicated in modulation of inflammatory responses and dysregulation of complement activation and C5 / C5a-mediated inflammation can play a role in the pathogenesis of autoimmune diseases including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.

[0143] In some embodiments, the first moiety of an immune TransTAC can bind to a cluster of differentiation 25 (CD25, also called Interleukin-2 receptor alpha chain, TAC antigen, or P55). CD25 is a protein involved in the assembly of the high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and gamma chain (IL2RG). This receptor interacts with Interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis. Levels of CD25 soluble form, called sIL-2Rα, has been connected to pathogenesis of autoimmune diseases.

[0144] In some embodiments, the first moiety of an immune TransTAC can bind to a B-cell receptor (BCR). BCR is a transmembrane protein on the surface of a B cell. B-cell receptor includes a membrane-bound immunoglobulin molecule and a signal transduction moiety that can transmit stimuli induced by (cognate) antigen recognition to downstream effector functions. BCR has been implicated in the pathophysiology of autoimmune disease including, but not limited to, granulomatosis with polyangitis, multiple sclerosis, and diabetes.

[0145] In some embodiments, the first moiety of an immune TransTAC can bind to an Interleukin-7 receptor α-chain (IL7Ra, also known as Interleukin-7 receptor subunit alpha (IL7R- α) and CD127 (Cluster of Differentiation 127)). IL7R-α is a type I cytokine receptor and is a subunit of the functional interleukin-7 receptor and thymic stromal lymphopoietin (TSLP) receptors. Genetic polymorphisms at IL7R, the locus encoding the alpha chain of the IL-7 receptor, can be associated with predisposition to several autoimmune diseases including Ankylosing Spondylitis, Multiple Sclerosis, and Primary Biliary Cirrhosis.

[0146] In some embodiments, the first moiety of an immune TransTACs can bind to an Interleukin 15 receptor, alpha subunit (IL15Ralfa). IL15Ralfa is a subunit of the interleukin 15DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 receptor. The IL-15 receptor is composed of three subunits: IL-15R alpha, CD122, and CD132. IL-15R alfa is implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoimmune type 1 diabetes (T1D).

[0147] In some embodiments, fusion proteins (e.g., Immune TransTAC molecules) are used to regulate immune system related cells. In some embodiments, these fusion proteins can reversibly modulate cells related to the immune system (e.g., T cells). Fusion Proteins

[0148] In some embodiments, strategies disclosed herein for regulating a molecule on a cell surface (e.g., proteins of interest) and / or regulatory activity of such molecules can use a fusion protein approach. In some embodiments, a fusion protein molecule can have at least two moieties. A first moiety (R1) can be a ligand that the cell-surface molecule(s) can bind or an antibody or antibody fragment (e.g., nanobody) that can bind to the cell-surface molecule(s) (e.g., proteins of interest). R1 can be a protein of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI). A second moiety (R3) can be a molecule that can bind to an internalizing receptor or membrane protein on a cell. In some embodiments, a second moiety can be an antibody or antibody fragment that binds to an internalizing receptor or membrane protein on a cell (e.g., transferrin receptor or TR). In some embodiments, R3 can bind transferrin receptor and can be called a transferrin receptor binder (TRB). In some embodiments, the fusion protein (or homodimer or heterodimer thereof) can be a bispecific antibody.

[0149] In some embodiments, R3 can be a means for binding a transferrin receptor (TR), wherein the TR binding means (also known as a means for binding TR) is non-competitive with endogenous transferrin for binding to the TR. In some embodiments, the nanobody can include a VHH from a camelid. In embodiments, the fusion protein can be a bispecific antibody. In some embodiments, the VHH includes VHHA (SEQ ID NO: 146-147). In some embodiments, the VHH includes VHHB (SEQ ID NO: 148-149). In some embodiments, the VHHA or VHHB can include amino acid substitutions. In some embodiments, the amino acid substitutions can affect binding affinity of TRB or TR binding means (also known as a means for binding TR) to transferrin receptor.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0150] In embodiments, a fusion protein having these two moieties can bind, or be bound by, a cell-surface or other molecule (e.g., proteins of interest), and can bind to an internalizing receptor or membrane protein (e.g., TR). After such bindings, the internalizing receptor or membrane protein can cause the POI to be internalized into the cell (e.g., endocytosis). In some embodiments, the internalized POI can be degraded. In embodiments, this decreases the amount of the POI on the surface of a cell. In embodiments, the internalized POIs are not able to function as POIs that would be on a cell surface. In some embodiments, the POI that is targeted by the first moiety of a fusion protein is different than the molecule targeted by the second moiety.

[0151] In some embodiments, administering the fusion proteins to a subject can be used for targeted internalization of membrane or other proteins. In some embodiments, administering the fusion proteins to a subject can be used for targeted degradation of membrane or other proteins.

[0152] In some embodiments, adding the fusion proteins to cells or administering to a patient can cause targeted internalization and / or degradation of proteins on the surface of a cell or outside of a cell. In some embodiments, this internalization / degradation is reversible. For example, when a cell is no longer exposed to the disclosed fusion proteins, the membrane proteins to which the fusion proteins are specific are no longer internalized / degraded. Generally, the membrane proteins are still synthesized and trafficked to the cell membrane. Therefore, when the fusion proteins are removed or are no longer administered to a subject, there is not a stimulus to internalize / degrade the proteins. In some embodiments, a cellular membrane protein that can be internalized by a fusion protein, but not degraded, can be both internalized and degraded using a fusion protein that also contains a protease-sensitive linker. As discussed elsewhere, placement of a protease-sensitive linker within a fusion protein can provide release of a targeted cellular protein of interest from the fusion protein inside of a cell.

[0153] In some embodiments, internalization and degradation of the cell surface or other molecule (e.g., proteins of interest) can kill the cell (e.g., in embodiments where the cell surface molecule is required for cell viability or cell division: EGFR in some embodiments). In some embodiments, internalization and degradation of the cell surface or other molecule does not kill the cell (e.g., in embodiments where the cell surface or other molecule is not required for cell viability or cell division: CD19 binding receptor in some embodiments).DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0154] In some embodiments, internalization of fusion proteins or parts thereof can involve receptor-mediated endocytosis, also called clathrin-mediated endocytosis. In some embodiments, internalization of fusion proteins can involve clathrin-independent endocytosis. In some embodiments, internalization of fusion proteins can involve phagocytosis.

[0155] In embodiments, the cell-surface molecule, or molecule that is targeted by the first moiety (R1) (e.g., a protein of interest, such as a protein of interest), can be a CAR molecule (a protein). In some embodiments, the CAR molecule can be on a CAR-T cell. In some embodiments, a strategy for regulating immune cell’s activities include internalizing immune related molecules (e.g., receptors and / or coreceptors) with a fusion protein.

[0156] In some embodiments, the protein of interest is a membrane protein. In embodiments, the membrane protein is an integral membrane protein. In embodiments, the membrane protein is a transmembrane protein that has one or more transmembrane domains. In some embodiments, the protein of interest can be a protein external to a cell, for example, an autoantibody, cytokine, enzyme, and the like.

[0157] In some embodiments, the protein of interest can bind a hormone, cytokine, growth factor, neurotransmitter, lipophilic signaling molecule (e.g., prostaglandin) or cell recognition molecule (e.g., integrin, selectin). In embodiments, the protein of interest is a receptor or a coreceptor. In embodiments, the protein of interest is a receptor tyrosine kinase (RTK) or transmembrane receptor (TMR), TCR receptor, coreceptors, or the like.

[0158] In some embodiments, the molecule of interest is a ligand-gated ion channel-linked receptor or an enzyme-linked receptor. Non-limiting embodiments of a ligand-gated ion channel-linked receptor are Na+, K+, Ca2+, or Cl- channels. Non-limiting embodiments of an enzyme-linked receptor are receptor tyrosine kinase, tyrosine-kinase-associated receptor (e.g., enzymes that associate with cytokines), receptor-like tyrosine phosphatase (e.g., that remove phosphate groups from tyrosines of intracellular proteins), receptor serine / threonine kinase, receptor guanylyl cyclase, or histidine-kinase-associated receptor.

[0159] In some embodiments, the protein of interest is a transporter. In some embodiments, the protein of interest is an ion transporter.

[0160] In some embodiments, the molecule that is targeted by the first moiety of a fusion protein (i.e., protein of interest) is a different molecule than the molecule targeted by the second moiety (e.g., transferrin receptor) of a fusion protein.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0161] In some embodiments, the fusion protein is a single molecule. In some embodiments, the fusion protein is a single polypeptide. In some embodiments, a single polypeptide can contain both the first moiety (R1) and the second moiety (TRB or TR binding means (also known as a means for binding TR)) of a fusion protein. In some embodiments, the first moiety (R1) is an antigen / autoantigen, or a protein complex (e.g., autoantigen-MHC complex) to which the molecule of interest can bind. In some embodiments, the antigen / autoantigen, or a protein complex can bind to a molecule of interest present in an immune cell (e.g., a receptor on an immune cell). In some embodiments, the receptor can be a T-cell receptor (TCR), a B-cell receptor (BCR), any receptor involved in the immune system, or any of the receptors and coreceptors described herein. In some embodiments, the immune cell receptor can be internalized after binding to the antigen / autoantigen, autoantigen-MHC complex.

[0162] In some embodiments, the first moiety (R1) can include an antibody or antibody fragment (e.g., a nanobody, peptide, and the like) that binds to a protein of interest present in or on an immune cell. In some embodiments, the protein of interest can be an immune system receptor / coreceptor (e.g., TCR receptor, BCR, and the like). In some embodiments, the protein of interest can be an antigen and / or antigen bound to an immune cell surface molecule. In some embodiments, the protein of interest can include an MHC I or an antigen / autoantigen MHC II complex in the surface of an immune cell. In some embodiments, the first moiety can include any of the antigens and / or autoantigens described herein. In some embodiments, the first moiety can include any of the antigens and / or autoantigens described herein and an MHC molecule.

[0163] In some embodiments, the protein of interest targeted by the first moiety can include any of the immune molecules described herein. In some embodiments, proteins of interest targeted by the first moiety include, but are not limited to, TCR, PD-L1, EGFR, CCR6, CCR2, CD19, CD20, CD22, CD38, BAFF R, TACI, BCMA, C5aR1, MHC, CD3, CD4, CD8, CD25, BCR, TCR, IL7Ra, IL15Ra, ORAI1-3, Kv1.3, FcRs, PGD2R, CRTH2, GPR44, FceR1, CXCR1 / 2, IFN Receptor, IL17Ra, gp130, IL23R, p2X7 receptor, and S1P-R.

[0164] In some embodiments, the protein of interest targeted by the first moiety can include any of the antigens and / or autoantigens described herein. In some embodiments, the antigens and / or autoantigens include, but are not limited to, myelin basic protein (MBP), proteolipid protein PLP-1, myelin oligodendrocyte glycoprotein, pro-insulin / insulin, glutamic acid decarboxylase (GAD), matrix metalloproteinase (MMP-1), type Il collagen, thyroglobulin, andDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 the like. For more examples of autoantigens see, e.g., Hirsch et al., ImmunoTargets and Therapy 2015:41–11, and WO2006012416, Wang et al., J Intern Med; 2015; 278: 369–395, the disclosures of which are incorporated by reference herein.

[0165] In some embodiments, the protein of interest targeted by the first moiety can include any of the antigens and / or autoantigens described herein and any of the MHC molecules described herein.

[0166] In some embodiments, the first moiety can include an antibody or antibody fragment (e.g., nanobody) that binds to any of the proteins of interest described herein (e.g., TCR, CD3, CD8, CD19, and the like).

[0167] CD19 molecule (Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T- Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein with two extracellular C2- set Ig-like domains and a relatively large, 240 amino acid, cytoplasmic tail that is highly conserved among mammalian species. CD19 overexpression can result in autoimmune diseases. In some embodiments, the first moiety can bind to CD19. In some embodiments, the first moiety can bind to CD19 in an activated CD8+ T cell. In some embodiments, the first moiety can bind to CD19 in an activated CD4+ T cell. In some embodiments, the first moiety can bind to CD19 in a naive CD8+ T cell. In some embodiments, the first moiety can bind to CD19 in a naive CD4+ T cell. In some embodiments, the first moiety is an antibody or fragment thereof (e.g., nanobody) that can bind CD19.

[0168] Cluster of differentiation 3 (CD3) is a protein complex and T cell co-receptor that is involved in activating CD8+ naive T cells and CD4+ naive T cells. In some embodiments, the first moiety can bind to CD3. In some embodiments, the first moiety can bind to CD3 in an activated CD8+ T cell. In some embodiments, the first moiety can bind to CD3 in an activated CD4+ T cell. In some embodiments, the first moiety can bind to CD3 in a naive CD8+ T cell. In some embodiments, the first moiety can bind to CD3 in a naive CD4+ T cell. In some embodiments, the first moiety can bind to any of CD3γ chain, a CD3 chain, and / or CD3ε chains. In some embodiments, the first moiety is an antibody or fragment thereof that can bind CD3. In some embodiments, the antibody or fragment thereof can bind any of the CD3 chains.

[0169] Cluster of differentiation 8 (CD8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD8 co-receptor can play a role in T cell signaling and aiding with cytotoxic T cell-antigen interactions. CD8 binds to a major histocompatibilityDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 complex I (MHC I) molecule. There are two isoforms of the protein, alpha and beta. In some embodiments, the first moiety can bind to CD8 in an activated CD8+ T cell. In some embodiments, the first moiety can bind to CD8 in an activated CD4+ T cell. In some embodiments, the first moiety can bind to CD8 in a naive CD8+ T cell. In some embodiments, the first moiety can bind to CD8 in a naive CD4+ T cell. In some embodiments, the first moiety is an antibody or fragment thereof that can bind CD8. In some embodiments, the antibody or fragment thereof can bind to the alpha isoform of CD8. In some embodiments, the antibody or fragment thereof can bind to the beta isoform of CD8.

[0170] In some embodiments, the first moiety can bind to a TCR receptor in an immune cell. In some embodiments, the first moiety can bind to a TCR receptor that recognizes a specific autoantigen presented in the context of an MHC molecule. In some embodiments, the first moiety can bind to a TCR receptor in a CD4+ T cell. In some embodiments, the first moiety can bind to a TCR receptor in a CD8+ T cell. In some embodiments, the first moiety can bind to a TCR receptor in an activated CD4+ T cell. In some embodiments, the first moiety can bind to a TCR receptor in an activated CD8+ T cell. In some embodiments, the first moiety can bind to a TCR receptor in a naive CD4+ T cell. In some embodiments, the first moiety can bind to a TCR receptor in a naive CD8+ T cell.

[0171] In some embodiments, the first moiety can be a protein complex. In some embodiments, the first moiety can include an autoantigen, self-antigen, or autoimmune antigen. In some embodiments, the autoantigen can be a normal molecule (a molecule that should not be recognized and / or attack by the subject’s own immune system), protein or complex of proteins (and sometimes DNA or RNA) that is recognized as foreign to the body and therefore attacked by the immune system. In some embodiments, the first moiety can include a major histocompatibility complex (MHC). In some embodiments, the protein complex can include an autoantigen and an MHC complex. In some embodiments, the MHC is an MHC II. In some embodiments, the MHC is an MHC I. In some embodiments, the autoantigen can be a full-length protein or fragment thereof or can comprise one or more epitopes. In some embodiments, the first moiety is an autoantigen-MHCI complex that can bind to a TCR receptor in an immune cell. In some embodiments, the first moiety is an autoantigen-MHCII complex that can bind to a TCR receptor in an immune cell.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0172] The fusion proteins disclosed herein can be used for the treatment of autoimmune diseases.

[0173] In embodiments, a fusion protein including an autoantigen or autoantigen-MHC complex can bind, or be bound by, a cell-surface or other molecule in an immune cell (e.g., proteins of interest, such as TCR), and the second moiety can bind to an internalizing receptor or membrane protein. After said binding, the internalizing receptor or membrane protein can cause the cell-surface or other molecule (e.g., TCR) to be internalized into the immune cell (e.g., endocytosis). In embodiments, the internalized cell-surface molecule (e.g., TCR) or another molecule can be degraded. In embodiments, this degradation decreases the amount of the cell- surface molecule (e.g., TCR) on the surface of the immune cell. In some embodiments, the internalized cell-surface molecules (e.g., TCR) cannot function normally. In some embodiments, the cell-surface molecule that is targeted by the first moiety of a fusion protein is different than the molecule targeted by the second moiety. In some embodiments, the internalization of the cell-surface molecules (e.g., TCR) can affect, modify, reduce, ameliorate, and / or eliminate activities, functions, and / or responses related to the immune system. In some embodiments, the fusion protein having an autoantigen-MHC complex that recognizes a specific TCR receptor, and the second moiety that can bind to an internalizing receptor or membrane protein can affect, modify, reduce, ameliorate, and / or eliminate activities, functions, and / or responses related to the specific autoantigen used as first motif without affecting immune related cells that do not respond to said autoantigen.

