Anti-PIK3IP1 antibodies and methods of use thereof

Abstract

This application relates to antibodies or antigen-binding fragments thereof that bind to phosphoinositide-3 -kinase interacting protein 1 (PIK3IP1) protein or antigen-binding fragments, as well as polynucleotides and vectors that encode for such antibodies or antigen-binding fragments. This application further relates to methods of producing the antibodies or antigen- binding fragments and using the antibodies or antigen-binding fragments for treatment of diseases.

Description

Attorney Docket No: 243735.000427 ANTI-PIK3IP1 ANTIBODIES AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 652,557, filedMay 28, 2024, the contents of which is incorporated by reference herein in their entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submittedelectronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 5, 2025, is named 243735_000427_SL.xml and is 44,731 bytes in size. FIELD OF THE INVENTION

[0003] This application relates to antibodies or antigen-binding fragments thereof that bind tophosphoinositide-3-kinase interacting protein 1 (PIK3IP1), as well as polynucleotides, and vectors that encode for such antibodies or antigen-binding fragments. This application further relates to methods of producing the antibodies or antigen-binding fragments and using the antibodies or antigen-binding fragments for treatment of diseases. BACKGROUND

[0004] The advance in immune checkpoint blockade (ICB) immunotherapy has reshaped thecancer treatment landscape. Anti-programmed death-1 / programmed death-ligand 1 (anti-PD- 1 / PD-L1; collectively referred to hereinafter as PD) therapy has been an exceptional example, demonstrating durable clinical responses with mild adverse effects across many different tumor types, by targeting general immune-evasion mechanism in the tumor microenvironment (TME) to potently repair tumor-specific T cell immunity. The successes of anti-PD therapy are generally thought to arise from “inflamed” tumors with abundant tumor-specific T cell responses, which are needed to effectively mount tumor immunity, especially the cytotoxic cluster of differentiation (CD) 8 positive (CD8+) T cells, for eliminating tumor cells. However, a large subset of patients either do not respond to anti-PD therapy or develop acquired resistance. These clinical observations emphasize the need to identify therapeutic approaches beyond the PD pathway for addressing cold tumors. 1Attorney Docket No: 243735.000427

[0005] Other than PD, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) representsanother category of T cell checkpoint inhibitors, primarily expressed on regulatory T cells (Treg) and some effector T cells. Targeted antibodies that block its immune suppressive function or deplete Tregs have been approved for melanoma and other cancers, often in combination with anti- PD therapies. Moreover, lymphocyte activation gene-3 (LAG-3) is another T cell checkpoint molecule mainly expressed on PD-1+ T cells, so called exhausted T cells. Relatlimab (BMS- 986016), one antibody targeting LAG-3 that blocks its engagement with LAG-3 ligands (major histocompatibility complex class II (MHC-II) and fibrinogen-like protein 1 (FGL1)) and its immune inhibitory function, has been recently approved for use in melanoma in combination with the anti-PD-1 therapy nivolumab. Generally speaking, anti-CTLA-4 therapy has more immune- mediated side-effects and is less efficacious in cancers, and to date, anti-LAG-3 therapies have not demonstrated efficacy as single-agent treatments. Unfortunately, recent clinical trials using monoclonal antibodies (mAbs) targeting many other immune checkpoint molecules (either receptors or ligands) such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), cluster of differentiation 47 (CD47), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T cell activation (VISTA) (also known as programmed death-1 homolog (PD-1H)), have shown weak or little response in human cancer trials. These results collectively emphasize the need for identifying additional therapies targeting T cell checkpoints different from the existing strategies to overcome immunotherapy resistance. SUMMARY OF THE INVENTION

[0006] As specified in the Background section above, there is a need in the art to identify novelT cell checkpoints and therapies targeting such T cell checkpoints. The present application addresses these and other needs.

[0007] In one aspect, provided herein is an antibody, or antigen-binding fragment thereof, thatspecifically binds to phosphoinositide-3-kinase interacting protein 1 (PIK3IP1) comprising: (i) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, 9, or 17, or a variant thereof; and / or 2Attorney Docket No: 243735.000427 (ii) a light chain variable region (LCVR) comprising the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, 13, or 21, or a variant thereof.

[0008] In some embodiments, the antibody or antigen-binding described herein comprises:(a) an HCVR that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, or a variant thereof, and an LCVR that comprises the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, or a variant thereof; (b) an HCVR that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 9, or a variant thereof, and an LCVR that comprises the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 13, or a variant thereof; and / or (c) an HCVR that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 17, or a variant thereof, and an LCVR that comprises the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 21, or a variant thereof.

[0009] In some embodiments, the antibody or antigen-binding fragment described hereincomprises: (a) an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 2, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 3, and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 4, and an LCVR that comprises an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 8; (b) an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 10, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 11, and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 12, and a LCVR that comprises an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 14, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16; and / or 3Attorney Docket No: 243735.000427 (c) an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 18, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 19, and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 20, and an LCVR that comprises an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 22, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 23, and an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 24.

[0010] In some embodiments, the antibody or antigen-binding described herein comprises:(i) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, 9, or 17, or a variant thereof; and (ii) an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, 13, or 21, or a variant thereof.

[0011] In some embodiments, the antibody or antigen-binding described herein comprises:(a) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, or a variant thereof; (b) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 9, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 13, or a variant thereof; and / or (c) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 17, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 21, or a variant thereof.

[0012] In another aspect, provided herein is an antibody or antigen-binding fragment thereof thatcompetes for binding to PIK3IP1 with an antibody or antigen-binding fragment described herein.

[0013] In another aspect, provided herein is an antibody or antigen-binding fragment thereof thatbinds to the same epitope of PIK3IP1 as an antibody or antigen-binding fragment described herein.

[0014] In some embodiments, the antibody or antigen-binding fragment binds to human PIK3IP1and / or mouse PIK3IP1.