[0174] In some embodiments, administering the fusion proteins to a subject can be used for targeted internalization of membrane or other proteins (e.g., CD3 and CD8). In embodiments, a fusion protein having a first moiety that is an antibody or fragment thereof that recognizes a specific coreceptor (e.g., CD3, CD8) can bind, or be bound by, a cell-surface or other molecule in an immune cell (e.g., CD3, CD8), and the second moiety can bind to an internalizing receptor or membrane protein. After such bindings, the internalizing receptor or membrane protein can cause the cell-surface (e.g., CD3, CD8) and / or other molecule (e.g., TCR) to be internalized into the immune cell (e.g., endocytosis). In embodiments, the internalized cell-surface (e.g., CD3, CD8) and / or TCR can be degraded. In embodiments, this degradation decreases the amount of the cell-surface molecule (e.g., CD3, CD8) and / or TCR on the surface of the immune cell. In embodiments, the internalized cell-surface molecules (e.g., CD3, CD8, TCR) are not functional.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 In embodiments, the internalization of CD3 and / or CD8 can affect, modify, reduce, ameliorate, and / or eliminate activities, functions, and / or responses related to the immune system.

[0175] In some embodiments, the antibody that is the first moiety (R1 or protein of interest binder) can be an scFv, Fab, single-domain antibody, nanobody, monobody, DARPin or affibody. Antibody fragments and other molecules that can be used are described in the section titled, “Antibodies” in this application.

[0176] In some embodiments, the second moiety (TRB or TR binding means (also known as a means for binding TR)) binds to a transferrin receptor (R3 of transferrin receptor binder or TRB or TR binding means (also known as a means for binding TR)) on a cell. In some embodiments, the receptor or membrane protein bound by the second moiety (i.e., TRB or TR binding means (also known as a means for binding TR)) is an internalizing receptor or membrane protein. In some embodiments, the TRB or TR binding means (also known as a means for binding TR) can mediate endocytosis. In embodiments, the second moiety (TRB or TR binding means (also known as a means for binding TR)) can also be an antibody or antibody fragment that binds the transferrin receptor.

[0177] In some embodiments, the internalizing receptor or membrane protein can be a transferrin receptor. In embodiments, a ligand (e.g., second moiety (TRB or TR binding means (also known as a means for binding TR)) that a transferrin receptor can bind can be transferrin or a fragment of transferrin. In some embodiments, the second moiety (TRB or TR binding means (also known as a means for binding TR)) that binds a transferrin receptor can be an antibody or antibody fragment.

[0178] In some embodiments, the internalizing receptor or membrane protein can be a transferrin receptor (TfR). The transferrin receptor can be transferrin receptor 1 or transferrin receptor 2.

[0179] In some embodiments, the transferrin receptor can have a high endocytosis rate of around 500 molecules per cell per second, making it good for inducing protein endocytosis. In some embodiments, transferrin receptor expression can be expressed in healthy tissues. In some embodiments, transferrin receptor expression can be expressed in non-healthy (e.g., diseased) tissues. In some embodiments, transferrin receptor expression can efficiently endocytose and degrade target proteins (POI) when the transferrin receptor is expressed.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0180] Transferrin receptor can be expressed in immune cells, like T lymphocytes, B lymphocytes, and the like; and in tissues that include but are not limited to brain, liver, breast, lung, colon, pancreas, skin, spleen, lymph nodes, bone marrow, thymus, and the like.

[0181] In some embodiments, the second moiety (TRB or TR binding means (also known as a means for binding TR)) can be an antibody, antibody fragment, or other molecule that can bind the internalizing receptor or membrane protein. In some embodiments, the second moiety (TRB or TR binding means (also known as a means for binding TR)) can be a scFv, Fab, single- domain antibody, nanobody, monobody, DARPin or affibody.

[0182] In some embodiments, H7 is competitive with transferrin for binding to TfR. M16 is competitive with transferrin for binding to TfR.

[0183] In some embodiments, the second moiety (R3) can bind to a transferrin receptor (TfR), and can be a non-competitive transferrin receptor binder that does not compete or competes insignificantly with endogenous (wild-type, full-length transferrin) transferrin for binding to transferrin receptor. In some embodiments, the TRB or TR binding means (also known as a means for binding TR) that does not compete or competes insignificantly with endogenous Tf for binding to TfR can be more efficient in binding, internalizing and / or degrading cell surface molecular targets (e.g., protein of interest or POI) than TransTAC molecules having a TRB or TR binding means (also known as a means for binding TR) that is competitive with endogenous Tf for binding to TfR.

[0184] In some embodiments, a competitive inhibitor of Tf binding to TfR can prevent or reduce Tf binding to TfR. In some embodiments, a competitive inhibitor of Tf binding to TfR does not bind to a TfR simultaneously with the non-competitive inhibitor (they both cannot bind to the same receptor). In some embodiments, a non-competitive inhibitor of Tf binding to TfR can bind to a TfR simultaneously with Tf binding to TfR (both molecules can simultaneously bind to a TfR). In some embodiments, a non-competitive inhibitor can insignificantly compete with Tf for binding to TfR. In some embodiments, insignificantly compete means that less than 50, 40, 30, 20, 10, 5 or 1% of non-competitive inhibitor molecules that bind to TfR inhibit a Tf from binding to TfR. In some embodiments, the non-competitive transferrin receptor binder binds to a different region of the transferrin receptor than does Tf. In some embodiments, the transferrin receptor binders used in the molecules disclosed herein are VHHA, VHHA-12, VHHA-5, VHHA-7 or VHHB. Other non-competitive transferrin receptor binders can be used.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0185] In some embodiments, when a non-competitive inhibitor is added to TfR in the presence of Tf, binding of Tf to TfR is not affected. In some embodiments, when increasing amounts of a non-competitive inhibitor are added to TfR in the presence of Tf, binding of Tf to TfR is affected less than if increasing amounts of a competitive inhibitor, instead of the non- competitive inhibitor, were used.

[0186] In some embodiments, the second moiety (R3) can be an antibody or antibody fragment that can bind transferrin receptor. In some embodiments, the R3 does not compete or competes insignificantly with endogenous Tf for binding to TfR. In some embodiments, the antibody or antibody fragment thereof (e.g., nanobody) that does not compete or competes insignificantly with endogenous Tf for binding to TfR can be VHHA or VHHB. VHHA or VHHB that have certain amino acid substitutions (i.e., VHHA-12 (SEQ ID NO: 154), VHHA-5 (SEQ ID NO: 155), and VHHA-7 (SEQ ID NO: 156)) can also be non-competitive with endogenous transferrin for binding to transferrin receptor. In some embodiments, VHHA can be more efficient in binding, internalizing and / or degrading POI targets than TransTAC molecules having a TRB or TR binding means (also known as a means for binding TR) that is competitive with endogenous Tf for binding to TfR. In some embodiments, VHHB can be more efficient in binding, internalizing and / or degrading POI targets than TransTAC molecules having a TRB or TR binding means (also known as a means for binding TR) that is competitive with endogenous Tf for binding to TfR.

[0187] Variable Domain of Camelid Heavy Chain-only (VHH) antibodies that bind to transferrin receptor are disclosed in U.S. Patent Publication Number 2023 / 0414780 A1, published on December 28, 2023, and filed on June 22, 2023, and which is incorporated herein by reference.

[0188] In one embodiment, an amino acid sequence of a competitive TRB, H7, can include the molecules below, or can include molecules at least 60, 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to the amino acid sequences below:

[0189] H7 scFV-LC (SEQ ID NO: 1):

[0190] SELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVMYGRNE RPSGVPDRFSGSKSGTSASLAISGLQPEDEANYYCAGWDDSLTGPVFGGGTKLTVLG*

[0191] H7 scFV-HC (SEQ ID NO: 2):DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0192] QVQLQESGGGVVQPGRSLRLSCAASRFTFSSYAMHWVRQAPGKGLEWVAVI SYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLSGYGDYPD YWGQGTLVTVSS

[0193] H7 -scFv (SEQ ID NO: 3)

[0194] SELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVMYGRNE RPSGVPDRFSGSKSGTSASLAISGLQPEDEANYYCAGWDDSLTGPVFGGGTKLTVLGGG GGSGGGGSGGGGSQVQLQESGGGVVQPGRSLRLSCAASRFTFSSYAMHWVRQAPGKG LEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLSG YGDYPDYWGQGTLVTVSS

[0195] M16 (SEQ ID NO: 4):

[0196] SELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVMYGRNE RPSGVPDRFSGSKSGTSASLAISGLQPEDEANYYCAGWDDSLTGPVFGGGTKLTVLGGG GGSGGGGSGGGGSQVQLQESGGGVVQPGRSLRLSCAASRYPFHHHDHHWVRQAPGKG LEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLSG YGDYPDYWGQGTLVTVSS

[0197] Immune TransTAC designs can employ binders that compete with natural transferrin (Tf) for binding to TfR1 (Tf-competitive binder), which could possibly affect iron import and cause toxicities to cells and tissues. Binders recognizing a non-competitive epitope on TfR1 (Tf non-competitive) can be effective at degrading a POI while reducing toxicity effects (e.g., less or no disruption of transferrin binding to transferrin receptor). Nanobodies VHHA and VHHB can bind to TfR1 in an epitope that is non-competitive with Tf. VHHA an VHHB can drive PD-L1 degradation as well as degradation of other targets. VHHA and VHHB can induce POI degradation potently and effectively.

[0198] TfR1 includes epitopes that are recognized and bound by the natural TFR1 ligand Transferrin (Tf) (Tf-competitive epitopes) and epitopes that are not recognized / bound by Tf (Tf non-competitive epitopes). TransTAC designs including second moieties (R3) with binders that compete with natural transferrin (Tf) for binding to Tf competitive epitopes (called Tf competitive TransTACs, e.g., v1.0 including H7 as a binder) can affect iron import and cause toxicities to certain cells and tissues. TransTAC designs including second moieties (R3) that do not compete with endogenous transferrin for binding to non-competitive epitopes (non- competitive TransTACs) can be effective at degrading a POI while reducing toxicity. These binders can be non-competitive with transferrin in binding to transferrin receptor. In some embodiments, non-competitive TRBs or TR binding means (also known as a means for binding TR) can limit toxicity that can occur when transferrin binding to transferrin receptor is affectedDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 (as when R3 is competitive with transferrin for binding to TfR).In some embodiments, an antibody or antibody fragment that can bind a transferrin receptor is a nanobody. This nanobody can be called “VHHA.” In some embodiments, VHHA binds to an epitope in TfR1 that does not compete for binding with natural / endogenous Tf. In some embodiments, a TransTAC including a first moiety including a molecule that binds PD-L1 and a second moiety (TRB or TR binding means (also known as a means for binding TR)) including VHHA binds to an epitope of TfR can drive PD-L1 degradation independently of the presence of natural transferrin (Tf). In some embodiments, binding of the TransTAC including VHHA to TfR1 is non-competitive with natural Tf. In some embodiments, non-competitive TRBs or TR binding means (also known as a means for binding TR) can limit toxicity that can occur if transferrin binding to TfR is affected by using an R3 that competes with transferrin for binding to TfR.

[0199] In some embodiments, an antibody or antibody fragment that can bind a transferrin receptor can be a nanobody. This nanobody can be called “VHHB .” In some embodiments, VHHB can bind to a non-competitive TfR1 epitope.

[0200] Nanobodies VHHA and VHHB can bind to non-competitive TfR1 epitopes. TransTACs including VHHA and / or VHHB are non-competitive TransTACs that can drive POI degradation independently of the presence of Tf. VHHA and VHHB TransTACs can induce POI degradation potently and effectively.

[0201] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including a molecule (e.g., a peptide, a nanobody, VHHA, VHHB) that can bind to a non-competitive epitope in an internalizing molecule (e.g., a non-competitive epitope in TfR1) can drive the internalization and degradation of the POI.

[0202] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including VHHA can bind to TfR and drive POI internalization / degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including VHHA can bind to a non-competitive epitope in TfR and drive POI degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) can bind to a competitive epitope in TfR and drive POI degradation. In some embodiments, theDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including VHHA can bind to TfR and drive POI degradation more efficiently and potently than a TransTAC including the same POI and a second moiety (R3) including a moiety that can bind a competitive TfR1 epitope (e.g., TRB).

[0203] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including VHHB can bind to TfR and drive POI internalization / degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including VHHB can bind to a non-competitive epitope in TfR and drive POI degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including a TRB that is non-competitive with transferrin in binding a transferrin receptor can bind to a epitope in TfR and drive POI degradation. In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind any of the POI described herein, and a second moiety (R3) including VHHB can bind to TfR and drive POI degradation more efficiently and potently than a TransTAC including the same POI and a second moiety (R3).

[0204] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind CD20, and a second moiety (R3) including VHHA can bind to a non-competitive epitope in TfR and drive CD20 degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind CD20, and a second moiety (R3) including VHHA can bind to TfR and drive POI degradation. In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind CD20, and a second moiety (R3) including VHHA can bind to TfR and drive CD20 degradation more efficiently and potently than a TransTAC including CD20 and a second moiety (R3) that can bind a competitive TfR1 epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0205] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind EGFR, and a second moiety (R3) including VHHA can bind to a non-competitive epitope in TfR and drive EGFR degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind EGFR, and a second moiety (R3) including VHHA can bind to TfR and drive EGFR degradation. In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind EGFR, and a second moiety (R3) including VHHA can bind to TfR and drive EGFR degradation more efficiently and potently than a TransTAC including EGFR and a second moiety (R3) that can bind a competitive TfR1 epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope. In some embodiments, non-competitive TRBs or TR binding means (also known as a means for binding TR) can limit toxicity that can occur when transferrin binding to TfR is affected by using an R3 that competes with transferrin for binding to TfR.

[0206] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind a CAR, and a second moiety (R3) including VHHA can bind to a non-competitive epitope in TfR and drive CAR degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind CAR, and a second moiety (R3) including VHHA can bind to TfR and drive CAR degradation. In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind CAR, and a second moiety (R3) including VHHA can bind to TfR and drive CAR degradation more efficiently and potently than a TransTAC including CAR and a second moiety (R3) that can bind a competitive TfR1 epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0207] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind CD20, and a second moiety (R3) including VHHB can bind to a non-competitive epitope in TfR and drive CD20 degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind CD20, and a second moiety (R3) including VHHB can bind to TfR and drive POI degradation. In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind CD20, and a second moiety (R3) including VHHB can bind to TfR and drive CD20 degradation more efficiently and potently than a TransTAC including CD20 and a second moiety (R3) that can bind a competitive TfR1 epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.

[0208] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind EGFR, and a second moiety (R3) including VHHB can bind to a non-competitive epitope in TfR and drive EGFR degradation. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind EGFR, and a second moiety (R3) including VHHB can bind to TfR and drive EGFR degradation. In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind EGFR, and a second moiety (R3) including VHHB can bind to TfR and drive EGFR degradation more efficiently and potently than a TransTAC including EGFR and a second moiety (R3) that can bind a competitive TfR1 epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.

[0209] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind a CAR, and a second moiety (R3) including VHHB can bind to a non-competitive epitope in TfR and drive CAR degradation. In some embodiments, a TransTAC including a firstDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 moiety (R1) including a molecule that can bind CAR, and a second moiety (R3) including VHHB can bind to TfR and drive CAR degradation. In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind CAR, and a second moiety (R3) including VHHB can bind to TfR and drive CAR degradation more efficiently and potently than a TransTAC including CAR and a second moiety (R3) that can bind a competitive TfR1 epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.

[0210] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can bind to TfR1 with a Kd at least about 2, 4, 5, 10, 30, 50, 100, 300, 400, 600, 1000, 1500, 2000 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3). In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can bind to TfR1 with a Kd between about 10 and about 100 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3). In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can bind to an internalizing molecule (e.g., TfR1) with a Kd at least about 100 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that can bind to an internalizing molecule (e.g. TfR1).

[0211] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can bind to an internalizing molecule (e.g., TfR1) with a Kd at least about 100 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that can bind to a competitive epitope in an internalizing molecule (e.g. TfR1). In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can bind to TfR1 with a Kd of about 1.7 nMDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 (nanomolar) and the TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that can bind to an internalizing molecule (e.g. TfR1) can be about 160 pM (picomolar). In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope (e.g., VHHA) may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.

[0212] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can bind to TfR1 with a Kd at least about 2, 4, 5, 10, 30, 50, 100, 300, 400, 600, 1000, 1500, 2000 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3). In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can bind to TfR1 with a Kd between about 10 and about 100 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3). In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can bind to an internalizing molecule (e.g., TfR1) with a Kd at least about 100 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that can bind to an internalizing molecule (e.g. TfR1).

[0213] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can bind to an internalizing molecule (e.g., TfR1) with a Kd at least about 100 times the Kd of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that can bind to a competitive epitope in an internalizing molecule (e.g. TfR1). In some embodiments, the TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can bind to TfR1 with a Kd of about 2.7 nM (nanomolar) and the TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that can bind to an internalizing moleculeDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 (e.g. TfR1) can be about 160 pM (picomolar). In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope (e.g., VHHB) may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.

[0214] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can bind to TfR1 with an affinity at least about 1, 5, 10, 50, 100, 2000, 500, 1000 higher that a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3). In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non- competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.

[0215] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can bind to TfR1 with an affinity at least about 1, 5, 10, 50, 100, 2000, 500, 1000 higher that a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3). In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non-competitive epitope may not bind to transferrin receptor better or substantially better than a TRB that binds a transferrin competitive epitope. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) that binds a transferrin non- competitive epitope may drive internalization and / or degradation of a POI better than a TRB that binds a transferrin competitive epitope.

[0216] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1 and a second moiety (R3) including VHHA can bind to TfR and drive PD-L1 degradation independently of the presence of natural transferrin (Tf). In someDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 embodiments binding of the TransTAC including VHHA to TfR1 is non-competitive with natural Tf.

[0217] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1 and a second moiety (R3) including VHHB can bind to TfR and drive PD- L1 degradation independently of the presence of natural transferrin (Tf). In some embodiments binding of the TransTAC including VHHB to TfR1 is non-competitive with natural Tf.

[0218] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can internalize and / or degrade the PD-L1 (e.g., TfR1) with an IC50 at least about 1, 2, 4, 5, 10, 30 times smaller than the IC50 of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that binds to an internalizing molecule (e.g. TfR1). In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can internalize and / or degrade the PD-L1 with an IC50 between about 0.05 to about 0.5 nM. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) that can internalize and / or degrade the PD-L1 with an IC50 of about 1.1 mM. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) that can internalize and / or degrade PD-L1 with an IC50 of about 1.2 mM. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD- L1, and a second moiety (R3) that can internalize and / or degrade PD-L1 with an IC50 of about 1.7 mM.

[0219] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can internalize and / or degrade PD-L1 with an IC50 at least about 1, 2, 4, 5, 10, 30 times smaller than the IC50 of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that binds to an internalizing molecule (e.g. TfR1). In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD- L1, and a second moiety (R3) including VHHB can internalize and / or degrade PD-L1 with an IC50 between about 0.05 to about 0.5 nM. In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) that can internalize and / or degrade PD-L1 with an IC50 of about 0.26 mM. In some embodiments, aDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) that can internalize and / or degrade PD-L1 with an IC50 of about 0.1 mM.

[0220] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHA can bind to, internalize and / or degrade the POI using an internalizing molecule (e.g. TfR1) with at least about 1, 5, 10, 50, 100, 200, 500, or 1000 times higher than a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) that can bind to a competitive epitope in an internalizing molecule (e.g. TfR1).

[0221] In some embodiments, a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including VHHB can bind to an internalizing molecule (e.g. TfR1) can bind to, internalize and / or degrade the POI with an affinity at least about 1, 5, 10, 50, 100, 200, 500, or 1000 times higher than the affinity of a TransTAC including a first moiety (R1) including a molecule that can bind PD-L1, and a second moiety (R3) including a binder that can bind to a competitive epitope in an internalizing molecule (e.g. TfR1).

[0222] In some embodiments, a TransTAC including VHHA degrades a POI with a potency of about between 0.01 and 0.03 nM EC50, about between 0.02 and 0.05 nM EC50, about between 0.04 and 0.1 nM EC50, about between 0.08 and 0.2 nM EC50, about between 0.15 and 0.3 nM EC50, about between 0.25 and 0.5 nM EC50, about between 0.4 and 1 nM EC50. In some embodiments, a TransTAC including VHHA (SEQ ID NO: 146-147) degrades a POI with a potency of 0.2 nM EC50. In some embodiments, a TransTAC including VHHA (SEQ ID NO: 148-149) and a first moiety binds PD-LI can degrade PD-L1 with a potency of 0.2 nM EC50.

[0223] In some embodiments, a TransTAC including VHHA degrades a POI with an efficiency of between about 50% and about 60%, between about 55% and about 65%, between about 65% to about 75%, between about 70% and about 80%, between about 80% to 90%, or between about 85% and about 95%, or between about 90% and about 100%. In some embodiments, a TransTAC including VHHA degrades a POI with an efficiency of about 80%.

[0224] In some embodiments, a TransTAC including VHHB can degrade a POI with a potency of about between 0.01 and 0.03 nM IC50, about between 0.02 and 0.05 nM IC50, about between 0.04 and 0.1 nM IC50, about between 0.08 and 0.2 nM IC50, about between 0.15 and 0.3 nM IC50, about between 0.25 and 0.5 nM IC50, about between 0.4 and 1 nM IC50. In some embodiments, a TransTAC including VHHB (SEQ ID NO: 148-149) can degrade a POI with aDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 potency of 0.1 nM IC50. In some embodiments, a TransTAC including VHHB (SEQ ID NO: 148-149) and a first moiety (R1) that can bind PD-LI and can degrade PD-L1 with a potency of about 0.1 nM IC50. In some embodiments, a TransTAC including VHHB (SEQ ID NO: 148- 149) and a first moiety (R1) that can bind PD-LI and can degrade PD-L1 with a potency of about 0.26 nM IC50.

[0225] In some embodiments, a TransTAC including VHHB can degrade a POI with an efficiency of between about 50% and about 60%, between about 55% and about 65%, between about 65% to about 75%, between about 70% and about 80%, between about 80% to 90%, or between about 85% and about 95%, or between about 90% and about 100%. In some embodiments, a TransTAC including VHHB can degrade a POI with an efficiency of about 100%. In some embodiments, a TransTAC including VHHB can degrade a POI with an efficiency of about 99%. In some embodiments, a TransTAC including VHHB can degrade a POI with an efficiency of about 98%. In some embodiments, a TransTAC including VHHB can degrade a POI with an efficiency of about 97%. In some embodiments, a TransTAC including VHHB can degrade a POI with an efficiency of about 96%.

[0226] In some embodiments, the Immune TransTAC includes a first moiety that binds to any of the first moiety targets described herein, and a second moiety (e.g., VHHA) that binds to an internalizing receptor (e.g., TfR). In some embodiments, the Immune TransTAC includes a first moiety that binds to any of the first moiety targets described herein, and a second moiety (e.g, VHHA) that binds transferrin with an EC50 of about 0.15 (FIG.4A). In some embodiments, the Immune TransTAC includes a first moiety that binds to PD-L1, and a second moiety that binds to TfR with an EC50 of about 0.15 (FIG.4A).

[0227] In some embodiments, an antibody or antibody fragment that can bind transferrin receptor is a nanobody. This nanobody can be called “VHHB.” In some embodiments, VHHB binds to an epitope in TfR1 that does not compete for binding with natural / endogenous Tf. In some embodiments, a TransTAC including a first moiety including a molecule that binds PD-L1, or another target, and a second moiety (e.g., VHHB) that binds to an epitope of TfR and drives PD-L1 degradation independently of the presence of natural transferrin (Tf). In some embodiments binding of the TransTAC including VHHB to TfR1 is non-competitive with natural Tf.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0228] In some embodiments, a TransTAC including VHHB degrades a POI with a potency of about between 0.01 and 0.03 nM EC50, about between 0.02 and 0.05 nM EC50, about between 0.04 and 0.1 nM EC50, about between 0.08 and 0.2 nM EC50, about between 0.15 and 0.3 nM EC50, about between 0.25 and 0.5 nM EC50, about between 0.4 and 1 nM EC50. In some embodiments, a TransTAC including VHHB (SEQ ID NO: 148-149) can degrade a POI with a potency of 0.1 nM EC50. In some embodiments, a TransTAC including VHHB (SEQ ID NO: 148-149) and a first moiety that binds PD-LI degrades PD-L1 with a potency of 0.1 nM EC50.

[0229] In some embodiments, a TransTAC including VHHB degrades a POI with an efficiency of between about 50% and about 60%, between about 55% and about 65%, between about 65% to about 75%, between about 70% and about 80%, between about 80% to 90%, or between about 85% and about 95%, or between about 90% and about 100%. In some embodiments, a TransTAC including VHHB degrades a POI with an efficiency of about 100%. In some embodiments, a TransTAC including VHHB degrades a POI with an efficiency of about 99%. In some embodiments, a TransTAC including VHHB degrades a POI with an efficiency of about 98%. In some embodiments, a TransTAC including VHHB degrades a POI with an efficiency of about 97%. In some embodiments, a TransTAC including VHHB degrades a POI with an efficiency of about 96%.

[0230] In some embodiments, the Immune TransTAC includes a first moiety that binds to any of the first moiety targets described herein, and a second moiety (e.g., VHHB) that binds to TfR. In some embodiments, the Immune TransTAC includes a first moiety that binds to any of the first moiety targets described herein, and a second moiety that binds to TfR with an EC50 of about 0.26 (FIG.4A). In some embodiments, the Immune TransTAC includes a first moiety that binds to PD-L1, and a second moiety that binds to TfR with an EC50 of about 0.26 (FIG.4A).

[0231] In some embodiments, a TransTAC including VHHA binds to TfR1 with a KD of about 2.7 nM. In some embodiments, a TransTAC including VHHB binds to TfR1 with a KD of about 1.7 nM. In some embodiments, a TransTAC including H7 binds to TfR1 with a KD of 160 pM.

[0232] In some embodiments, a TransTAC including VHHA and a first moiety (POIB) that binds to PD-L1 can bind to TfR1 more efficiently than a TransTAC including H7 and a first moiety that binds to PD-L1 (FIG.4A). In some embodiments, a TransTAC including VHHB andDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 a first motif that binds to PD-L1 binds to TfR1 more efficiently than a TransTAC including H7 and a first motif that binds to PD-L1.

[0233] In some embodiments, a TransTAC including VHHA and a first moiety that binds to PD-L1 degrades a POI more potently than a TransTAC including H7 and a first moiety that binds to PD-L1. In some embodiments, a TransTAC including VHHB and a first moiety that binds to PD-L1 degrades a POI more potently than a TransTAC including H7 and a first moiety that binds to PD-L1. In some embodiments, a TransTAC including VHHA and a first moiety that binds to PD-L1 degrades a POI more efficiently than a TransTAC including H7 and a first moiety that binds to PD-L1. In some embodiments, a TransTAC including VHHB and a first moiety that binds to PD-L1 degrades a POI more efficiently than a TransTAC including H7 and a first motif that binds to PD-L1.

[0234] In some embodiments, a TransTAC including VHHA degrades a POI more potently than a TransTAC including H7. In some embodiments, a TransTAC including VHHB degrades a POI more potently than a TransTAC including H7. In some embodiments, a TransTAC including VHHA degrades a POI more efficiently than a TransTAC including H7. In some embodiments, a TransTAC including VHHB degrades a POI more efficiently than a TransTAC including H7.

[0235] In one embodiment, an amino acid sequence of VHHA molecules can include the molecules below, or can include molecules at least 60, 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to the amino acid sequences below:

[0236] EVQLVESGGGVVQPGGSLKLSCVASGTDFSINFIRWYRQAPGKQREFVAGFTA TGNTNYADSMKGRFTISRDNTKNAVYLQIDSLKPEDTAVYYCYMLDKWGQGTQVTVS S***(SEQ ID NO: 146)

[0237] In one embodiment, a nucleotide sequence of VHHA molecules can include the molecules below, or can include molecules at least 60, 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to the nucleotide sequences below:

[0238] GAGGTGcAGCTGGTGGAGTCTGGGGGAGGCGTGGTGCAGCCTGGGGGGTC TCTAAAACTCTCCTGCGTAGCCTCGGGAACGGACTTCAGTATCAATTTTATACGCTG GTACCGCCAGGCTCCAGGGAAGCAGCGCGAGTTCGTCGCAGGATTTACTGCGACTG GTAACACAAACTATGCAGACTCCATGAAGGGGCGATTCACCATCTCCAGAGACAACDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 ACCAAGAACGCGGTGTATCTGCAAATAGACAGCCTGAAACCTGAGGACACGGCCGT GTATTACTGCTATATGTTGGACAAGTGGGGCCAGGGGACCCAGGTCACAGTATCCTC C***(SEQ ID NO: 147).

[0239] In embodiments, the VHHA TRB or TR binding means (also known as a means for binding TR) can be modified as follows: EVQLVESGGGVVQPGGSLKLSCVASGTDFSINFIRWYRQAPGKQREFVAGFTATGNTN YADSMKGRFTISRDNTKNAVYLQIDSLKPEDTAVYYCYMLDKWGQGTQVTVSS*** (111 amino acids; SEQ ID NO: 146). The italicized, bolded and underlined amino acid sections correspond to CDR1, CDR2, and CDR3, respectively. In embodiments, the shaded amino acids in CDR2 and CDR3 can be substituted for a neutral amino acid(s). In embodiments, the modifications can be amino acid substitutions in CDR2. In embodiments, the modifications can be amino acid substitutions in CDR3.

[0240] Table 1. Amino Acid Sequences of VHHA Molecules Disclosed Herein. VHHA (SEQ ID NO: 146) EVQLVESGGGVVQPGGSLKLSCVASGTDFSINFIRWYRQAPGKQREFVAGFTATGNT T T

[0241] Table 2. Amino Acid Sequences of Complementarity Determining Regions (CDRs) of VHHA Molecules Disclosed Herein. VHHA Molecule CDR1 CDR2 CDR3DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 VHHA12 GTDFSINF ITATGNT YMLDK (SEQ ID NO: 154)(SEQ ID NO: 175)(SEQ ID NO: 176) (SEQ ID NO: 177)molecules below, or can include molecules at least 60, 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to the amino acid sequences below:

[0243] EVQLVESGGGVVQPGGSLRLSCAASGEIFSINFMRWYRQAPGKQREWVAGFT RDGSTNYPDSAKGRFTISRDNAKNTVYLQIDSLKPEDTAVYYCYMLDTWGQGTQVTVS S***(SEQ ID NO: 148).

[0244] In one embodiment, a nucleotide sequence of VHHB molecules can include the molecules below, or can include molecules at least 60, 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to the nucleotide sequences below:

[0245] GAgGTGCAGCTGGTGGAGTCTGGGGGagGCGTGGTGCAGCCTGGGGGGTCT CTGAGACTCTCCTGTGCAGCCTCTGGAGAGATCTTCAGTATCAATTTTATGCGCTGGT ACCGCCAGGCTCCAGGGAAGCAGCGCGAGTGGGTCGCAGGTTTTACTAGGGATGGA AGCACAAACTATCCAGACTCCGCGAAGGGCCGATTCACCATCTCTAGAGACAACGC CAAGAACACGGTGTATCTGCAAATAGACAGCCTGAAACCTGAGGACACGGCCGTCT ATTATTGTTATATGTTGGACACCTGGGGCCAGGGGACCCAGGTCACAGTATCCTCC** *(SEQ ID NO: 149).

[0246] Herein, disclosed are new mechanisms for modulating proteins at the cell membrane of immune cells. Endocytosis is a common machinery of regulating membrane protein recycling and degradation. Among the various transmembrane proteins regulated by endocytosis, transferrin receptor (TfR) is a well-characterized recycling receptor with a rapid internalization rate (500 molecules / cell / s). TfR imports iron by binding to a plasma protein transferrin (Tf) in complex with iron. TfR is expressed in various cell types and tissues including, but not limited to, CD4+ T cells and CD8+ T cells (FIG.38).DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0247] The methods and compositions disclosed herein are a novel platform for degrading proteins using recombinant biological molecules. The methods and compositions disclosed herein provide a platform approach for degrading membrane / extracellular proteins and, thus, manipulating cell behaviors, which can be used therapeutically or as a research tool, expanding extracellular targets available for degradation, such as those targets that have been a problem for previous PROTAC technologies. The recombinant nature of Immune TransTAC allows for a broad range of targets and binding properties.

[0248] In some embodiments, the fusion proteins disclosed herein have an antigen to which a CD19 receptor binds and a ligand for an internalizing receptor or membrane protein (e.g., transferrin receptor). In some embodiments, the fusion proteins disclosed herein have an antibody that binds to CD19 receptor, or to another POI on the cell surface such as CCR6, EGFR, PD-L1, CD20, TCR, CD3, CD8, and a ligand for an internalizing receptor or membrane protein (e.g., proteins of interest, such as (e.g., a nanobody including VHHA and VHHB)).

[0249] In some embodiments, the fusion proteins can be fusion proteins of the formula R1- R2-R3. In some embodiments, the fusion proteins can be fusion proteins of the formula R3-R2- R1. For example, R1 or R3 can be located at the C-terminus or N-terminus of fusion proteins disclosed herein. In some embodiments, the fusion proteins can be dimers of R1-R2-R3 or R3- R2-R1 (homodimers).

[0250] In some embodiments, R1 is a protein of interest binder (POIB), or a POI binding means (also known as a means for binding POI). In some embodiments, R1 is a protein of interest (POI) binder (POIB) or POI binding means (also known as a means for binding POI) for binding CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or a TCR. In some embodiments, the POIB or POI binding means (also known as a means for binding POI) can be an antibody that binds to the POI. The POIB or POI binding means (also known as a means for binding POI) can bind to a protein of interest such as cell surface POI. In some embodiments, the POIB or POI binding means (also known as a means for binding POI) can bind to an extracellular domain of a transmembrane protein. In some embodiments the POIB or POI binding means (also known as a means for binding POI) can be an antibody (e.g., scFv) that binds to an extracellular domain of a transmembrane protein. Antibodies that bind to an extracellular domain of many different transmembrane proteins are known in the art. In some embodiments, the POIB or POI binding means (also known as a means for binding POI) can bind to an extracellular domain of aDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 chimeric antigen receptor (CAR) in an immune cell, a TCR, a CD3 or a CD8 co-receptor, a receptor tyrosine kinase, a checkpoint inhibitor binding molecule, a cell lineage-specific marker, and the like. In some embodiments, the POIB or POI binding means (also known as a means for binding POI) can bind to an extracellular domain of CCR6, a TCR receptor, a coreceptor (e.g., CD3, CD8) an epidermal growth factor receptor (EGFR), a programmed death-ligand (PD-L1) or CD20. In some embodiments, the POIB or POI binding means (also known as a means for binding POI) can bind to an extracellular domain of a B cell receptor (BCR), human leukocyte antigen (HLA), fibroblast growth factor receptor (FGFR), Notch proteins, or claudin-18.2. Binding of a POIB means to other transmembrane proteins is contemplated. The POI binding means (also known as a means for binding POI) (R1), as part of a fusion protein (R1-R2-R3), can bind to a POI on the surface of a cell and can result in the POI being internalized and, optionally degraded, as described below. Amino acid sequences of example POIBs are shown in Table 3. Amino acid sequences of CDRs from these POIBs are shown in Table 4.