[0015] In some embodiments, the antibody or antigen-binding fragment is recombinant.

[0016] In some embodiments, the antibody or antigen-binding fragment is a human antibody, ahumanized antibody, a chimeric antibody, a murine antibody, a monoclonal antibody, a single chain antibody, a bispecific antibody or antigen-binding fragment thereof, a bi-epitopic antibody 4Attorney Docket No: 243735.000427 or antigen-binding fragment thereof, a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a VH domain, or a nanobody.

[0017] In some embodiments, the bispecific antibody or antigen-binding fragment thereof is abispecific T-cell engager (BiTE), a bispecific natural killer (NK)-cell engager (BiKE), or a bispecific macrophage engager (BiME). In some embodiments, the BiTE comprises an antigen- binding domain that specifically binds to cluster of differentiation (CD)3 (CD3), alpha beta T cell receptor (TCR), or gamma delta TCR. In some embodiments, the BiKE comprises an antigen- binding domain that specifically binds to Fc gamma receptor III (FcγRIII or CD16), natural killer group 2, member D (NKG2D), or natural cytotoxicity triggering receptor 3 (NCR3). In some embodiments, the BiME comprises an antigen-binding domain that specifically binds to Fc gamma receptor III (FcγRIII or CD16), dendritic cell-associated C-type lectin 1 (Dectin-1), cluster of differentiation (CD47), signal regulatory protein alpha (SIRPA), or Tyro3, Axl, and MerTK (TAM) receptor(s).

[0018] In some embodiments, the bispecific antibody or antigen-binding fragment thereofcomprises an antigen-binding domain that specifically binds to an immune checkpoint, a cytokine or a receptor thereof, a tumor-associated antigen (TAA), or an immune stimulatory receptor.

[0019] In some embodiments, the immune checkpoint is programmed cell death protein 1 (PD-1),programmed death-ligand 1 (PD-L1), lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), CD47, T cell immunoglobulin and mucin do-main-containing protein 3 (TIM-3), B7 homolog 3 protein (B7-H3 or CD276), B7-H4, V-domain Ig suppressor of T cell activation (VISTA or programmed death-1 homolog (PD-1H)), T cell immunoreceptor with Ig and ITIM Domains (TIGIT), signal regulatory protein alpha (SIRPA), signaling lymphocytic activation molecule family members (SLAMF), poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R), adenosine A2A receptor (A2aR), adenosine A2b receptor (A2bR), G protein-coupled receptor 171 (GPR171), insulin like growth factor binding protein 7 (IGFBP7), CD93, CD96, CD226, natural killer group protein 2A (NKG2A), natural killer group protein 2D (NKG2D), a killer cell lectin like receptor G1 (KLRG1), a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2), a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3), sialic acid-binding immunoglobulin-like lectin (Sigelac)-15, CD24, sialic acid-binding immunoglobulin-like lectin (Sigelac)-10, P-selectin 5Attorney Docket No: 243735.000427 glycoprotein ligand-1 (PSGL-1), V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing super-family member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)), leucine rich repeats and immunoglobulin like domains 1 (LRIG1), fibrinogen-like protein 1 (FGL1), B and T lymphocyte attenuator (BTLA), leukocyte associated immunoglobulin like receptor 1 (LAIR-1), CD160, leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), leukocyte immunoglobulin-like receptor (LILRB4), angiopoietin 2 (Ang2), or vascular endothelial growth factor (VEGF), or a combination thereof.

[0020] In some embodiments, the immune checkpoint is PD-1, PD-L1, LAG-3, or CTLA-4, or acombination thereof.

[0021] In some embodiments, the cytokine is interleukin (IL)-2 (IL-2), IL-6, IL-10, IL-15, IL-21,interferon alpha (IFN-α), interferon beta (IFN-β), interferon gamma (IFN-γ), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL-18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF), or a receptor thereof, or a combination thereof.

[0022] In some embodiments, the tumor-associated antigen (TAA) is oncofetal antigen 5T4(5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD123), CD19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms-like tyro-sine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein-coupled receptor class C group 5 member D (GPRC5D), human epidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal-epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor-associated calcium signal transducer 2 (TROP2 or TACSTD2), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (γδTCR), Kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibro-sarcoma (RAF), CD22, 6Attorney Docket No: 243735.000427 carcinoembryonic antigen-related cell adhesion molecule (CEA-CAM) 5 (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

[0023] In some embodiments, the immune stimulatory receptor is cluster of differentiation (CD)28 (CD28), inducible T-cell costimulatory (ICOS), CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2), natural cytotoxicity receptor (NCR) 3 (NCR3), NCR1, NCR2, tumor necrosis factor receptor superfamily member 9 (4-1BB), tumor necrosis factor receptor superfamily member 4 (OX40), CD30, CD40, death receptor (DR) 3 (DR3), CD226, class I restricted T cell-associated molecule (CRTAM), CD27, herpes virus entry mediator (HVEM), tumor necrosis factor receptor (TNFR) 1 (TNFR1), TNFR2, CD2, CD7, toll- like receptor (TLR) 4 (TLR4), TLR7, TLR9, or glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), or a combination thereof.

[0024] In some embodiments, the antibody or antigen-binding fragment is an IgG antibody.

[0025] In some embodiments, the antibody or antigen-binding fragment is of IgG1, IgG2, IgG3,or IgG4 subclass.

[0026] In some embodiments, the antibody or antigen-binding fragment is of IgG1 subclass.

[0027] In some embodiments, the antibody or antigen-binding fragment:(i) improves anti-cancer T cell response upon binding to PIK3IP1 expressed on a T cell; (ii) inhibits or antagonizes an immune suppressive function of PIK3IP1 on a T cell; and / or iii) stimulates the release of IFN-γ, MCP-1, TNF, IL-2, IL-6, and / or IL-10 from a T cell.