[0251] Table 3. Amino Acid Sequences of POIBs Disclosed Herein. pLS15 Anti-CCR6_B368-G29A_HC-Knob_Fc-His (SEQ ID NO: 300) MRMQLLLLIALSLALVTNSTSEVQLVESGGGLVQPGGSLRLSCAASGFSFSDYYMYW Y P T N Y E E T S G LDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 PPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGSSHHHHHHC V E D H D

[0252] Table 4. Amino Acid Sequences of Heavy Chain (VH) Complementarity Determining Regions (CDRs) of POIBs Disclosed Herein. POIB VH CDR1 VH CDR2 VH CDR3 LS15 Anti-CCR6 B368- GFSFSDY TTGGR PLRGAWFAY

[0253] Table 5. Amino Acid Sequences of Light Chain (VL) Complementarity Determining Regions (CDRs) of POIBs Disclosed Herein. POIB VL CDR1 VL CDR2 VL CDR3DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 pLS16-Anti- RSSQSIVHSNANTYL KVSNRF FQGTYLPLT CCR6_B3G8- E (SEQ ID NO: 204) (SEQ ID NO: 205) 2 A L E ID N 2, (also known as a means for binding TR) (R3) that can bind TfR better is more efficient at internalizing and / or degrading a POI than a fusion protein that has a single moiety that can bind TfR. In some embodiments, fusion proteins include one copy of a TRB or TR binding means (also known as a means for binding TR). In some embodiments, fusion proteins include two copies of a TRB or TR binding means (also known as a means for binding TR). In some embodiments, fusion proteins include three or more copies of a TRB or TR binding means (also known as a means for binding TR). In some embodiments, different TRBs are combined in a fusion protein.

[0255] In some embodiments, a fusion protein with two R3 is more efficient at internalizing and / or degrading a POI than a fusion protein including two R1 (e.g., H7 in v0.6 vs. v0.7, FIG. 37A). In some embodiments, a fusion protein with two R3 is at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI than a fusion protein including two R1.

[0256] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), a linker (not R2), and one copy of R3, respectively, and another monomer including an Fc (hole), a linker (not R2), and one copy of R3, wherein both monomers are bound by knob / hole interactions (e.g., v0.6 FIG. 37A) are more efficient at internalizing and / or degrading a POI (e.g, CD20, EGFR, PD-L1, andDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 the like) than fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), and an Fc (hole), and a second monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7 in FIG.37A).

[0257] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), a linker (not R2), and one copy of R3, respectively; and another monomer including an Fc (hole), a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.6) are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI (e.g., CD20, EGFR, PD-L1, and the like) than fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), and an Fc (hole), and a second monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7).

[0258] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), an Fc (knob), a linker (not R2), and one copy of R3, respectively; and another monomer including an Fc (hole) a linker (not R2) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.6) are more efficient at internalizing and / or degrading a POI than heterodimeric fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), and an Fc (hole), and a second monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), an Fc (knob), a linker (not R2) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7).

[0259] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), an Fc (knob), a linker (notDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 R2), and one copy of R3, respectively, and another monomer including an Fc (hole) a linker (not R2) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.6) are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI (e.g, CD19 binding receptor) than heterodimeric fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), and an Fc (hole), and a second monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), an Fc (knob), a linker (not R2) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7).

[0260] In some embodiments, a fusion protein with two R3 is more efficient at internalizing and / or degrading a POI than a fusion protein including one R3 (FIG.37A). In some embodiments, a fusion protein with two R3 is at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI than a fusion protein including one R3.

[0261] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, and another monomer including one copy of R1, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by the Fc (e.g., v0.5 FIG.37A) are more efficient at internalizing and / or degrading a POI (e.g, CD20, EGFR, PD-L1, and the like) than fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), and an Fc (hole), and a second monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an FcDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 (knob), a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7 in FIG.37A).

[0262] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, and another monomer including one copy of R1, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by the Fc (e.g., v0.5 FIG.37A) are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI (e.g, CD20, EGFR, PD-L1, and the like) than fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), and an Fc, and a second monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7 in FIG. 37A).

[0263] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of a CD19NT.1 binder, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, and another monomer including one copy of a CD19NT.1 binder, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by the Fc (e.g., v0.5 FIG.37A) are more efficient at internalizing and / or degrading a POI (e.g, CD20, EGFR, PD-L1, and the like) than fusion proteins including one monomer including from N terminus to C terminus one copy of a CD19NT.1 binder, a linker (not R2), and an Fc, and a second monomer including from N terminus to C terminus one copy of a CD19NT.1 binder, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7 in FIG. 37A).

[0264] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of a CD19NT.1 binder, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, and another monomer including one copy of a CD19NT.1DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 binder, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by the Fc (e.g., v0.5 FIG.37A) are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient more efficient at internalizing and / or degrading a POI (e.g, CD20, EGFR, PD-L1, and the like) than fusion proteins including one monomer including from N terminus to C terminus one copy of a CD19NT.1 binder, a linker (not R2), and an Fc, respectively, and a second monomer including from N terminus to C terminus one copy of a CD19NT.1 binder, a linker (not R2), an Fc, a linker (not R2), and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.7 in FIG.37A).

[0265] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), and an Fc (hole), respectively, and a second monomer including from N terminus to C terminus one copy of R3, a linker (not R2) and an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.8; FIG.37A), are more efficient at internalizing and / or degrading a POI than fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (hole), a linker (not R2), and one copy of R3, respectively, and another monomer including an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.9; FIG.37A).

[0266] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), and an Fc (hole), and a second monomer including from N terminus to C terminus one copy of R3, a linker (not R2), and an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.8), are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI (e.g., CD20, PD-L1, EGFR, and the like) than fusion proteins includingDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (hole), a linker (not R2), and one copy of R3, respectively, and another monomer including an Fc (knob), wherein both monomers are bound by knob / hole interactions (e.g., v0.9).

[0267] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), and an Fc (hole), and a second monomer including from N terminus to C terminus one copy of R3, a linker (not R2) and an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.8), are more efficient at internalizing and / or degrading a POI than heterodimeric fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), an Fc (hole), a linker (not R2), and one copy of R3, respectively, and another monomer including an Fc (knob), wherein both monomers are bound by knob / hole interactions (e.g., v0.9).

[0268] In some embodiments, heterodimeric fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), and an Fc (hole), respectively, and a second monomer including from N terminus to C terminus one copy of R3, a linker (not R2), and an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v0.8), are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI (e.g., CD19 binding receptor) than fusion proteins including one monomer including from N terminus to C terminus one copy of CD19NT.1, a linker (not R2), an Fc (hole), a linker (not R2), and one copy of R3, respectively, and another monomer including an Fc (knob), wherein both monomers are bound by knob / hole interactions (e.g., v0.9).

[0269] In some embodiments, a fusion protein includes two copies of an R3 located in tandem (e.g., two R3 contiguous to each other; e.g., v1.2 in FIG.1A). In some embodiments, more than two contiguous R3 can be used.

[0270] In some embodiments, a fusion protein with two R3s located in tandem (e.g., two or more R3 contiguous to each other (e.g., v1.2 in FIG.1A and SEQ ID NO: 150-151, FIG.3A) isDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 more efficient at internalizing and / or degrading a POI than a fusion protein including two R3 that are not in tandem (e.g., v1.4 in FIG.1A; SEQ IDs NO: 152-153; FIG.3B; and v1.0 in FIG.1A). In some embodiments, a fusion protein with two R3s located in tandem (e.g., two R3 contiguous to each other (e.g., v1.2 in FIG.1A and SEQ ID NO: 150-151, FIG.3A) is at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI than a fusion protein including two R3 that are not in tandem (e.g., v1.4 in FIG.1A; SEQ IDs NO: 152-153; FIG.3B; and v1.0 in FIG.1A).

[0271] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), respectively, and another monomer including from N terminus to C terminus two in tandem copies of R3, and an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.2; FIG.1A) are more efficient at internalizing and / or degrading a POI than fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), and one copy of R3, respectively, and a second monomer including from N terminus to C terminus an Fc (hole) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.4; FIG.1 and FIG.3).

[0272] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), respectively, and another monomer including from N terminus to C terminus two in tandem copies of R3, and an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.2), are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI than fusion proteins including one monomer including from N terminus to C terminus one copy of R1, a linker (not R2), an Fc (knob), and one copy of R3, respectively,DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 and a second monomer including from N terminus to C terminus an Fc (hole) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.4; FIG.1 and FIG.3).

[0273] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of a PD-L1 binder, a linker (not R2), an Fc (knob), respectively, and another monomer including from N terminus to C terminus two in tandem copies of R3, and an Fc (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.2), are more efficient at internalizing and / or degrading a POI than heterodimeric fusion proteins including one monomer including from N terminus to C terminus one copy of an PD-L1 binder, a linker (not R2), an Fc (knob), and one copy of R3, respectively, and a second monomer including from N terminus to C terminus an Fc (hole) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.4; FIG.1 and FIG.3).

[0274] In some embodiments, fusion proteins including one monomer including from N terminus to C terminus one copy of a PD-L1 binder, a linker (not R2), an Fc (knob), respectively, and another monomer including from N terminus to C terminus two in tandem copies of R3, and an FC (knob), respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.2), are at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI than heterodimeric fusion proteins including one monomer including from N terminus to C terminus one copy of an PD-L1 binder, a linker (not R2), an Fc (knob), and one copy of R3, respectively, and a second monomer including from N terminus to C terminus an Fc (hole) and one copy of R3, respectively, wherein both monomers are bound by knob / hole interactions (e.g., v1.4; FIG.1 and FIG.3).

[0275] In some embodiments, the location of a protease-sensitive linker (e.g., cathepsin sensitive linker) within a fusion protein modulates the efficiency of the fusion protein at internalizing and / or degrading a POI. In some embodiment, a fusion protein can include a cathepsin B-sensitive linker between the Fc domain and the R3 (e.g., v0.3, FIG.34). In some embodiments, a fusion protein includes a cathepsin B-sensitive linker between R1 and the FcDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 domain (e.g., v0.4, FIG.34). In some embodiments, a fusion protein including a cathepsin B- sensitive linker between R1 and the Fc domain (e.g., v0.4) is more efficient at internalizing and / or degrading a POI than a fusion protein including a cathepsin B-sensitive linker between the Fc domain (e.g., R4) and the R3 (e.g., v0.3; FIG.34D).

[0276] In some embodiments, a fusion protein including a cathepsin B-sensitive linker between R1 and the Fc domain (e.g., v0.4) is at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI than a fusion protein including a cathepsin B-sensitive linker between the Fc domain and the R3 (e.g., v0.3; FIG.34B).

[0277] In some embodiments, a fusion protein including two monomers bound by Fc interactions, each monomer including from N terminus to C terminus and R1, a cathepsin linker, and Fc, and an R3 (e.g., v0.4) is more efficient at internalizing and / or degrading a POI than a fusion protein including two monomers bound by Fc interactions, each monomer including from N terminus to C terminus and R1, and Fc, a cathepsin linker, and an R3 (e.g., v0.3; FIG.34).

[0278] In some embodiments, a fusion protein including two monomers bound by Fc interactions, each monomer including from N terminus to C terminus and R1, a cathepsin linker, and Fc, and an R3 (e.g., v0.4) is at least between about 10 to about 20%, about 15 to about 25%, about 20% to about 30%, about 25 to about 35%, about 30 and about 40%, about 35 and about 45%, about 40% and about 50%, about 45 and about 55%, about 50 to about 60%, about 55 to about 65%, about 60 to about 70%, about 65 to about 75%, about 70% to about 80%, about 75% to about 85%, about 80 to about 90%, about 85% to about 95%, about 90 to about 100% more efficient at internalizing and / or degrading a POI (e.g., CD20, PD-L1, EGFR, CD19 binding chimeric receptor, and the like) than a fusion protein including two monomers bound by Fc interactions, each monomer including from N terminus to C terminus and R1, and Fc, a cathepsin linker, and an R3 (e.g., v0.3; FIG.34B).

[0279] In some embodiments, R3 is a transferrin receptor (TR) binding means (also known as a means for binding TR). The TRB or TR binding means (also known as a means for binding TR) can bind to a transferrin receptor on the surface of cells. In some embodiments, the TRB orDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 TR binding means (also known as a means for binding TR) is a molecule that binds to a transferrin receptor (TfR). In some embodiments, the TRB or TR binding means (also known as a means for binding TR) is transferrin or a part of transferrin that can bind to a TfR. In some embodiments, the TRB or TR binding means (also known as a means for binding TR) is an antibody that binds to the transferrin receptor. In some embodiments, a TRB or TR binding means (also known as a means for binding TR) is non-competitive for binding to a TfR (e.g., VHHA or VHHB). The TRB or TR binding means (also known as a means for binding TR) (R3), as part of a fusion protein molecule (e.g., R1-R2-R3), binds to transferrin (Tf) on the surface of a cell and is internalized into the cell. When the protein of interest binder (POIB or POI binding means (also known as a means for binding POI); R1) in the fusion protein binds a protein of interest (POI) on a cell surface, internalization of the TRB or TR binding means (also known as a means for binding TR) can also cause internalization of the POI Internalized POIs can be degraded once internalized by a cell.

[0280] The TRB or TR binding means (also known as a means for binding TR) (R3) can bind to a transferrin receptor on the surface of cells. In some embodiments, the TRB or TR binding means (also known as a means for binding TR) can be an antibody that binds to the transferrin receptor (e.g., H7 or M16). In some embodiments, the TRB or TR binding means (also known as a means for binding TR) can be a nanobody that binds to the transferrin receptor. In some embodiments, the TRB or TR binding means (also known as a means for binding TR) can be a nanobody that binds to the transferrin receptor without competing with endogenous Tf for binding to the TfR1. In some embodiments, the TRB or TR binding means (also known as a means for binding TR) can be VHHA (SEQ IDs NO: 146-147). In some embodiments, the TRB or TR binding means (also known as a means for binding TR) can be VHHB (SEQ IDs NO: 148- 149).

[0281] In some embodiments, a TR binder or TR binding means (also known as a means for binding TR can have CDRs. In some embodiments, the CDRs can be a VH CDR1 comprising the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 comprising the amino acid sequence of ITATGNT (SEQ ID NO: 176), and a VH CDR3 comprising the amino acid sequence of YMLDK (SEQ ID NO: 177), a VH CDR1 comprising the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 comprising the amino acid sequence of FTATGNT (SEQ ID NO: 179), and a VH CDR3 comprising the amino acid sequence of AMLDK (SEQ IDDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 NO: 180), or a VH CDR1 comprising the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 comprising the amino acid sequence of FTATGNT (SEQ ID NO: 179), and a VH CDR3 comprising the amino acid sequence of YMADK (SEQ ID NO: 183).

[0282] In some embodiments, R2 is a linker of the formula R4-R5 or R5-R4. In some embodiments, R4 is a Fc region from an antibody. In some embodiments, R4 is a Fc region from IgG, IgM, IgA, IgE or IgD. In some embodiments, R5 is an optional protein-sensitive linking means (also known as a means for linking). In some embodiments, an Fc region is (SEQ ID NO: 6):

[0283] DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0284] In some embodiments, the Fc regions can dimerize, forming homodimers or heterodimer structures. In some embodiments, the Fc regions have, or can be modified to have, cysteine amino acids that are capable of forming disulfide bonds. In some embodiments, dimers of the R1-R2-R3 fusion proteins can form through disulfide bonds (1 or more, such as 2 disulfide bonds) between cysteine residues in R2 regions of separate fusion protein molecules. In some embodiments, the disulfide bonds form between R4 in separate fusion molecules (e.g., Fc with disulfides can be a type of dimerization domain). In some embodiments, disulfide bonds form between fusion proteins of a homodimer.

[0285] In some embodiments (e.g., heterodimers), one monomer of the heterodimer can have a “knob”, and the second monomer of the heterodimer can have a “hole” structure. In some embodiments, the knob and hole structures of two monomers can be in the Fc regions (R4) of the monomers. Knob-into-hole technologies are well known in the art (Xu et al., MAbs.2015 Jan- Feb; 7(1): 231–242).

[0286] In embodiments, the Fc region is a variant comprising an amino acid substitution which alters antigen-independent effector functions, like the circulating half-life of a molecule to which it is linked. Molecules linked to these Fc regions can exhibit either increased or decreased binding to FcRn (neonatal Fc receptor) compared to Fc regions lacking these substitutions and can have an increased or decreased half-life in serum, respectively. Fc variants with improved affinity for FcRn are anticipated to have longer serum half-lives, and such molecules have usefulDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 applications in methods long half-life of the linked molecule is desired. In contrast, Fc variants with decreased FcRn binding affinity are expected to have shorter half-lives, and such molecules are also useful, for example, where a shortened circulation time can be advantageous. Fc variants with decreased FcRn binding affinity are also less likely to cross the placenta. In addition, other applications in which reduced FcRn binding affinity can be desired include those applications in which localization to the brain, kidney, and / or liver is desired. In one embodiment, the Fc variant-linked molecules can exhibit reduced transport across the epithelium of kidney glomeruli from the vasculature. See Ko, S., Jo, M. & Jung, S.T. Recent Achievements and Challenges in Prolonging the Serum Half-Lives of Therapeutic IgG Antibodies Through Fc Engineering. BioDrugs 35, 147–157 (2021).

[0287] In another embodiment, the Fc variant-linked molecules exhibit reduced transport across the blood brain barrier (BBB) from the brain, into the vascular space. In one embodiment, an Fc region with altered FcRn binding comprises an Fc domain having one or more amino acid substitutions within the "FcRn binding loop" of an Fc domain. The FcRn binding loop is comprised of amino acid residues 280-299 (according to EU numbering). Exemplary amino acid substitutions with altered FcRn binding activity are disclosed in PCT Publication No. WO05 / 047327 which is incorporated by reference herein. In embodiments, the fusion proteins disclosed herein comprise an Fc domain having one or more of the following substitutions: V284E, H285E, N286D, K290E and S304D (EU numbering).

[0288] In some embodiments, a molecule disclosed herein is linked to an Fc variant comprising an amino acid substitution which alters glycosylation. For example, the Fc variant can have reduced glycosylation (e.g., N- or O-linked glycosylation). In some embodiments, the Fc variant comprises reduced glycosylation of the N-linked glycan normally found at amino acid position 297 (EU numbering). In another embodiment, the molecules can have an amino acid substitution near or within a glycosylation motif, for example, an N-linked glycosylation motif that contains the amino acid sequence NXT or NXS. In a particular embodiment, the Fc variant can have amino acid substitution at amino acid position 228 or 299 (EU numbering). Exemplary amino acid substitutions which confer reduced or altered glycosylation are described in PCT Publication No, WO05 / 018572, which is incorporated by reference herein in its entirety.

[0289] In some embodiments, the molecules disclosed herein can be modified to eliminate glycosylation and can be referred to as "agly" molecules. Exemplary agly molecules, can haveDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 an aglycosylated Fc region of an IgG4 antibody which is devoid of Fc-effector function thereby eliminating the potential for Fc mediated toxicity to the normal vital tissues and cells. In yet other embodiments, the molecules disclosed herein can have an altered glycan. For example, there can be a reduced number of fucose residues on an N-glycan at Asn297 of the Fc region, i.e., is afucosylated. In some embodiments, there can be an altered number of sialic acid residues on the N-glycan at Asn297 of the Fc region.

[0290] In some embodiments, the CH2 or CH3 region of the Fc antibody domain is truncated or modified to adjust the half-life of the molecule. In some embodiments, an Fc truncation includes CH3 or CH2 (e.g., Gehlsen, Kurt R., et al. "Pharmacokinetics of engineered human monomeric and dimeric CH2 domains." MAbs. Vol.4. No.4. Taylor & Francis, 2012; Ying, Tianlei, et al. "Engineered soluble monomeric IgG1 CH3 domain: generation, mechanisms of function, and implications for design of biological therapeutics." Journal of Biological Chemistry 288.35 (2013): 25154-25164).

[0291] In some embodiments, R4 is a dimerization domain. The dimerization domain can be any region that can associate with another dimerization domain, through covalent or non- covalent bonds, to form a dimer (e.g., a fusion protein that is a homodimer or heterodimer).

[0292] There are many protein dimerization domains known in the art (e.g., see Dang, Dung Thanh. "Molecular Approaches to Protein Dimerization: Opportunities for Supramolecular Chemistry." Frontiers in Chemistry 10 (2022): 829312). An example dimerization domain can include zipper motifs, like a leucine zipper.

[0293] In some embodiments, the dimerization can form between regions of the fusion proteins that are not R4 regions.

[0294] In some embodiments, R5 is a protease-sensitive linking means (also known as a means for linking). In some embodiments, R5 is an optional feature. In some embodiments, the protease-sensitive linking means (also known as a means for linking) is an amino acid sequence that can be cleaved by a protease. In some embodiments, the protease can be a protease in an endosome or lysosome. In some embodiments, the protease can be a cathepsin (e.g., cathepsin B) and the protease-sensitive linking means (also known as a means for linking) can be a cathepsin-cleavable peptide. Some example protease-sensitive linking means (also known as a means for linking) are shown in FIG.35. In some embodiments, the protease-sensitive linking means (also known as a means for linking) can be GGFLGGVRGVDG (SEQ ID NO: 7) orDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 GSGSGGEVRGVDG (SEQ ID NO: 8). Sequences of other protease-sensitive linking means (also known as a means for linking) are disclosed herein (e.g., FK, VA, VK, SEQ ID NO: 7, 8, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145). In some embodiments, sequences that are at least 80, 84, 88, 92 or 96 percent identical to these sequences can be used. Functional alternative amino acid sequences that can be cleaved by a protease (e.g., cathepsin) are known in the art. Use of other protease-sensitive linkers are contemplated.

[0295] In some embodiments, a linkage noted as a “-“ (not R2) can be located between various sections of the R1-R2-R3 fusion In embodiments, a linkage can be locatedbetween R2 and R3. In some embodiments, can be located between R1 and R2. In some embodiments, the linkage can be a glycine-rich linker (“GS linker”). In some embodiments, a “GS” linker can be a combination of glycine and serine amino acids. In some embodiments, the GS linker can be GSSGGSGGSGGS (SEQ ID NO: 9). Other sequences are possible. In some embodiments, the GS linker can be SGGGG (SEQ ID NO: 10), SGGGSGGG (SEQ ID NO: 11), GSSGGSGGSGGS (SEQ ID NO: 12), GSGS (SEQ ID NO: 13), GSGGS (SEQ ID NO: 14), GSSGSS (SEQ ID NO: 15), GSSSSSS (SEQ ID NO: 16) and the like. In some embodiments, a GS linker can have at least 4 amino acids that are glycine and / or serine. In some embodiments, other amino acids can be part of a GS linker, as long as glycine and serine are in the majority. In some embodiments, optionally, a linker (e.g., glycine-rich) can be comprised between R2 and R3. In some embodiments, optionally, a linker can be comprised between R1 and R2.

[0296] In some embodiments, the GS linkers are one to 50 amino acids in length (e.g., 1, 2, 3, 4, 5, 10, 12, 1-10, 1-12, or 1-20, or more amino acids) containing various types of amino acids (e.g., US Patent No.11,041,023, incorporated by reference herein in its entirety on March 14, 2024). In some embodiments, the GS linker is 12 amino acids in length. In some embodiments, the GS linker can be 20, 25, 30, 35, 40, 45 or 50 amino acids in length. In embodiments, the amino acids include a combination of one or more glycine(s) and / or serine(s). In embodiments, the peptide linker comprises the amino acid sequence comprising GGGGS (SEQ ID NO: 305). In embodiments, the peptide linker comprises or consists of 2, 3, 4, 5, 6, or 7 consecutive repeats of the amino acid sequence GGGGS (SEQ ID NO: 305). Particularly in embodiments, theDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 peptide linker comprises or consists of the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 306).

[0297] In some embodiments, fusion proteins that can bind to a dimeric TfR (e.g., that can bind to two TfRs) can be more efficient at internalizing and / or degrading a POI than a fusion protein that can bind a monomeric TfR (e.g., that can bind to one TfR). In some embodiments, fusion proteins can include one copy of R3. In some embodiments, fusion proteins can include two copies of R3. In some embodiments, fusion proteins can include three or more copies of R3. In some embodiments, different R3s can be combined in a fusion protein.

[0298] In some embodiments, the fusion proteins disclosed herein can include the following nucleotide and amino acid sequences, and molecules at least 60, 65, 70, 75, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 percent identical to the nucleotide and amino acid sequences below. Specifically, the amino acid sequences of the fusion proteins can be labeled as follows:

[0299] Times New Roman font underlined is signal peptide;

[0300] Times New Roman font bolded is anti-protein of interest Fab-heavy chain, scFv, or affibody;

[0301] Times New Roman italicized font is linker encoded by restriction enzyme site creation;

[0302] Times New Roman underlined and bolded font is GS linker;

[0303] Times New Roman underlined, italicized, and bolded font is cleavable linker;

[0304] Courier New font is H7-scFv;

[0305] Courier New underlined font is Fc domain;

[0306] Courier New bolded font is TEV site;

[0307] Courier New italicized font is fragment from Transferrin;

[0308] Courier New underlined and bolded font is His-Tag;

[0309] Courier New bolded and italicized is light chain, and

[0310] Courier New underlined, italicized, and bolded font is Avi-Tag.

[0311] pDP14-CD19 ETD_Hole Fc Nucleic Acid Sequence (SEQ ID NO: 17)

[0312] atgcgAatgcagctgctgctgctgattgcgctgagcctggcgctggtgaccaacagcactagtcccgaggaacctctagtg gtgaaggtggaagagggagataacgctgtgctgcagtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcggga gtccccgcttaaacccttcttaaaactcagcctggggctgccaggcctgggaatccacatgaggcccctggccatctggcttttcatcttcaaDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 cgtctctcaacagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtgga gggcagcggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagct ccccttccgggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccac cgagggacagcctgaaccagagcctcagccaggacctcaccatggcccctggctccacactctggctgtcctgtggggtaccccctgact ctgtgtccaggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccgg ccagagatatgtgggtaatggagacgggtctgttgttgccccgggccacagctcaagacgctggaaagtattattgtcaccgtggcaacctg accatgtcattccacctggagatcactgctcggccagtactatggcactggctgctgaggactggtggctggaagactagtTCTGGTG GTGGTGGTGAGAATCTGTACTTTCAGAGCTCGGGCGGAGGATCgggtggaggcgagcccaaatc ttgtgacaaaactcacacatgcCCCCCCTGCCCAGCGCCAGAATTGCTGGGCGGACCCAGCGTGT TCCTGTTCCCCCCCAAACCTAAAGACACCCTGATGATCAGCCGAACCCCTGAGGTGA CCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGGTGAAGTTCAACTGGTAT GTGGACGGCGTGGAGGTCCACAATGCCAAAACGAAGCCCAGGGAGGAGCAGTACA ACAGCACCTACAGGGTAGTGAGCGTCTTGACCGTGCTGCACCAGGACTGGCTGAAC GGCAAGGAATACAAATGCAAGGTCAGCAATAAGGCTCTGCCGGCTCCTATCGAGAA GACAATCAGCAAGGCAAAGGGCCAGCCACGCGAACCGCAGGTGTATACTCTGCCCC CCAGCCGGGACGAGCTGACCAAGAACCAGGTGTCCCTGAGCTGTGCCGTGAAAGGC TTCTACCCCAGCGACATCGCTGTGGAGTGGGAGAGTAACGGGCAGCCCGAGAACAA CTACAAGACCACGCCTCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGGTGAGCAA GCTCACCGTGGACAAGAGCAGGTGGCAACAGGGCAACGTGTTCAGCTGCTCTGTGA TGCACGAGGCCCTGCACAACCATTACACCCAGAAGAGTCTCAGTCTGAGCCCGGGA AAGGGTGGAGGCGGATCCGGCCTGAACGACATCTTCGAGGCTCAGAAAATCGAATG GCACGAAGGCtaa

[0313] pDP14-CD19 ETD_Hole Fc Amino Acid Sequence (SEQ ID NO: 18)

[0314] MRMQLLLLIALSLALVTNSTSPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQ LTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEK AWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVW AKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWT HVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMS FHLEITARPVLWHWLLRTGGWKTSSGGGGENLYFQSSGGGSGGGEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGLNDIFEAQKIEWHEG*

[0315] pDP16-EGFR-Affibody-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 19)

[0316] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGCTGCAGGTAGATAACAAATTCAACAAAGAAATGTGGGCGGCGTGGGA AGAAATTCGCAACCTGCCGAACCTGAACGGCTGGCAGATGACCGCGTTTATTGCGA GCCTGGTGGATGACCCAAGCCAAAGCGCTAACTTGCTAGCAGAAGCTAAAAAGCTA AATGATGCTCAGGCGCCGAAAGTAGACGGCAGCGGCAGCGACAAAACTCACACATG CCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCC AAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGG TGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACC GTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAA AGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGG ACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAggatcctctggggg aagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttcc gggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccatt gccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggc cgagttctacggcagcaaagaggacccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagc tgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgag ccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtc agctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgac gtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacac cagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagag gatctgatctgggagctgctgaaccaggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacgg caaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgt gaccgccatccggaacctgagagagggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccac cacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatc gccaagatcatgaacggcgaggccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctg gccgagaactacaacaagagcgacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcg acctgacctgggacaatctgaagggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctg tacaacaagatcaaccactgcagattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctg tgcatgggcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaa gggggacgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacga gaaggactacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacg ccgtggtcacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactg cagcggcaacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaa cacctacgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgca cctttcgcagacctTAA

[0317] pDP16-EGFR-Affibody-FC-Tf Amino Acid Sequence (SEQ ID NO: 20)

[0318] MYRMQLLSCIALSLALVTNSLQVDNKFNKEMWAAWEEIRNLPNLNGWQM TAFIASLVDDPSQSANLLAEAKKLNDAQAPKVDGSGSDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGPSVAC VKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVAVVKK DSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCADGTDF PQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLCLDNT RKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGKDLLF KDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKCDEWS VNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCEDTPE AGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEGCAPGDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 SKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNPDPWA KNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSNVTDC SGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACTFRRP*

[0319] pDP18-EGFR-affibody Nucleic Acid Sequence (SEQ ID NO: 21)

[0320] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGCTGCAGGTAGATAACAAATTCAACAAAGAAATGTGGGCGGCGTGGGA AGAAATTCGCAACCTGCCGAACCTGAACGGCTGGCAGATGACCGCGTTTATTGCGA GCCTGGTGGATGACCCAAGCCAAAGCGCTAACTTGCTAGCAGAAGCTAAAAAGCTA AATGATGCTCAGGCGCCGAAAGTAGACGGTGAGAATCTGTACTTTCAGAGCTCGGG CGGAGGATCGGGTGGAGGCCACCACCATCATCACCACCATCACGGATCCGGCCTGA ACGACATCTTCGAGGCTCAGAAAATCGAATGGCACGAAGGCggatcctctgggggaagtggaggt agcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacat gaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatg aggccgacgccgtgacactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctac ggcagcaaagaggacccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggca agaagtcctgtcacaccggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaag cctctggaaaaggccgtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgcc ccggctgtggctgcagcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcg tgaagcacagcaccatcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcc cgtggacgagtacaaggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatct gggagctgctgaaccaggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatct gctgttcaaggacagcgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccat ccggaacctgagagagggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcg gctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatc atgaacggcgaggccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaa ctacaacaagagcgacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacct gggacaatctgaagggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaa gatcaaccactgcagattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgg gcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaaggggga cgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggac tacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggt cacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcgg caacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacaccta cgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcg cagacctTAA

[0321] pDP18-EGFR-affibody Amino Acid Sequence (SEQ ID NO: 22)

[0322] MYRMQLLSCIALSLALVTNSLQVDNKFNKEMWAAWEEIRNLPNLNGWQM TAFIASLVDDPSQSANLLAEAKKLNDAQAPKVDGENLYFQSSGGGSGGGHHHHHHHHG SGLNDIFEAQKIEWHEGGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDG PSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAV AVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCA DGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELL CLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHG KDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 CDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNC EDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSE GCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKN PDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGS NVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEAC TFRRP*

[0323] pDP20-EGFR-Affibody-FC Nucleic Acid Sequence (SEQ ID NO: 23)

[0324] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGCTGCAGGTAGATAACAAATTCAACAAAGAAATGTGGGCGGCGTGGGA AGAAATTCGCAACCTGCCGAACCTGAACGGCTGGCAGATGACCGCGTTTATTGCGA GCCTGGTGGATGACCCAAGCCAAAGCGCTAACTTGCTAGCAGAAGCTAAAAAGCTA AATGATGCTCAGGCGCCGAAAGTAGACGGCAGCGGCAGCGACAAAACTCACACATG CCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCC AAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGG TGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACC GTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAA AGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATG AGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGG ACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATAA

[0325] pDP20-EGFR-Affibody-FC Amino Acid Sequence (SEQ ID NO: 24)

[0326] MYRMQLLSCIALSLALVTNSLQVDNKFNKEMWAAWEEIRNLPNLNGWQM TAFIASLVDDPSQSANLLAEAKKLNDAQAPKVDGSGSDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK*

[0327] pDP22-EGFR-affibody Nucleic Acid Sequence (SEQ ID NO: 25)

[0328] ATGCGAATGCAGCTGCTGCTGCTGATTGCGCTGAGCCTGGCGCTGGTGACC AACAGCACTAGTCTGCAGGTAGATAACAAATTCAACAAAGAAATGTGGGCGGCGTG GGAAGAAATTCGCAACCTGCCGAACCTGAACGGCTGGCAGATGACCGCGTTTATTG CGAGCCTGGTGGATGACCCAAGCCAAAGCGCTAACTTGCTAGCAGAAGCTAAAAAG CTAAATGATGCTCAGGCGCCGAAAGTAGACGGCAGCGGCAGCACTAGTTCTGGTGG TGGTGGTGAGAATCTGTACTTTCAGAGCTCGGGCGGAGGATCGGGTGGAGGCCACC ACCATCATCACCACCATCACGGATCCGGCCTGAACGACATCTTCGAGGCTCAGAAA ATCGAATGGCACGAAGGCTAA

[0329] pDP22-EGFR-affibody Amino Acid Sequence (SEQ ID NO: 26)DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0330] MRMQLLLLIALSLALVTNSTSLQVDNKFNKEMWAAWEEIRNLPNLNGWQ MTAFIASLVDDPSQSANLLAEAKKLNDAQAPKVDGSGSTSSGGGGENLYFQSSGGGS GGGHHHHHHHHGSGLNDIFEAQKIEWHEG*