[0028] In some embodiments, the T cell is PD-1 and / or LAG-3 negative.

[0029] In some embodiments, the T cell is a memory T cell.

[0030] In another aspect, provided herein is an antibody-drug conjugate comprising an antibodyor antigen-binding fragment described herein, conjugated to a heterologous moiety.

[0031] In some embodiments, the heterologous moiety is an immune checkpoint inhibitor, acytokine, a tumor-associated antigen (TAA) targeting agent, an immune agonist, a cytotoxic agent, a siRNA, or an antisense oligonucleotide.

[0032] In some embodiments, the immune checkpoint inhibitor is a programmed cell death protein1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) 7Attorney Docket No: 243735.000427 inhibitor, a B7-H4 inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or programmed death-1 homolog (PD-1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD122R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-10 inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR-1) inhibitor, a CD160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, angiopoietin 2 (Ang2), or vascular endothelial growth factor (VEGF), or a combination thereof.

[0033] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1inhibitor, a LAG-3 inhibitor, or a CTLA-4 inhibitor, or a combination thereof.

[0034] In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is nivolumab,pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, 8Attorney Docket No: 243735.000427 sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

[0035] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor.

[0036] In some embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), ABL501, CB213,EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO- 7247669), TSR-033, tuparstobart (INCAGN02385), or BGA-1953, or a variant or a combination thereof.

[0037] In some embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), or a variantthereof.

[0038] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0039] In some embodiments, the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab,BNT316 / ONC-392 (gotistobart), or porustobart (HBM4003), or a variant or a combination thereof.

[0040] In some embodiments, the cytokine is interleukin (IL)-2 (IL-2), IL-6, IL-10, IL-15, IL-21,interferon alpha (IFN-α), interferon beta (IFN-β), interferon gam-ma (IFN-γ), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL-18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF), or a receptor or a combination thereof.

[0041] In some embodiments, the tumor-associated antigen (TAA)-targeting agent targetsoncofetal antigen 5T4 (5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD123), CD19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms-like tyro-sine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein-coupled receptor class C group 5 member D (GPRC5D), human epidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal-epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell 9Attorney Docket No: 243735.000427 antigen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor-associated calcium signal transducer 2 (TROP2 or TACSTD2), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (γδTCR), kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibro-sarcoma (RAF), CD22, carcinoembryonic antigen-related cell adhesion molecule (CEA-CAM) 5 (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

[0042] In some embodiments, the immune agonist is a cluster of differentiation (CD) 28 (CD28)agonist, an inducible T-cell costimulatory (ICOS) agonist, a CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2) agonist, a natural cytotoxicity receptor (NCR) 3 (NCR3) agonist, a NCR1 agonist, a NCR2 agonist, a tumor necrosis factor receptor superfamily member 9 (4-1BB) agonist, a tumor necrosis factor receptor superfamily member 4 (OX40) agonist, a CD30 agonist, a CD40 agonist, a death receptor (DR) 3 (DR3) agonist, a CD226 agonist, a class I restrict-ed T cell-associated molecule (CRTAM) agonist, a CD27 agonist, a herpes virus entry mediator (HVEM) agonist, a tumor necrosis factor receptor (TNFR) 1 (TNFR1) agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, a toll-like receptor (TLR) 4 (TLR4) agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist, or a combination thereof.

[0043] In another aspect, provided herein is a polynucleotide encoding an antibody or antigen-binding fragment described herein.

[0044] In another aspect, provided herein is a vector comprising a polynucleotide described herein.

[0045] In another aspect, provided herein is a host cell expressing an antibody or antigen-bindingfragment described herein, or comprising a polynucleotide of described herein or a vector described herein.

[0046] In some embodiments, the antibody or antigen-binding fragment is recombinantlyproduced.

[0047] In another aspect, provided herein is a method of producing the antibody or antigen-bindingfragment described herein, and the method comprises culturing a host cell described herein, and isolating the antibody or antigen-binding fragment.

[0048] In another aspect, provided herein is a pharmaceutical composition comprising an antibodyor antigen-binding fragment described herein, an antibody-drug conjugate described herein, a 10Attorney Docket No: 243735.000427 polynucleotide described herein, or a vector described herein, and a pharmaceutically acceptable carrier or diluent.

[0049] In some embodiments, the pharmaceutical composition can further comprise one or moreimmune checkpoint inhibitors, cytokines, tumor-associated antigen (TAA)-targeting agents, immune agonists, cytotoxic agents, siRNAs, or antisense oligonucleotides, or combination thereof.

[0050] In some embodiments, the immune checkpoint inhibitor is a programmed cell death protein1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or programmed death-1 homolog (PD-1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD122R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-10 inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR-1) inhibitor, a CD160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte 11Attorney Docket No: 243735.000427 immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, or a vascular endothelial growth factor (VEGF) inhibitor, or a combination thereof.

[0051] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1inhibitor, a LAG-3 inhibitor, and / or a CTLA-4 inhibitor, or a combination thereof.

[0052] In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is nivolumab,pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

[0053] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor.

[0054] In some embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), ABL501, CB213,EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO- 7247669), TSR-033, tuparstobart (INCAGN02385), or BGA-1953, or a variant or a combination thereof.

[0055] In some embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), or a variantthereof.

[0056] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0057] In some embodiments, the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab,BNT316 / ONC-392 (gotistobart), or porustobart (HBM4003), or a variant or a combination thereof.

[0058] In some embodiments, the cytokine is interleukin (IL) 2 (IL-2), IL-6, IL-10, IL-15, IL-21,interferon alpha (IFN-α), interferon beta (IFN-β), interferon gamma (IFN-γ), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL-18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF), or a receptor thereof, or a combination thereof. 12Attorney Docket No: 243735.000427

[0059] In some embodiments, the tumor-associated antigen (TAA)-targeting agent targetsoncofetal antigen 5T4 (5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD123), CD19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms-like tyro-sine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein-coupled receptor class C group 5 member D (GPRC5D), ), human epidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal-epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell anti-gen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor-associated calcium signal transducer 2 (TROP2 or TACSTD2), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (γδTCR), kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibrosarcoma (RAF), CD22, carcinoembryonic antigen-related cell adhesion molecule (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

[0060] In some embodiments, the immune agonist is a cluster of differentiation (CD28) agonist,an inducible T-cell costimulatory (ICOS) agonist, a CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2) agonist, a natural cytotoxicity receptor (NCR) 3 (NCR3) agonist, a NCR1 agonist, a NCR2 agonist, a tumor necrosis factor receptor superfamily member 9 (4-1BB agonist), , a tumor necrosis factor receptor superfamily member 4 (OX40) agonist, a CD30 agonist, a CD40 agonist, a death receptor (DR) 3 (DR3) agonist, a CD226 agonist, a class I restrict-ed T cell-associated molecule (CRTAM) agonist, a CD27 agonist, a herpes virus entry mediator (HVEM) agonist, a tumor necrosis factor receptor (TNFR) 1 (TNFR1) agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, a toll-like receptor (TLR) 4 (TLR4) agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist, or a combination thereof.

[0061] In another aspect, provided herein is a kit comprising (i) an antibody or antigen-bindingfragment described herein, an antibody-drug conjugate described herein, a polynucleotide 13Attorney Docket No: 243735.000427 described herein, or a vector described herein, and (ii) optionally, packaging for the same and / or instructions for use.

[0062] In another aspect, provided herein is a method for improving an anti-cancer T cell responsein a subject in need thereof, and the method comprises administering to the subject an effective amount of an agent that targets PIK3IP1 such that the anti-cancer T cell response of the T cells is improved.

[0063] In some embodiments, the T cell is PD-1 and / or LAG-3 negative, or is a memory T cell.

[0064] In some embodiments, the agent that targets PIK3IP1 comprises an antibody or antigen-binding fragment described herein, an antibody-drug conjugate described herein, a polynucleotide described herein, a vector described herein, or a pharmaceutical composition described herein.

[0065] A method of treating or preventing a cancer in a subject in need thereof, comprisingadministering to the subject an effective amount of an agent that targets PIK3IP1.

[0066] In some embodiments, the agent that targets PIK3IP1 protein is selected from a smallmolecule, a protein, a protein-drug conjugate, a nucleotide molecule, a gene editing system, an engineered cell system, and any combination thereof.

[0067] In some embodiments, the protein is selected from a peptide; an antibody or antigen-binding fragment thereof; a monobody; engineered, low-density-lipoprotein-receptor-derived, A domain (LDLR-A) (e.g., Avimers™); a designed ankyrin repeat protein (DARPin) lipocalin (e.g., anticalins); an affibody; engineered, Protein-A-derived, Z domain (Affibodies™) CTLD3 (e.g., Tetranectin); C-type lectin-like domain scaffolds; Sac7d-derived polypeptides (e.g., Nanoffitins® or affitins); engineered, tenascin-derived, tenascin type III domain (e.g., Centyrin™), thioredoxin (e.g., peptide aptamer); KALBITOR®; the β-sandwich (e.g., iMab); gamma-B crystallin-derived scaffold or engineered, ubiquitin-derived scaffold (e.g., Affilins); engineered, protease inhibitor- derived, Kunitz domain (e.g., EETI-II / AGRP, BPTI / LACI-D1 / ITI-D2); engineered antibody mimics; miniproteins; engineered, Fyn-derived, SH2 domain (e.g., Fynomers®); genetically manipulated counterparts of the foregoing that retains its binding functionality, and any combination thereof.

[0068] In some embodiments, the antibody or antigen-binding fragment thereof is selected froman intact antibody, an antigen-binding (Fab) fragment, an Fab’ fragment, an (Fab’)2 fragment, an Fd, an Fv, a dAb, a single domain fragment or single monomeric variable antibody domain, a single-chain Diabody (scDb), a single-chain variable fragment (scFv), a VH domain, a nanobody, 14Attorney Docket No: 243735.000427 a Bi-specific T-cell engager (BiTE), a bispecific killer cell engager (BiKE), a bi-specific macrophage engager (BiME), a CrossMab, a tri-specific binding partner, and any combination thereof.

[0069] In some embodiments, the nucleotide molecule is selected from an antisenseoligonucleotide, a micro RNA (miRNA), a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a single guide RNA (sgRNA), and any combination thereof.

[0070] In some embodiments, the gene editing system comprises a CRISPR-associated protein(Cas) nuclease, a zinc finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a meganuclease, any endo- or exo-nuclease, variants thereof, fragments thereof, or any combination thereof.

[0071] In some embodiments, the engineered cell system comprises a chimeric antigen receptor(CAR) modified cell comprising a fragment that targets PIK3IP1.

[0072] In some embodiments, CAR-modified cell is a CAR-modified T cell (CAR-T cell), a CAR-modified natural killer (NK) cell (CAR-NK cell), or a CAR-macrophage (CAR-M).

[0073] In some embodiments, the agent is conjugated to a detectable label, a chemotherapeuticagent, a radioisotope, an affinity tag, or a toxin.

[0074] In some embodiments, the agent that targets PIK3IP1 comprises an antibody or antigen-binding fragment described herein, an antibody-drug conjugate described herein, a polynucleotide described herein, a vector described herein, or a pharmaceutical composition described herein.

[0075] In some embodiments, the cancer is resistant to an immunotherapy comprising one or moreimmune checkpoint inhibitors.