[0331] pDP24-CD19-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 27)

[0332] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGcccgaggaacctctagtggtgaaggtggaagagggagataacgctgtgctgcagtgcctcaaggggacctcagat ggccccactcagcagctgacctggtctcgggagtccccgcttaaacccttcttaaaactcagcctggggctgccaggcctgggaatccaca tgaggcccctggccatctggcttttcatcttcaacgtctctcaacagatggggggcttctacctgtgccagccggggcccccctctgagaag gcctggcagcctggctggacagtcaatgtggagggcagcggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggc ctgaagaacaggtcctcagagggccccagctccccttccgggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctga gatctgggagggagagcctccgtgtctcccaccgagggacagcctgaaccagagcctcagccaggacctcaccatggcccctggctcca cactctggctgtcctgtggggtaccccctgactctgtgtccaggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattg ctgagcctagagctgaaggacgatcgcccggccagagatatgtgggtaatggagacgggtctgttgttgccccgggccacagctcaaga cgctggaaagtattattgtcaccgtggcaacctgaccatgtcattccacctggagatcactgctcggccagtactatggcactggctgctgag gactggtggctggaagGTAGACGGCAGCGGCAGCGACAAAACTCACACATGCCCACCGTGCC CAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCC ACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAAT GCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAG CCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGG ACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGC AGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACA CGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgc ccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatcccc agcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtga cactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggac ccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacac cggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggcc gtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgca gcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcacc atcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtaca aggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaac caggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacag cgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagag agggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacg agtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgagg ccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagc gacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaa gggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgca gattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaac ctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaaDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 caccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgt ctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggaca aagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttca gaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctggg cgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0333] pDP24-CD19-FC-Tf Amino Acid Sequence (SEQ ID NO: 28)

[0334] MYRMQLLSCIALSLALVTNSPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQ LTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEK AWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVW AKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWT HVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMS FHLEITARPVLWHWLLRTGGWKVDGSGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGPSVACVKKASYLD CIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVAVVKKDSGFQMNQ LRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCADGTDFPQLCQLCP GCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLCLDNTRKPVDEYK DCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGKDLLFKDSAHGFL KVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKCDEWSVNSVGKIE CVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCEDTPEAGYFAIAV VKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEGCAPGSKKDSSLC KLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNPDPWAKNLNEKDY ELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSNVTDCSGNFCLFR SETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACTFRRP*

[0335] pDP25-pFUSE-Tf-knob-Fc Nucleic Acid Sequence (SEQ ID NO: 29)

[0336] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGgtgcccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggacca catgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaa tgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttcta cggcagcaaagaggacccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggc aagaagtcctgtcacaccggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaa gcctctggaaaaggccgtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgc cccggctgtggctgcagcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttc gtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagc ccgtggacgagtacaaggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatc tgggagctgctgaaccaggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatct gctgttcaaggacagcgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccat ccggaacctgagagagggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcg gctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatc atgaacggcgaggccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaa ctacaacaagagcgacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacct gggacaatctgaagggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaaDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 gatcaaccactgcagattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgg gcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaaggggga cgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggac tacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggt cacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcgg caacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacaccta cgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcg cagacctCCATGGgagcccaaatcttgtgacaaaactcacacatgcCCCCCCTGCCCAGCGCCAGAATTGCT GGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAACCTAAAGACACCCTGATGATCAG CCGAACCCCTGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGG TGAAGTTCAACTGGTATGTGGACGGCGTGGAGGTCCACAATGCCAAAACGAAGCCC AGGGAGGAGCAGTACGGAAGCACCTACAGGGTAGTGAGCGTCTTGACCGTGCTGCA CCAGGACTGGCTGAACGGCAAGGAATACAAATGCAAGGTCAGCAATAAGGCTCTGC CGGCTCCTATCGAGAAGACAATCAGCAAGGCAAAGGGCCAGCCACGCGAACCGCA GGTGTATACTCTGCCCCCCAGCCGGGACGAGCTGACCAAGAACCAGGTGTCCCTGT GGTGTCTGGTGAAAGGCTTCTACCCCAGCGACATCGCTGTGGAGTGGGAGAGTAAC GGGCAGCCCGAGAACAACTACAAGACCACGCCTCCTGTGCTGGACAGCGACGGCAG CTTCTTCCTGTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAACAGGGCAACG TGTTCAGCTGCTCTGTGATGCACGAGGCCCTGCACAACCATTACACCCAGAAGAGTC TCAGTCTGAGCCCGGGAAAGggtggctctcatcatcaccatcaccactga

[0337] pDP25-pFUSE-Tf-knob-Fc Amino Acid Sequence (SEQ ID NO: 30)

[0338] MYRMQLLSCIALSLALVTNSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGPS VACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVAV VKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCADG TDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLCL DNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGKD LLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKCD EWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCED TPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEGC APGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNPD PWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSNV TDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACTF RRPPWEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGSHHHHHH*

[0339] pDP32-CD19-FC-CD19 Nucleic Acid Sequence (SEQ ID NO: 31)

[0340] atgcgAatgcagctgctgctgctgattgcgctgagcctggcgctggtgaccaacagcactagtcccgaggaacctctagtg gtgaaggtggaagagggagataacgctgtgctgcagtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcggga gtccccgcttaaacccttcttaaaactcagcctggggctgccaggcctgggaatccacatgaggcccctggccatctggcttttcatcttcaa cgtctctcaacagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtgga gggcagcggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagct ccccttccgggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccac cgagggacagcctgaaccagagcctcagccaggacctcaccatggcccctggctccacactctggctgtcctgtggggtaccccctgactDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 ctgtgtccaggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccgg ccagagatatgtgggtaatggagacgggtctgttgttgccccgggccacagctcaagacgctggaaagtattattgtcaccgtggcaacctg accatgtcattccacctggagatcactgctcggccagtactatggcactggctgctgaggactggtggctggaagactagtTCTGGTG GTGGTGGTGAGAATCTGTACTTTCAGAGCTCGGGCGGAGGATCgggtggaggcgagcccaaatc ttgtgacaaaactcacacatgcCCCCCCTGCCCAGCGCCAGAATTGCTGGGCGGACCCAGCGTGT TCCTGTTCCCCCCCAAACCTAAAGACACCCTGATGATCAGCCGAACCCCTGAGGTGA CCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGGTGAAGTTCAACTGGTAT GTGGACGGCGTGGAGGTCCACAATGCCAAAACGAAGCCCAGGGAGGAGCAGTACA ACAGCACCTACAGGGTAGTGAGCGTCTTGACCGTGCTGCACCAGGACTGGCTGAAC GGCAAGGAATACAAATGCAAGGTCAGCAATAAGGCTCTGCCGGCTCCTATCGAGAA GACAATCAGCAAGGCAAAGGGCCAGCCACGCGAACCGCAGGTGTATACTCTGCCCC CCAGCCGGGACGAGCTGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAAGGC TTCTACCCCAGCGACATCGCTGTGGAGTGGGAGAGTAACGGGCAGCCCGAGAACAA CTACAAGACCACGCCTCCTGTGCTGGACAGCGACGGCAGCTTCTTCCTGTATAGCAA GCTCACCGTGGACAAGAGCAGGTGGCAACAGGGCAACGTGTTCAGCTGCTCTGTGA TGCACGAGGCCCTGCACAACCATTACACCCAGAAGAGTCTCAGTCTGAGCCCGGGA AAGGGTGGAGGCGGATCCggaggtagcggtggttctGGAcccgaggaacctctagtggtgaaggtggaagagggag ataacgctgtgctgcagtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgcttaaacccttctta aaactcagcctggggctgccaggcctgggaatccacatgaggcccctggccatctggcttttcatcttcaacgtctctcaacagatgggggg cttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagcggggagctgttcc ggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttccgggaagctcatga gccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgagggacagcctgaaccag agcctcagccaggacctcaccatggcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtccaggggccccctctc ctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagagatatgtgggtaatgga gacgggtctgttgttgccccgggccacagctcaagacgctggaaagtattattgtcaccgtggcaacctgaccatgtcattccacctggaga tcactgctcggccagtactatggcactggctgctgaggactggtggctggaagGGCCTGAACGACATCTTCGAGGCT CAGAAAATCGAATGGCACGAAGGCtaa

[0341] pDP32-CD19-FC-CD19 Amino Acid Sequence (SEQ ID NO: 32)

[0342] MRMQLLLLIALSLALVTNSTSPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQ LTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEK AWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVW AKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWT HVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMS FHLEITARPVLWHWLLRTGGWKTSSGGGGENLYFQSSGGGSGGGEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGSGGSGPEEPLVVKVEEGDNAVLQCL KGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYY CHRGNLTMSFHLEITARPVLWHWLLRTGGWKGLNDIFEAQKIEWHEG*

[0343] pDP44-CD19 NT.1-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 33)DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0344] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGcccgaggaacctctagtggtgaaggtggaagagggagataccgctgctctgtggtgcctcaaggggacctcagat ggccccactcagcagctgacctggtctcgggagtccccgcttaaacccttcttaaaatacagcctgggggtgccaggcctgggagtccac gtcaggcccgatgccatctctgtcgtcatcaggaacgtctctcaacagatggggggcttctacctgtgccagccggggcccccctctgaga aggcctggcagcctggctggacagtcaatgtggagggcagcggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtg gcctgaagaacaggtcctcagagggccccagctccccttccgggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccct gagatctgggagggagagcctccgtgtctcccaccgagggacagcctgaaccagagcctcagcagggacctcaccgtagcccctggct ccacactctggctgtcctgtggggtaccccctgactctgtgtccaggggccccctctcctggacccatgtgcaccccaaggggcctaagtc attgctgagcctagagctgaaggacgatcgcccggccagagatatgtgggtaatgggtacgtcactgatgttgccccgggccacagctca agacgctggaaagtggtattgtcaccgtggcaacgtaaccacctcattccacctggaggtaatcgctcggccagtaaaggctcactcagac ctgaggactggtggctggaagGTAGACGGCAGCGGCAGCGACAAAACTCACACATGCCCACCGT GCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTG AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA TAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGG GCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCA AGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCG TGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggt tctgtgcccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtg atccccagcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgc cgtgacactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaaga ggacccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtc acaccggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaa ggccgtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggc tgcagcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacag caccatcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgag tacaaggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctg aaccaggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaagga cagcgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctga gagagggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcg acgagtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcg aggccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaag agcgacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatct gaagggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccact gcagattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctg aacctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtg aaacaccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctg tgtctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaagg acaaagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctg ttcagaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacct gggcgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAADOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0345] pDP44-CD19 NT.1-FC-Tf Amino Acid Sequence (SEQ ID NO: 34)

[0346] MYRMQLLSCIALSLALVTNSPEEPLVVKVEEGDTAALWCLKGTSDGPTQQ LTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFYLCQPGPPSEK AWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVW AKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDSVSRGPLSWT HVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKWYCHRGNVTT SFHLEVIARPVKAHSDLRTGGWKVDGSGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGPSVACVKKASYLD CIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVAVVKKDSGFQMNQ LRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCADGTDFPQLCQLCP GCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLCLDNTRKPVDEYK DCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGKDLLFKDSAHGFL KVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKCDEWSVNSVGKIE CVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCEDTPEAGYFAIAV VKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEGCAPGSKKDSSLC KLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNPDPWAKNLNEKDY ELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSNVTDCSGNFCLFR SETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACTFRRP*

[0347] pDP49-CD19 NT.1-FC-GFLG-Tf Nucleic Acid Sequence (SEQ ID NO: 35)

[0348] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGcccgaggaacctctagtggtgaaggtggaagagggagataccgctgctctgtggtgcctcaaggggacctcagat ggccccactcagcagctgacctggtctcgggagtccccgcttaaacccttcttaaaatacagcctgggggtgccaggcctgggagtccac gtcaggcccgatgccatctctgtcgtcatcaggaacgtctctcaacagatggggggcttctacctgtgccagccggggcccccctctgaga aggcctggcagcctggctggacagtcaatgtggagggcagcggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtg gcctgaagaacaggtcctcagagggccccagctccccttccgggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccct gagatctgggagggagagcctccgtgtctcccaccgagggacagcctgaaccagagcctcagcagggacctcaccgtagcccctggct ccacactctggctgtcctgtggggtaccccctgactctgtgtccaggggccccctctcctggacccatgtgcaccccaaggggcctaagtc attgctgagcctagagctgaaggacgatcgcccggccagagatatgtgggtaatgggtacgtcactgatgttgccccgggccacagctca agacgctggaaagtggtattgtcaccgtggcaacgtaaccacctcattccacctggaggtaatcgctcggccagtaaaggctcactcagac ctgaggactggtggctggaagGTAGACGGCAGCGGCAGCGACAAAACTCACACATGCCCACCGT GCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTG AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCA TAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGG GCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCA AGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCG TGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAggatcctctggggggTTCCTGggaagcgg tggttctgtgcccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtc cgtgatccccagcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccg acgccgtgacactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagca aagaggacccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtc ctgtcacaccggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctgg aaaaggccgtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctg tggctgcagcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagca cagcaccatcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggac gagtacaaggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagct gctgaaccaggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttca aggacagcgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaac ctgagagagggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagt gcgacgagtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacg gcgaggccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaac aagagcgacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaa tctgaagggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaacc actgcagattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggc ctgaacctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggctttt gtgaaacaccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactg ctgtgtctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaa ggacaaagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcc tgttcagaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtac ctgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctacc ggtCACCACCATCATCACCACCATCACTAA

[0349] pDP49-CD19 NT.1-FC-GFLG-Tf Amino Acid Sequence (SEQ ID NO: 36)

[0350] MYRMQLLSCIALSLALVTNSPEEPLVVKVEEGDTAALWCLKGTSDGPTQQ LTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFYLCQPGPPSEK AWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVW AKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDSVSRGPLSWT HVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKWYCHRGNVTT SFHLEVIARPVKAHSDLRTGGWKVDGSGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGSSGGFLGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGPSVACVKKASYLD CIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVAVVKKDSGFQMNQ LRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCADGTDFPQLCQLCP GCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLCLDNTRKPVDEYK DCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGKDLLFKDSAHGFL KVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKCDEWSVNSVGKIE CVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCEDTPEAGYFAIAV VKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEGCAPGSKKDSSLC KLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNPDPWAKNLNEKDY ELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSNVTDCSGNFCLFRDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 SETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACTFRRPTGHHHHHH HH*

[0351] pDP50-His8-CD19 NT.1-GFLG-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 37)

[0352] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtgggTTCCTGggaggc GTAGACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGG GGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCG GACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCA AGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGG GAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCA GGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAG CCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG TACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTG CCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCT TCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC TCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCC CTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgcc gtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgt gaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatg cctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctactacgccgtggcc gtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctgg aacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgc gccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctaca gcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggcc gaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccat ctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacacttcggcaagga caagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccc cagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccgaggcccccacc gatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaag atcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctggacggcggct tcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatacccccgaggcc ggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgccacaccgccgt gggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcagcgagggctg cgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaacaaagaggg ctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgccccagaacaccggDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 cggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccggaagccagtgga ggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtccacaagatcctgc ggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaaggacctcctgttcc gggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaaggccgtgggcaa tctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0353] pDP50-His8-CD19 NT.1-GFLG-FC-Tf Amino Acid Sequence (SEQ ID NO: 38)

[0354] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGVDGDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPS DGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYY AVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAP CADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYE LLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSP HGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHER LKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSD NCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFF SEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGG KNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLF GSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLE ACTFRRP*

[0355] pDP85-cd20-scfv-GFLG-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 39)

[0356] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGCAGATTGTTCTGAGCCAGTCCCCGGCAATCCTCTCTGCCAGCCCAGGC GAAAAGGTGACAATGACTTGCCGAGCGAGTTCCAGTGTCTCTTATATCCACTGGTTC CAGCAAAAGCCGGGAAGCAGCCCTAAACCATGGATATATGCAACGTCTAACCTGGC GAGCGGGGTCCCAGTGAGATTTTCCGGAAGCGGCAGCGGAACTAGTTACTCTTTGAC AATAAGCAGAGTGGAGGCTGAGGACGCTGCTACTTACTATTGCCAGCAATGGACGA GTAACCCGCCGACGTTTGGAGGTGGAACGAAGCTGGAGATTAAAGGTGGAGGTGGT TCTGGCGGAGGTGGTTCCGGTGGTGGTGGAAGTCAGGTGCAGCTCCAACAGCCTGG TGCCGAACTTGTCAAACCTGGGGCTAGTGTGAAGATGAGTTGCAAAGCTTCAGGGT ACACGTTTACGTCATACAACATGCATTGGGTAAAGCAAACACCAGGACGCGGCTTG GAATGGATCGGCGCGATATATCCAGGAAACGGTGACACTTCTTATAACCAGAAGTT CAAGGGGAAAGCTACTCTCACAGCGGACAAATCTTCTTCAACAGCGTATATGCAGTT GTCAAGCCTTACTAGCGAGGACAGTGCTGTTTATTACTGCGCCCGGTCCACCTATTA TGGGGGTGATTGGTACTTTAATGTTTGGGGCGCGGGTACTACCGTTACTGTGTCCGC GGGTGGCAGCGGCAGCggtgggTTCCTGggaGGCGTAGACGGCGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 CAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTG GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGT GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTA CAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAT GAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAG CGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTG GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggg gaagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttc cgggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccat tgccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtgg ccgagttctacggcagcaaagaggacccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccag ctgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccga gccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtg tcagctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcga cgtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaaca ccagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaaga ggatctgatctgggagctgctgaaccaggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacg gcaaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacg tgaccgccatccggaacctgagagagggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagcca ccacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtat cgccaagatcatgaacggcgaggccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgct ggccgagaactacaacaagagcgacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagc gacctgacctgggacaatctgaagggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgct gtacaacaagatcaaccactgcagattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagct gtgcatgggcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggaga agggggacgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacg agaaggactacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcac gccgtggtcacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgact gcagcggcaacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccgga acacctacgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgc acctttcgcagacctTAA