[0076] In some embodiments, the immune checkpoint inhibitor is a programmed cell death protein1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or programmed death-1 homolog (PD-1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) 15Attorney Docket No: 243735.000427 inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-10 inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) inhibitor, a CD160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, or a vascular endothelial growth factor (VEGF) inhibitor, or a combination thereof.

[0077] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1inhibitor, or a combination thereof.

[0078] In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is nivolumab,pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, dan- vilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

[0079] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor.16Attorney Docket No: 243735.000427

[0080] In some embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), ABL501, CB213,EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO- 7247669), TSR-033, tuparstobart (INCAGN02385), or BGA-1953, or a variant or a combination thereof.

[0081] In some embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), or a variantthereof.

[0082] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0083] In some embodiments, the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab,BNT316 / ONC-392 (gotistobart), porustobart (HBM4003), or a variant or combination thereof.

[0084] In some embodiments, the method further comprises administering to the subject one ormore additional anti-cancer therapies.

[0085] In some embodiments, the one or more additional anti-cancer therapies comprise animmunotherapy, a chemotherapy, a targeted therapy, or a radiotherapy, or a combination thereof.

[0086] In some embodiments, the one or more additional anti-cancer therapies comprise animmunotherapy.

[0087] In another aspect, provided herein is a method of increasing effectiveness of animmunotherapy in a subject in need thereof, and the method comprises co-administering to the subject an immunotherapy with an effective amount of an agent that targets PIK3IP1.

[0088] In some embodiments, the agent that targets PIK3IP1 is selected from a small molecule, aprotein, a protein-drug conjugate, a nucleotide molecule, a gene editing system, an engineered cell system, and any combination thereof.

[0089] In some embodiments, the protein is selected from a peptide; an antibody or antigen-binding fragment thereof; a monobody; engineered, low-density-lipoprotein-receptor-derived, A domain (LDLR-A) (e.g., Avimers™); a designed ankyrin repeat protein (DARPin) lipocalin (e.g., anticalins); an affibody; engineered, Protein-A-derived, Z domain (Affibodies™) CTLD3 (e.g., Tetranectin); C-type lectin-like domain scaffolds; Sac7d-derived polypeptides (e.g., Nanoffitins® or affitins); engineered, tenascin-derived, tenascin type III domain (e.g., Centyrin™), thioredoxin (e.g., peptide aptamer); KALBITOR®; the β-sandwich (e.g., iMab); gamma-B crystallin-derived scaffold or engineered, ubiquitin-derived scaffold (e.g., Affilins); engineered, protease inhibitor- 17Attorney Docket No: 243735.000427 derived, Kunitz domain (e.g., EETI-II / AGRP, BPTI / LACI-D1 / ITI-D2); engineered antibody mimics; miniproteins; engineered, Fyn-derived, SH2 domain (e.g., Fynomers®); genetically manipulated counterparts of the foregoing that retains its binding functionality, and any combination thereof.

[0090] In some embodiments, the antibody or antigen-binding fragment thereof is selected froman intact antibody, an antigen-binding (Fab) fragment, an Fab’ fragment, an (Fab’)2 fragment, an Fd, an Fv, a dAb, a single domain fragment or single monomeric variable antibody domain, a single-chain Diabody (scDb), a single-chain variable fragment (scFv), a VH domain, a nanobody, a Bi-specific T-cell engager (BiTE), a bispecific killer cell engager (BiKE), a bi-specific macrophage nano-engager (BiME), a CrossMab, a tri-specific binding partner, and any combination thereof.

[0091] In some embodiments, the nucleotide molecule is selected from an antisenseoligonucleotide, a miRNA, an siRNA, an shRNA, an sgRNA, and any combination thereof.

[0092] In some embodiments, the gene editing system comprises a CRISPR-associated protein(Cas) nuclease, a zinc finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a meganuclease, any endo- or exo-nuclease, variants thereof, fragments thereof, or any combination thereof.

[0093] In some embodiments, the engineered cell system comprises a chimeric antigen receptor(CAR) modified cell comprising a fragment that targets PIK3IP1.

[0094] In some embodiments, the CAR-modified cell is a CAR-modified T cell (CAR-T cell), aCAR-modified natural killer (NK) cell (CAR-NK cell), or a CAR-macrophage (CAR-M).

[0095] In some embodiments, the agent is conjugated to a detectable label, a chemotherapeuticagent, a radioisotope, or a toxin.

[0096] In some embodiments, the agent that targets PIK3IP1 comprises an antibody or antigen-binding fragment described herein, an antibody-drug conjugate described herein, a polynucleotide described herein, a vector of described herein, or a pharmaceutical composition described herein.

[0097] In some embodiments, an immunotherapy described herein and an antibody or antigen-binding fragment described herein, an antibody-drug conjugate described herein, a polynucleotide described herein, a vector described herein, or a pharmaceutical composition described herein are administered sequentially. 18Attorney Docket No: 243735.000427

[0098] In some embodiments, an immunotherapy described herein and an antibody or antigen-binding fragment described herein, an antibody-drug conjugate described herein, a polynucleotide described herein, a vector described herein, or a pharmaceutical composition described herein are administered simultaneously in one composition or in separate compositions.

[0099] In some embodiments, the immunotherapy comprises one or more immune checkpointinhibitors, cytokines, tumor-associated antigen (TAA)-targeting agents, or immune agonists.

[0100] In some embodiments, the immune checkpoint inhibitor is a programmed cell deathprotein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a (B7-H4) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or programmed death-1 homolog (PD-1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor- related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat- associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin- like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-10 inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR-1) inhibitor, a CD160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte 19Attorney Docket No: 243735.000427 immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, or a vascular endothelial growth factor (VEGF) inhibitor, or a combination thereof.

[0101] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, and / or a CTLA-4 inhibitor.

[0102] In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is nivolumab,pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, dan- vilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

[0103] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor.