[0357] pDP85-cd20-scfv-GFLG-FC-Tf Amino Acid Sequence (SEQ ID NO: 40)

[0358] MYRMQLLSCIALSLALVTNSQIVLSQSPAILSASPGEKVTMTCRASSSVSYIH WFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQ WTSNPPTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLQQPGAELVKPGASVKMSC KASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSS TAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSAGGSGSGGFLGG VDGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 HEATKCQSFRDHMKSVIPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNL KPVVAEFYGSKEDPQTFYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPE PRKPLEKAVANFFSGSCAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFV KHSTIFENLANKADRDQYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQ AQEHFGKDKSKEFQLFSSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPE APTDECKPVKWCALSHHERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVY IAGKCGLVPVLAENYNKSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWN IPMGLLYNKINHCRFDEFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLV EKGDVAFVKHQTVPQNTGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVT RKDKEACVHKILRQQQHLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGE EYVKAVGNLRKCSTSSLLEACTFRRP*

[0359] pDP95-Herceptin_HC_Fc-N297G,S427C Nucleic Acid Sequence (SEQ ID NO: 41)

[0360] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGgaggttcagctggtggagtctggcggtggcctggtgcagccagggggctcactccgtttgtcctgtgcagcttctgg cttcaacATCAAGGACACCTATATCcactgggtgcgtcaggccccgggtaagggcctggaatgggttgcaCGCATC TACCCGACGAATGGCTACACGCGCTatgccgatAGCgtcaagggccgtttcactataagcGCAGACACA TCCAAAAACACAGCCtacctacaaatgaacagcttaagagctgaggacactgccgtctattattgtTCACGCTGGGG GGGAGATGGGTTTTATGCAATGgactactggggtcaaggaaccctggtcaccgtctcctcggcctccaccaagggtc catcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaac cggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcag cagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtcgaca aAAAGGTCgagcccaaatcttgtgacaaaactcacacatgcCCCCCCTGCCCAGCGCCAGAATTGCTGG GCGGACCCAGCGTGTTCCTGTTCCCCCCCAAACCTAAAGACACCCTGATGATCAGCC GAACCCCTGAGGTGACCTGCGTGGTGGTGGACGTGAGCCACGAGGACCCCGAGGTG AAGTTCAACTGGTATGTGGACGGCGTGGAGGTCCACAATGCCAAAACGAAGCCCAG GGAGGAGCAGTACGGCAGCACCTACAGGGTAGTGAGCGTCTTGACCGTGCTGCACC AGGACTGGCTGAACGGCAAGGAATACAAATGCAAGGTCAGCAATAAGGCTCTGCCG GCTCCTATCGAGAAGACAATCAGCAAGGCAAAGGGCCAGCCACGCGAACCGCAGGT GTATACTCTGCCCCCCAGCCGGGACGAGCTGACCAAGAACCAGGTGTCCCTGACCT GTCTGGTGAAAGGCTTCTACCCCAGCGACATCGCTGTGGAGTGGGAGAGTAACGGG CAGCCCGAGAACAACTACAAGACCACGCCTCCTGTGCTGGACAGCGACGGCAGCTT CTTCCTGTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAACAGGGCAACGTGT TCTGCTGCTCTGTGATGCACGAGGCCCTGCACAACCATTACACCCAGAAGAGTCTCA GTCTGAGCCCGGGAAAGtaa

[0361] pDP95-Herceptin_HC_Fc-N297G,S427C Amino Acid Sequence (SEQ ID NO: 42)

[0362] MYRMQLLSCIALSLALVTNSEVQLVESGGGLVQPGGSLRLSCAASGFNIKD TYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSL RAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFCCSVMHEALHNHYTQKSLSLSPGK*DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0363] pDP69-His8-CD19 NT.1-2XGFLG-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 43)

[0364] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtggaTTtCTGggcggcg ggTTCCTGggaggcGTAGACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCT GAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTC ATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGA CCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA CAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAA AGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAG AAGAGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataag acagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacg gccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggat gccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagac cttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgg gcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaa cttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctga accagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgaga acctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgcc acctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccag gaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacgg ctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctg tcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgt gaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatg agcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcga ggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaa gctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagt tcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcc caacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgt gccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcac ccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctg cgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagaDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 caaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatat gtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0365] pDP69-His8-CD19 NT.1-2XGFLG-FC-Tf Amino Acid Sequence (SEQ ID NO: 44)

[0366] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGGFLGGVDGDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMK SVIPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDP QTFYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFS GSCAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKAD RDQYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQ LFSSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCAL SHHERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAEN YNKSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCR FDEFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVP QNTGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQ QQHLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCST SSLLEACTFRRP*

[0367] pDP70-His8-CD19 NT.1-3XGFLG-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 45)

[0368] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtggaTTCCTGggcggc gggTTtCTGggaggcggaTTtCTGggaggcGTAGACGGCGACAAAACTCACACATGCCCACCG TGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC AAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGC ATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAA GGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAG GGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtg gttctgtgcccgataagacagtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccg tgatccccagcgacggccctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgac gccgtgacactggatgccggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaa gaggacccccagaccttctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctg tcacaccggcctgggcagaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaa aggccgtggccaacttcttcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtgg ctgcagcaccctgaaccagtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcaca gcaccatcttcgagaacctggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacga gtacaaggactgccacctcgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgct gaaccaggcccaggaacacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaagg acagcgcccacggctttctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctg agagagggcacctgtcccgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgc gacgagtggagcgtgaacagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggc gaggccgatgccatgagcctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaa gagcgacaactgcgaggatacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatc tgaagggcaagaaaagctgccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccac tgcagattcgacgagttcttcagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcct gaacctgtgcgagcccaacaacaaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgt gaaacaccagaccgtgccccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgct gtgtctcgacggcacccggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaag gacaaagaggcctgcgtccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcct gttcagaagcgagacaaaggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacc tgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0369] pDP70-His8-CD19 NT.1-3XGFLG-FC-Tf Amino Acid Sequence (SEQ ID NO: 46)

[0370] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGGFLGGGFLGGVDGDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQS FRDHMKSVIPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFY GSKEDPQTFYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKA VANFFSGSCAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFEN LANKADRDQYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKD KSKEFQLFSSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKP VKWCALSHHERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 PVLAENYNKSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYN KINHCRFDEFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFV KHQTVPQNTGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACV HKILRQQQHLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGN LRKCSTSSLLEACTFRRP*

[0371] pDP71-His8-CD19 NT.1-GFLG-FK-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 47)

[0372] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtgggTTCCTGggaggc TTCAAAggcGTAGACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAA CTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTC CTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGC CCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC CACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACG GCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGG AACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG AGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagt gcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggcccta gcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggc ctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctac tacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaa gcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttca gcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagt acttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctgg ccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgc ccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacact tcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctga aggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccga ggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacag cgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctg gacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatac ccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgccDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 acaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcag cgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaa caaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgcccc agaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccgga agccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtcca caagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaagg acctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaag gccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0373] pDP71-His8-CD19 NT.1-GFLG-FK-FC-Tf Amino Acid Sequence (SEQ ID NO: 48)

[0374] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGFKGVDGDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSV IPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQT FYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGS CAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRD QYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLF SSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSH HERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYN KSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFD EFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQN TGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQ HLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSS LLEACTFRRP*

[0375] pDP72-His8-CD19 NT.1-GFLG-VA-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 49)

[0376] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtgggTTCCTGggaggc GTAgctggcGTAGACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGADOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 TCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCT GAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA GCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCC TGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACC ACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCC TGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGC AATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGA ACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGA GCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagtg cggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggccctag cgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggcc tggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctact acgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaag cgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttcag cggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagta cttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctggc caacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgcc caggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacactt cggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctga aggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccga ggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacag cgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctg gacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatac ccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgcc acaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcag cgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaa caaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgcccc agaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccgga agccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtcca caagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaagg acctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaag gccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0377] pDP72-His8-CD19 NT.1-GFLG-VA-FC-Tf Amino Acid Sequence (SEQ ID NO: 50)

[0378] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGVAGVDGDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 IPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQT FYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGS CAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRD QYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLF SSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSH HERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYN KSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFD EFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQN TGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQ HLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSS LLEACTFRRP*

[0379] pDP73-His8-CD19 NT.1-GFLG-VK-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 51)

[0380] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtgggTTCCTGggaggc GTAAAAggcGTAGACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAA CTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTC CTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGC CCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC CACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACG GCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGG AACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG AGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagt gcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggcccta gcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggc ctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctac tacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaa gcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttca gcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagt acttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctgg ccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgc ccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacact tcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctgaDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 aggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccga ggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacag cgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctg gacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatac ccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgcc acaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcag cgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaa caaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgcccc agaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccgga agccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtcca caagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaagg acctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaag gccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0381] pDP73-His8-CD19 NT.1-GFLG-VK-FC-Tf Amino Acid Sequence (SEQ ID NO: 52)

[0382] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGVKGVDGDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSV IPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQT FYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGS CAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRD QYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLF SSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSH HERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYN KSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFD EFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQN TGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQ HLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSS LLEACTFRRP*

[0383] pDP74-His8-CD19 NT.1-GFLG-VR-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 53)

[0384] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgagggaDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtgggTTCCTGggaggc GTACGGggcGTAGACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAA CTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATG ATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTC CTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGC CCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC CACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACG GCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGG AACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG AGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagt gcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggcccta gcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggc ctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctac tacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaa gcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttca gcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagt acttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctgg ccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgc ccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacact tcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctga aggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccga ggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacag cgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctg gacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatac ccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgcc acaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcag cgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaa caaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgcccc agaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccgga agccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtcca caagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaagg acctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaag gccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0385] pDP74-His8-CD19 NT.1-GFLG-VR-FC-Tf Amino Acid Sequence (SEQ ID NO: 54)

[0386] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDSDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGVRGVDGDKTHTCPPCPAPE LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC SVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSV IPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQT FYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGS CAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRD QYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLF SSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSH HERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYN KSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFD EFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQN TGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQ HLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSS LLEACTFRRP*

[0387] pDP75-His8-CD19 NT.1-GFLG-GGFG-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 55)

[0388] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtgggTTCCTGggaggc ggtgggTTCgggGTAGACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGA ACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACC CTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGT CCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG CCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAA CCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAA GAGCCTCTCCCTGTCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagaca gtgcggtggtgcgccgtgtctgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggcc ctagcgtggcctgtgtgaagaaggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 ggcctggtgtacgatgcctacctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagacctt ctactacgccgtggccgtggtcaagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggca gaagcgccggctggaacatccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttct tcagcggcagctgcgccccttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaacc agtacttcggctacagcggcgccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacc tggccaacaaggccgaccgggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacct cgcccaggtgccatctcacacagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaa cacttcggcaaggacaagagcaaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggcttt ctgaaggtgccccccagaatggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcc cgaggcccccaccgatgagtgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaa cagcgtgggcaagatcgagtgcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagc ctggacggcggcttcgtgtacattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgagga tacccccgaggccggctactttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagct gccacaccgccgtgggaaggaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttctt cagcgagggctgcgctcccggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaa caacaaagagggctactacggctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgc cccagaacaccggcggcaagaaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcaccc ggaagccagtggaggaatacgccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgt ccacaagatcctgcggcagcagcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaa aggacctcctgttccgggacgacaccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtg aaggccgtgggcaatctgcggaagtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0389] pDP75-His8-CD19 NT.1-GFLG-GGFG-FC-Tf Amino Acid Sequence (SEQ ID NO: 56)

[0390] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGGFLGGGGFGVDGDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKS VIPSDGPSVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQ TFYYAVAVVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSG SCAPCADGTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADR DQYELLCLDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQL FSSPHGKDLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALS HHERLKCDEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENY NKSDNCEDTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRF DEFFSEGCAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQ NTGGKNPDPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQ QHLFGSNVTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTS SLLEACTFRRP*DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025

[0391] pDP76-His8-CD19 NT.1-FK-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 57)

[0392] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggcTTCAAAggcGTAG ACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGA CCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACC CCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTT CAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGT CAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGG AGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT ACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGC TCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtctgag cacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaagaagg ccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctacctgg cccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctactacgccgtggccgtggtcaag aaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctggaacatcccca tcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgcgccccttgtgc tgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctacagcggcgccttc aagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccgggacc agtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccatctcacacagtg gtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacacttcggcaaggacaagagcaaag agttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccccagaatggacg ccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccgaggcccccaccgatgagtgcaa gcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagtgcgt gagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctggacggcggcttcgtgtacattg ccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatacccccgaggccggctactttgcc atcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgccacaccgccgtgggaaggaccg ccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcagcgagggctgcgctcccggcag caagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacggctac acaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaagaacc ccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacgccaa ctgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagcagcag cacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacgacaccDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 gtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtg cagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0393] pDP76-His8-CD19 NT.1-FK-FC-Tf Amino Acid Sequence (SEQ ID NO: 58)

[0394] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGFKGVDGDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGP SVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVA VVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCAD GTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLC LDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGK DLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKC DEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCE DTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEG CAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNP DPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSN VTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACT FRRP*

[0395] pDP77-His8-CD19 NT.1-VA-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 59)

[0396] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggcGTAgctggcGTAGA CGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG AGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCC ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC CCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 CAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGG AGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT ACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGC TCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtctgag cacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaagaagg ccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctacctgg cccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctactacgccgtggccgtggtcaag aaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctggaacatcccca tcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgcgccccttgtgc tgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctacagcggcgccttc aagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccgggacc agtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccatctcacacagtg gtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacacttcggcaaggacaagagcaaag agttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccccagaatggacg ccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccgaggcccccaccgatgagtgcaa gcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagtgcgt gagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctggacggcggcttcgtgtacattg ccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatacccccgaggccggctactttgcc atcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgccacaccgccgtgggaaggaccg ccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcagcgagggctgcgctcccggcag caagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacggctac acaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaagaacc ccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacgccaa ctgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagcagcag cacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacgacacc gtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcggaagtg cagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0397] pDP77-His8-CD19 NT.1-VA-FC-Tf Amino Acid Sequence (SEQ ID NO: 60)

[0398] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGVAGVDGDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGP SVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVA VVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCAD GTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLC LDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGK DLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKC DEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCEDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 DTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEG CAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNP DPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSN VTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACT FRRP*

[0399] pDP78-His8-CD19 NT.1-VK-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 61)

[0400] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggcGTAAAAggcGTA GACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGG ACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGAC CCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGT TCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAG GAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCC CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC ACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCT GGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC CGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC TCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCA TGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTG TCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtc tgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaaga aggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctac ctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctactacgccgtggccgtggt caagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctggaacat ccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgcgcccc ttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctacagcggc gccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccg ggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccatctcaca cagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacacttcggcaaggacaagag caaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccccagaat ggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccgaggcccccaccgatgag tgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagt gcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctggacggcggcttcgtgta cattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatacccccgaggccggctact ttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgccacaccgccgtgggaagDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 gaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcagcgagggctgcgctccc ggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacg gctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaag aaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacg ccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagca gcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacga caccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcgga agtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0401] pDP78-His8-CD19 NT.1-VK-FC-Tf Amino Acid Sequence (SEQ ID NO: 62)

[0402] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGVKGVDGDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGP SVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVA VVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCAD GTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLC LDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGK DLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKC DEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCE DTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEG CAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNP DPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSN VTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACT FRRP*

[0403] pDP79-His8-CD19 NT.1-VR-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 63)

[0404] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggcGTACGGggcGTA GACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGG ACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 CCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGT TCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAG GAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCC CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC ACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCT GGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC CGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC TCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCA TGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTG TCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtc tgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaaga aggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctac ctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctactacgccgtggccgtggt caagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctggaacat ccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgcgcccc ttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctacagcggc gccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccg ggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccatctcaca cagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacacttcggcaaggacaagag caaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccccagaat ggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccgaggcccccaccgatgag tgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagt gcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctggacggcggcttcgtgta cattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatacccccgaggccggctact ttgccatcgcagtcgtgaagaagtccgccagcgacctgacctgggacaatctgaagggcaagaaaagctgccacaccgccgtgggaag gaccgccgggtggaatattcctatggggctgctgtacaacaagatcaaccactgcagattcgacgagttcttcagcgagggctgcgctccc ggcagcaagaaagacagcagcctgtgcaagctgtgcatgggcagcggcctgaacctgtgcgagcccaacaacaaagagggctactacg gctacacaggggccttccggtgtctggtggagaagggggacgtggcttttgtgaaacaccagaccgtgccccagaacaccggcggcaag aaccccgacccctgggccaagaacctgaacgagaaggactacgaactgctgtgtctcgacggcacccggaagccagtggaggaatacg ccaactgtcacctggccagagcccccaatcacgccgtggtcacccggaaggacaaagaggcctgcgtccacaagatcctgcggcagca gcagcacctgttcggcagcaacgtgaccgactgcagcggcaacttctgcctgttcagaagcgagacaaaggacctcctgttccgggacga caccgtgtgtctggccaagctgcacgaccggaacacctacgagaagtacctgggcgaggaatatgtgaaggccgtgggcaatctgcgga agtgcagcacctctagcctgctggaagcctgcacctttcgcagacctTAA