[0104] In some embodiments, the LAG-3 inhibitor is ABL501, CB213, EMB-02,favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), relatlimab (BMS-986016), Sym022, tebotelimab (MGD013), tobemstomig (RG- 6139 / RO-7247669), TSR-033, tuparstobart (INCAGN02385), or BGA-1953, or a variant or a combination thereof.

[0105] In some embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), or avariant thereof.

[0106] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0107] In some embodiments, the CTLA-4 inhibitor is ipilimumab, tremelimumab,quavonlimab, BNT316 / ONC-392 (gotistobart), or porustobart (HBM4003), or a variant or a combination thereof.

[0108] In some embodiments, the cytokine is interleukin (IL) 2 (IL-2), IL-6, IL-10, IL-15,IL-21, interferon alpha (IFN-α), interferon beta (IFN-β), interferon gamma (IFN-γ), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL-18, monocyte chemoattractant protein-1 20Attorney Docket No: 243735.000427 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM- CSF), or granulocyte colony stimulating factor (G-CSF) or a receptor or a combination thereof.

[0109] In some embodiments, the tumor-associated antigen (TAA) targeting agent targetsoncofetal antigen 5T4 (5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD123), CD19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms-like tyrosine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein-coupled receptor class C group 5 member D (GPRC5D), human epidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal-epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor-associated calcium signal transducer 2 (TROP2 or TACSTD2), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (γδTCR), kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibrosarcoma (RAF), CD22, carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5 (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

[0110] In some embodiments, the immune agonist is a cluster of differentiation (CD) 28(CD28) agonist, an inducible T-cell costimulatory (ICOS) agonist, a CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2) agonist, a natural cytotoxicity receptor (NCR) 3 (NCR3) agonist, a NCR1 agonist, a NCR2 agonist, a tumor necrosis factor receptor superfamily member 9 (4-1BB) agonist, a tumor necrosis factor receptor superfamily member 4 (OX40) agonist, a CD30 agonist, a CD40 agonist, a death receptor (DR) 3 (DR3) agonist, a CD226 agonist, a class I restricted T cell-associated molecule (CRTAM) agonist, a CD27 agonist, a herpes virus entry mediator (HVEM) agonist, a tumor necrosis factor receptor (TNFR) 1 (TNFR1) agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, a toll-like receptor (TLR) 4 (TLR4) agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a glucocorticoid- induced tumor necrosis factor receptor-related protein (GITR) agonist, or a combination thereof. 21Attorney Docket No: 243735.000427

[0111] In some embodiments, the subject has a solid cancer.

[0112] In some embodiments, the solid cancer is a lung cancer, a glioma, a thyroid cancer,a colorectal cancer, a head and neck cancer, a gastric cancer, a stomach cancer, a liver cancer, a pancreatic cancer, a renal cancer, a urothelial cancer, a prostate cancer, a testis cancer, a breast cancer, a cervical cancer, an endometrial cancer, an ovarian cancer, a gallbladder cancer, a sarcoma, or a melanoma.

[0113] In some embodiments, the solid cancer is a colorectal cancer or a melanoma.

[0114] In some embodiments, the subject has a hematologic cancer.

[0115] In some embodiments, the hematologic cancer is acute myeloid leukemia (AML),acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage, hairy cell leukemia, multiple myeloma, chronic myeloid neoplasm, non-Hodgkin lymphoma, Hodgkin lymphoma, chronic leukemia, dendritic / histiocytic neoplasm, or lymphoproliferative disorder.

[0116] In some embodiments, the hematologic cancer is acute myeloid leukemia (AML)or acute lymphoblastic leukemia (ALL).

[0117] In some embodiments, a method of the present disclosure further comprisesadministering to a subject one or more additional anti-cancer therapies.

[0118] In some embodiments, the one or more additional anti-cancer therapies comprise achemotherapy, a targeted therapy, a radiotherapy, or a combination thereof.

[0119] In some embodiments, the administering is via intertumoral, intravenous,intradermal, intraperitoneal, subcutaneous, intramuscular, inhalation, oral delivery, lipid nanoparticle (LNP)-based delivery, cellular delivery, viral and / or non-viral delivery, or gene editing, or as a cargo in a cell, or a combination thereof.

[0120] In some embodiments of any of the above-described methods, the subject is humanor veterinary animal. BRIEF DESCRIPTION OF THE DRAWINGS

[0121] Figure 1 depicts expression of PDCD1 (also referred to herein as PD-1), LAG-3, andPIK3IP1 in infiltrating T cells in tumors from melanoma patients by single-cell RNA sequencing (RNAseq) analysis. 22Attorney Docket No: 243735.000427

[0122] Figures 2A-2B depict binding of anti-PIK3IP1 antibodies HM16 (Figure 2A) and HM69(Figure 2B) to PIK3IP1 in CHO cells, with or without transient expression of human (h) or mouse (m) PIK3IP1, as analyzed by flow cytometry.

[0123] Figures 3A-3B depict anti-PIK3IP1 antibody promotion of T cell responses in vitro.Figure 3A shows an example of an in vitro study scheme. T cell activation was measured by levels of IL-2, IFN-γ, and MCP-1 (Figure 3B) after 48 hours of co-culture.

[0124] Figure 4 depicts anti-PIK3IP1 antibody promotion of T cell activation in vitro. T cellactivation was measured by levels of TNF, MCP-1, IL-6, and IL-10 after 24 hours and 48 hours of co-culture.

[0125] Figures 5A-5C depict anti-PIK3IP1 antibody promotion of T cell responses in vivo.Figure 5A shows an example of an in vivo study scheme. Figure 5B shows the percentage of OT- 1 (also referred to herein as OT1)+ / CD8+ T cells present in blood samples obtained from each mouse based on flow cytometry analysis. Figure 5C shows representative flow cytometry plots defined by CD8+ and OT1 tetramer.

[0126] Figures 6A-6D show anti-PIK3IP1 antibody as a monotherapy controls tumor growth ina MC38 colon cancer model. Figures 6A-6C show quantification of tumor volumes of MC38 tumors from mice transplanted with MC38 cells. Figure 6D shows Kaplan-Meier survival curves of mice transplanted with MC38 cells.

[0127] Figures 7A-7C show anti-PIK3IP1 antibody as a monotherapy controls tumor growth ina B16-F10 melanoma model. Figures 7A-7C show quantification of tumor volumes of B16-F10 tumors from mice transplanted with B16-F10 cells.

[0128] Figures 8A-8C show anti-PIK3IP1 antibody as a monotherapy controls tumor growth ina Yummer1.7 mouse melanoma model. Figures 8A-8C show quantification of tumor volumes of Yummer1.7 tumors from mice transplanted with Yummer1.7 cells. Figure 8D shows Kaplan- Meier survival curves of mice transplanted with Yummer1.7 cells.

[0129] Figures 9A-9D show anti-tumor efficacy of an anti-PIK3IP1 is dependent on adaptiveimmunity. Figures 9A-9C show quantification of the tumor volumes of MC38 tumors from Rag2- / -mice transplanted with MC38 cells. Figure 9D shows Kaplan-Meier survival curves of Rag2- / -mice transplanted with MC38 cells.

[0130] Figures 10A-10C demonstrate anti-PIK3IP1 antibody in combination with PD-1checkpoint blockade is highly effective in controlling tumor growth. Figures 10A-10B show 23Attorney Docket No: 243735.000427 quantification of tumor volumes of MC38 tumors from mice transplanted with MC38 cells. Figure 10C shows Kaplan-Meier survival curves of mice transplanted with MC38 cells.

[0131] Figures 11A-11E show anti-PIK3IP1 antibody therapy significantly promotesintratumoral T cell responses. Figure 11A shows tumor weights of MC38 tumors at day 17.Figures 11B-11D depict the quantification of CD4+ T cells (Figure 11B), CD8+ T cells (Figure11C), and NK1.1+ T cells (Figure 11D) per tumor cells in MC38 tumors from IgG2a isotype and anti-PIK3IP1 antibody treatment groups (n=5), as determined by flow cytometry. The quantification of granzyme B+ cells per CD8+ T cells in MC38 tumors from IgG2a isotype and anti-PIK3IP1 antibody treatment groups (n=5), as determined by flow cytometry analysis, is depicted in Figure 11E. Data are represented as mean ± SEM. ns, not significant; *, p< 0.05; **, p< 0.01. DETAILED DESCRIPTION

[0132] Phosphoinositide-3-kinase interacting protein 1 (PIK3IP1), also known astransmembrane inhibitor of PI3K (TrIP), is distinct from other immune checkpoint proteins that belong to the immunoglobulin (Ig) family. PIK3IP1 is characterized by an extracellular Kringle domain, distinguishing it from the IgG-like domains commonly present in immune checkpoint proteins. PIK3IP1 does not contain the typical immunoreceptor tyrosine-based inhibition motif (ITIM) or immunoreceptor tyrosine-based switch motif (ITSM), which are associated with the inhibitory functions of proteins, e.g., programmed death-1 (PD-1) receptor. The intracellular tail of PIK3IP1 includes a motif similar to the p110-binding inter-Src homology 2 (SH2) domain found in the p85 subunit of phosphoinositide 3-kinase (PI3K). This suggests that PIK3IP1 may play a role in modulating PI3K signaling pathways, potentially influencing cellular processes in a manner distinct from conventional immune checkpoint protein.

[0133] Human PIK3IP1 has been found to inhibit PI3K signaling by binding of p110 subunit viathe p85-like domain. Furthermore, the overexpression of PIK3IP1 in mouse hepatocytes has been shown to attenuate PI3K signaling and inhibit progression of hepatocellular carcinoma, indicating a potential role as a tumor suppressor. However, later studies suggested that PIK3IP1 can be specifically expressed on T cells and negatively control T cell responses (see, e.g., DeFrances et al., Eur J Immunol. 2012 Oct;42(10):2754-9; Chen et al., Clin Cancer Res. 2019 Oct 15;25(20):6180-6194; Xie et al., Sci Adv.2022 Sep 30;8(39):eabo4250; Uche et al., J Exp Med. 24Attorney Docket No: 243735.000427 2018 Dec 3;215(12):3165-3179). These data collectively suggest that PIK3IP1 may exert an inhibitory effect on T cells and could be implicated in the pathogenesis of human cancers and / or autoimmune diseases. To date, no functional antibodies targeting PIK3IP1 have been generated, nor has its therapeutic potential in immunotherapy of cancer or autoimmune diseases been investigated.

[0134] The present disclosure illustrates a role of PIK3IP1 as a T cell checkpoint receptor,predominately expressed on PD-1 or lymphocyte activation gene-3 (LAG-3) negative T cells. The phrase “PD-1 and / or LAG-3 negative” used in relation to T cells as described herein encompasses PD-1 negative, LAG-3 negative, and PD-1 and LAG-3 negative T cells. As described in further detail herein, antibodies targeting PIK3IP1 can functionally recover T cell function and show therapeutic potential in multiple mouse syngeneic tumor models, either as monotherapy or in combination with other immunotherapies. Definitions