[0405] pDP79-His8-CD19 NT.1-VR-FC-Tf Amino Acid Sequence (SEQ ID NO: 64)

[0406] MYRMQLLSCIALSLALVTNSGHHHHHHHHTGPEEPLVVKVEEGDTAALWCL KGTSDGPTQQLTWSRESPLKPFLKYSLGVPGLGVHVRPDAISVVIRNVSQQMGGFY LCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGK LMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSRDLTVAPGSTLWLSCGVPPDS VSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMGTSLMLPRATAQDAGKW YCHRGNVTTSFHLEVIARPVKAHSDLRTGGWKGVRGVDGDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGKGSSGGSGGSGGSVPDKTVRWCAVSEHEATKCQSFRDHMKSVIPSDGPDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 SVACVKKASYLDCIRAIAANEADAVTLDAGLVYDAYLAPNNLKPVVAEFYGSKEDPQTFYYAVA VVKKDSGFQMNQLRGKKSCHTGLGRSAGWNIPIGLLYCDLPEPRKPLEKAVANFFSGSCAPCAD GTDFPQLCQLCPGCGCSTLNQYFGYSGAFKCLKDGAGDVAFVKHSTIFENLANKADRDQYELLC LDNTRKPVDEYKDCHLAQVPSHTVVARSMGGKEDLIWELLNQAQEHFGKDKSKEFQLFSSPHGK DLLFKDSAHGFLKVPPRMDAKMYLGYEYVTAIRNLREGTCPEAPTDECKPVKWCALSHHERLKC DEWSVNSVGKIECVSAETTEDCIAKIMNGEADAMSLDGGFVYIAGKCGLVPVLAENYNKSDNCE DTPEAGYFAIAVVKKSASDLTWDNLKGKKSCHTAVGRTAGWNIPMGLLYNKINHCRFDEFFSEG CAPGSKKDSSLCKLCMGSGLNLCEPNNKEGYYGYTGAFRCLVEKGDVAFVKHQTVPQNTGGKNP DPWAKNLNEKDYELLCLDGTRKPVEEYANCHLARAPNHAVVTRKDKEACVHKILRQQQHLFGSN VTDCSGNFCLFRSETKDLLFRDDTVCLAKLHDRNTYEKYLGEEYVKAVGNLRKCSTSSLLEACT FRRP*

[0407] pDP80-His8-CD19 NT.1-GGFG-FC-Tf Nucleic Acid Sequence (SEQ ID NO: 65)

[0408] ATGTACAGGATGCAACTCCTGTCTTGCATTGCACTAAGTCTTGCACTTGTC ACGAATTCGGGCCACCACCATCATCACCACCATCACaccggtcccgaggaacctctagtggtgaaggtg gaagagggagataccgctgctctgtggtgcctcaaggggacctcagatggccccactcagcagctgacctggtctcgggagtccccgctt aaacccttcttaaaatacagcctgggggtgccaggcctgggagtccacgtcaggcccgatgccatctctgtcgtcatcaggaacgtctctca acagatggggggcttctacctgtgccagccggggcccccctctgagaaggcctggcagcctggctggacagtcaatgtggagggcagc ggggagctgttccggtggaatgtttcggacctaggtggcctgggctgtggcctgaagaacaggtcctcagagggccccagctccccttcc gggaagctcatgagccccaagctgtatgtgtgggccaaagaccgccctgagatctgggagggagagcctccgtgtctcccaccgaggga cagcctgaaccagagcctcagcagggacctcaccgtagcccctggctccacactctggctgtcctgtggggtaccccctgactctgtgtcc aggggccccctctcctggacccatgtgcaccccaaggggcctaagtcattgctgagcctagagctgaaggacgatcgcccggccagaga tatgtgggtaatgggtacgtcactgatgttgccccgggccacagctcaagacgctggaaagtggtattgtcaccgtggcaacgtaaccacct cattccacctggaggtaatcgctcggccagtaaaggctcactcagacctgaggactggtggctggaagggtgggTTCggaggcGTA GACGGCGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGG ACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGAC CCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGT TCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAG GAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGA CTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCC CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC ACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCT GGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC CGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC TCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCA TGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTG TCTCCGGGTAAAggatcctctgggggaagtggaggtagcggtggttctgtgcccgataagacagtgcggtggtgcgccgtgtc tgagcacgaggccaccaagtgccagagcttccgggaccacatgaagtccgtgatccccagcgacggccctagcgtggcctgtgtgaaga aggccagctacctggactgcatccgggccattgccgccaatgaggccgacgccgtgacactggatgccggcctggtgtacgatgcctac ctggcccccaacaacctgaagcccgtggtggccgagttctacggcagcaaagaggacccccagaccttctactacgccgtggccgtggt caagaaggacagcggcttccagatgaaccagctgcggggcaagaagtcctgtcacaccggcctgggcagaagcgccggctggaacat ccccatcggcctgctgtactgcgatctgcccgagccccggaagcctctggaaaaggccgtggccaacttcttcagcggcagctgcgcccc ttgtgctgacggaaccgacttcccccagctgtgtcagctgtgccccggctgtggctgcagcaccctgaaccagtacttcggctacagcggc gccttcaagtgcctgaaggacggcgctggcgacgtggccttcgtgaagcacagcaccatcttcgagaacctggccaacaaggccgaccg ggaccagtacgagctgctgtgcctggacaacaccagaaagcccgtggacgagtacaaggactgccacctcgcccaggtgccatctcaca cagtggtggcccggtccatgggcggcaaagaggatctgatctgggagctgctgaaccaggcccaggaacacttcggcaaggacaagag caaagagttccagctgttcagcagcccccacggcaaggatctgctgttcaaggacagcgcccacggctttctgaaggtgccccccagaatDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 ggacgccaagatgtacctgggctacgagtacgtgaccgccatccggaacctgagagagggcacctgtcccgaggcccccaccgatgag tgcaagcccgtgaagtggtgcgccctgagccaccacgagcggctgaagtgcgacgagtggagcgtgaacagcgtgggcaagatcgagt gcgtgagcgccgagacaaccgaggactgtatcgccaagatcatgaacggcgaggccgatgccatgagcctggacggcggcttcgtgta cattgccggcaagtgcggcctggtgcctgtgctggccgagaactacaacaagagcgacaactgcgaggatacccccgaggccggctac...

Claims

DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 CLAIMS What is claimed:

1. A fusion protein of Formula I: R1-R2-R3 (I): wherein: R1 is a protein of interest (POI) binder (POIB), or POI binding means for binding CCR6, CD19, CD20, a programmed death-ligand (PD-L1), an epidermal growth factor receptor (EGFR), CD8, CD3 or a T cell receptor (TCR); R2 is a linker of the formula R4-R5 or R5-R4, wherein: R4 is IgG Fc region; and R5 is an optional protease-sensitive linking means; and R3 is a transferrin receptor (TR) binding (TRB) means for binding a transferrin receptor, wherein the TR binding means is non-competitive with endogenous transferrin for binding to the TR, and optionally, comprising a glycine-rich linker between R2 and R3.

2. The fusion protein of claim 1, wherein the POIB or POI binding means is for binding CCR6, CD19, CD20, PD-L1 or EGFR.

3. The fusion protein of claim 1, wherein the TR binding means is VHHA-12 (SEQ ID NO: 154), VHHA (SEQ ID NO: 146), VHHA-5 (SEQ ID NO: 155), VHHA-7 (SEQ ID NO: 156) or VHHB (SEQ ID NO: 148).

4. The fusion protein of claim 1, wherein the protease-sensitive linking means comprises a cathepsin-cleavable peptide.

5. The fusion protein of claim 4, wherein the cathepsin-cleavable peptide linker is selected from the group consisting of FK, VA, VK, SEQ ID NO: 7, 8, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144 and 145.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 6. The fusion protein of claim 1, wherein the fusion protein of Formula I is a homodimer.

7. The fusion protein of claim 6, wherein the TR binding means within the homodimer has a binding affinity to TB (Kd) of about 0.001-50 nM.

8. The fusion protein of claim 1, wherein the fusion protein of Formula I is a heterodimer linked to a fusion protein of Formula II: R4’-R3’ (II): wherein: R4’ is IgG Fc region; and R3’ is a TR binding means; and optionally, wherein a linkage between R3’ and R4’ is a protease-sensitive linking means.

9. The fusion protein of claim 8, wherein the TR binding means within the heterodimer has a binding affinity to TB (Kd) of about 0.1-200 nM.

10. The fusion protein of claim 1, wherein the TR binding means comprises an antibody or polypeptide.

11. The fusion protein of claim 1, wherein the TR binding means is an antibody fragment having a heavy chain variable region.

12. The fusion protein of claim 1, wherein the TRB comprises: a. a VH CDR1 comprising the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 comprising the amino acid sequence of ITATGNT (SEQ ID NO: 176), and a VH CDR3 comprising the amino acid sequence of YMLDK (SEQ ID NO: 177). b. a VH CDR1 comprising the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 comprising the amino acid sequence of FTATGNT (SEQ IDDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 NO: 179), and a VH CDR3 comprising the amino acid sequence of AMLDK (SEQ ID NO: 180); or c. a VH CDR1 comprising the amino acid sequence of GTDFSINF (SEQ ID NO: 175), a VH CDR2 comprising the amino acid sequence of FTATGNT (SEQ ID NO: 179), and a VH CDR3 comprising the amino acid sequence of YMADK (SEQ ID NO: 183).

13. The fusion protein of claim 1, wherein the POIB or POI binding means comprises an antibody.

14. The fusion protein of claim 1, wherein the POIB or POI binding means binds to an extracellular domain of a transmembrane protein.

15. The fusion protein of claim 1, wherein the POIB or POI binding means binds to an extracellular domain of the CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or TCR.

16. The fusion protein of claim 1, wherein the POIB or POI binding means binds CCR6 and comprises: a. a VH CDR1 comprising the amino acid sequence of GFSFSDY (SEQ ID NO: 200), a VH CDR2 comprising the amino acid sequence of TTGGR (SEQ ID NO: 201), and a VH CDR3 comprising the amino acid sequence of PLRGAWFAY (SEQ ID NO: 202); or b. a VL CDR1 comprising the amino acid sequence of RSSQSIVHSNANTYLE (SEQ ID NO: 203), a VH CDR2 comprising the amino acid sequence of KVSNRF (SEQ ID NO: 204), and a VH CDR3 comprising the amino acid sequence of FQGTYLPLT (SEQ ID NO: 205).

17. The fusion protein of claim 1, wherein the POIB or POI binding means binds CD8 and comprises: a. a VH CDR1 comprising the amino acid sequence of GFTFDDY (SEQ ID NO: 206), a VH CDR2 comprising the amino acid sequence of RIFDRH (SEQ ID NO:DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 207), and a VH CDR3 comprising the amino acid sequence of GSFWACTRPEGAMDY (SEQ ID NO: 208); or b. a VH CDR1 comprising the amino acid sequence of GFSLISD (SEQ ID NO: 209), a VH CDR2 comprising the amino acid sequence of WADGS (SEQ ID NO: 210), and a VH CDR3 comprising the amino acid sequence of NRESYYFDY (SEQ ID NO: 211); or c. a VL CDR1 comprising the amino acid sequence of QASQNIDKYIA (SEQ ID NO: 212), a VL CDR2 comprising the amino acid sequence of YTSTLVS (SEQ ID NO: 213), and a VL CDR3 comprising the amino acid sequence of LQYDTLYT (SEQ ID NO: 214).

18. The fusion protein of claim 1, wherein the glycine-rich linker is selected from the group consisting of SEQ ID NO: 9, 10, 11, 12, 13, 14, 15 and 16.

19. A nucleic acid sequence encoding the fusion protein of claim 1.

20. A method for treating a subject that has an immune related disease, the method comprising administering the fusion protein of claim 1 to the subject.

21. The fusion protein of claim 1 for use in treating an immune related disease in a patient.

22. Use of the fusion protein of claim 1 for treating a subject having an immune related disease.

23. A homodimer of a fusion protein of Formula I: R1-R2-R3 (I): wherein: R1 is a protein of interest (POI) binder (POIB), or POI binding means for binding CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or a TCR; R2 is a linker of the formula R4-R5 or R5-R4, wherein: R4 is IgG Fc region; and R5 is an optional protease-sensitive linking means; andDOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 R3 is a TR binding means, wherein the TR binding means is non-competitive with endogenous transferrin for binding to the TR, and optionally, comprising a glycine-rich linker between R2 and R3 is a glycine-rich linker.

24. The homodimer of a fusion protein of claim 23, wherein the TR binding means is VHHA-12 (SEQ ID NO: 154), VHHA (SEQ ID NO: 146), VHHA-5 (SEQ ID NO: 155), VHHA-7 (SEQ ID NO: 156) or VHHB (SEQ ID NO: 148).

25. The homodimer of a fusion protein of claim 23, further comprising a disulfide bond between cysteine amino acids in R4 of separate fusion proteins.

26. A homodimer of a fusion protein of Formula III: R1-R6-R3 (III): wherein: R1 is a protein of interest (POI) binder (POIB), or POI binding means for binding CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or a TCR; R6 is a; and R3 is a TR binding means, wherein the TR binding means is non-competitive with endogenous transferrin for binding to the TR; wherein the homodimer optionally has a protease-sensitive linking means between R1 and R6.

27. The homodimer of a fusion protein of claim 26, wherein the TR binding means is VHHA-12 (SEQ ID NO: 154), VHHA (SEQ ID NO: 146), VHHA-5 (SEQ ID NO: 155), VHHA-7 (SEQ ID NO: 156) or VHHB (SEQ ID NO: 148).

28. A pharmaceutical composition, comprising the fusion protein or homodimer of a fusion protein of any one of claims 1, 6, 8, 23 or 26.

29. A heterodimer of fusion proteins of Formula IV and V: R1-R2 (IV);DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 R3-R2’ (V): wherein: R1 is a protein of interest (POI) binder (POIB), or POI binding means for binding CCR6, CD19, CD20, PD-L1, EGFR, CD8, CD3 or a TCR; R2 and R2’ are linkers of the formula R4 or optionally R4-R5, wherein: R4 is an IgG Fc region; R5 is an optional protease-sensitive linking means; and R3 is at least one TR binding means, wherein the TR binding means is non-competitive with endogenous transferrin for binding to the TR.

30. The heterodimer of fusion proteins of claim 29, wherein the TR binding means is VHHA-12 (SEQ ID NO: 154), VHHA (SEQ ID NO: 146), VHHA-5 (SEQ ID NO: 155), VHHA-7 (SEQ ID NO: 156) or VHHB (SEQ ID NO: 148).

31. The heterodimer of fusion proteins of claim 29, wherein the R4 of separate fusion proteins have complementary knob and hole structures.

32. A heterodimer of fusion proteins of Formula I and VI: R1-R2-R3 (I); R2’ (VI): wherein: R1 is a protein of interest (POI) binder (POIB), or POI binding means for binding TCR, CD3, CD8, EGFR, PD-L1, CD20 or CCR6; R2 is a linker of the formula R4-R5 or R5-R4, wherein: R4 is an IgG Fc region; R5 is an optional protease-sensitive linking means; R3 is at least one TR binding means, wherein the TR binding means is non-competitive with endogenous transferrin for binding to the TR; and R2’ is a linker of the formula R4 or optionally R4-R5.DOCKET NO: 5031461-000159-WO1 DATE OF FILING: March 17, 2025 33. The heterodimer of fusion proteins of claim 32, wherein the TR binding means is VHHA-12 (SEQ ID NO: 154), VHHA (SEQ ID NO: 146), VHHA-5 (SEQ ID NO: 155), VHHA-7 (SEQ ID NO: 156) or VHHB (SEQ ID NO: 148).

34. The heterodimer of fusion proteins of claim 32, wherein the R4 of separate fusion proteins have complementary knob and hole structures.

35. A fusion protein of Formula I: R1-R2-R3 (I): wherein: R1 is a protein of interest (POI) binder (POIB), or POI binding means for binding CD8; R2 is a linker of the formula R4-R5 or R5-R4, wherein: R4 is IgG Fc region; and R5 is an optional protease-sensitive linking means; and R3 is a transferrin receptor binding (TRB) means for binding a transferrin receptor (TR), wherein the TR binding means is non-competitive with endogenous transferrin for binding to the TR, and optionally, comprising a glycine-rich linker between R2 and R3 is a glycine-rich linker.

36. The fusion protein of claim 35, wherein the TR binding means is VHHA-12 (SEQ ID NO: 154), VHHA (SEQ ID NO: 146), VHHA-5 (SEQ ID NO: 155), VHHA-7 (SEQ ID NO: 156) or VHHB (SEQ ID NO: 148).

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