[0135] The term “antibody” refers to an immunoglobulin molecule capable of specific bindingto a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region(s) of the immunoglobulin molecule. As used herein, the term “antibody”, e.g., anti- PIK3IP1 antibody, encompasses not only intact (e.g., full- length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (such as Fab, Fab', F(ab')2, Fv), single chain (scFv), mutants thereof, fusion proteins comprising an antibody portion, humanized antibodies, chimeric antibodies, diabodies, nanobodies, linear antibodies, single chain antibodies, multi-specific antibodies (e.g., bispecific antibodies) and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. An antibody, e.g., anti- PIK3IP1 antibody, includes an antibody of any class, such as IgD, IgE, IgG, IgA, or IgM (or sub- class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant domain of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit 25Attorney Docket No: 243735.000427 structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0136] A typical antibody molecule comprises a heavy chain variable region (HCVR or VH)and a light chain variable region (LCVR or VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into regions of hypervariability, also known as “complementarity determining regions” (“CDR”), interspersed with regions that are more conserved, which are known as “framework regions” (“FR”). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework region and CDRs can be precisely identified using methodology known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, the EU definition, the “Contact” numbering scheme, the “IMGT” numbering scheme, the “Aho” numbering scheme, and / or the contact definition, all of which are well known in the art. (See, e.g., Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242, Chothia et al., (1989) Nature 342:877; Chothia, C. et al. (1987) J. Mol. Biol.196:901-917, Al-lazikani et al (1997) J. Molec. Biol.273:927-948; Edelman et al., Proc Natl Acad Sci U S A.1969 May;63(1):78-85; and Almagro, J. Mol. Recognit.17:132-143 (2004); MacCallum et al., J. Mol. Biol.262:732-745 (1996), Lefranc M P et al., Dev Comp Immunol, 2003 January; 27(1):55-77; and Honegger A and Pluckthun A, J Mol Biol, 2001 Jun.8; 309(3):657-70. See also hgmp.mrc.ac.uk and bioinf.org.uk / abs).

[0137] In some embodiments, the anti-PIK3IP1 antibody described herein is a full-lengthantibody, which contains two heavy chains and two light chains, each including a variable domain and a constant domain. Alternatively, the anti-PIK3IP1 antibody can be an antigen-binding fragment of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding fragment” of a full length antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab’)2 fragment, a bivalent fragment including two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544- 546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) that retains functionality. Furthermore, although the two domains of the Fv fragment, VL 26Attorney Docket No: 243735.000427 and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules known as single chain Fv (scFv). See e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0138] Any of the antibodies described herein, e.g., anti-PIK3IP1 antibody, can be eithermonoclonal or polyclonal. A “monoclonal antibody” refers to a homogenous antibody population and a “polyclonal antibody” refers to a heterogeneous antibody population. These two terms do not limit the source of an antibody or the manner in which it is made.

[0139] As used herein “specifically binds”, “specific binding”, “specifically recognizes” or“specifically recognition” refers to the ability of the antibodies or antigen-binding fragments of the disclosure to bind to a predetermined antigen (e.g., PIK3IP1 protein) with a dissociation constant (KD) of, for example, about 1×10−6M or less, for example about 1×10−7M or less, about 1×10−8M or less, about 1×10−9M or less, about 1×10−10M or less, about 1×10−11M or less, about 1×10−12M or less, or about 1×10−13M or less. In some embodiments, the KDmay be, for example, about 1×10-8or less. As another example, a KD described herein may be about 2×10−7M or less, about 2×10−8M or less, about 2×10−9M or less, about 2×10−10M or less, about 2×10−11M or less, about 2×10−12M or less, or about 2×10−13M or less. In some embodiments, the KDmay be, for example, about 2×10-9or less. In some embodiments, the antibody or antigen-binding fragment binds to an antigen (e.g., PIK3IP1 protein) with a KD that can be at least ten-fold less than its KD for a nonspecific antigen (for example bovine serum albumin (BSA) or casein) as measured by, e.g., surface plasmon resonance using, for example, a Proteon Instrument (BioRad).

[0140] “Isolated” means a biological component (such as a nucleic acid, peptide or protein) hasbeen substantially separated, produced apart from, or purified away from other biological components of the organism in which the component naturally occurs, i.e., other chromosomal and extrachromosomal DNA and RNA, and proteins. Nucleic acids, peptides, and proteins that have been “isolated” thus include nucleic acids and proteins purified by standard purification methods. “Isolated” nucleic acids, peptides, and proteins can be part of a composition and still be isolated if such composition is not part of the native environment of the nucleic acid, peptide, or protein. The term also embraces nucleic acids, peptides, and proteins prepared by recombinant expression in a host cell, as well as chemically synthesized nucleic acids in the polynucleotides that encode for an antibody or antigen-binding fragment described herein. An “isolated” antibody or antigen-binding 27Attorney Docket No: 243735.000427 fragment, as used herein, is intended to refer to an antibody or antigen-binding fragment which is substantially free of other antibodies or antigen-binding fragments having different antigenic specificities; for instance, an antibody that specifically binds to an intended antigen (e.g., PIK3IP1 protein) can be substantially free of other antibodies that specifically bind antigens other than the intended antigen (e.g., PIK3IP1 protein).

[0141] The term “polynucleotide” as referred to herein means a polymeric form of nucleotidesof at least 10 bases in length, either ribonucleotides or deoxyribonucleotides, or a modified form of either type of nucleotide. The term includes single and double stranded forms.

[0142] The term “isolated polynucleotide” as used herein means a polynucleotide of genomic,cDNA, or synthetic origin or some combination thereof, which by virtue of its origin or source of derivation, the “isolated polynucleotide” has one to three of the following: (1) is not associated with all, or a portion of, a polynucleotide with which the “isolated polynucleotide” is found in nature, (2) is operably linked to a polynucleotide to which it is not linked in nature, or (3) does not occur in nature as part of a larger sequence. “Operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest.

[0143] The term “expression control sequence” as used herein means polynucleotide sequencesthat are necessary to effect the expression and / or processing of coding sequences to which they are ligated. Expression control sequences include, without limitation, appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (e.g., Kozak consensus sequences); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences, generally, can include promoter, ribosomal binding site, and transcription termination sequences; in eukaryotes, generally, such control sequences can include promoters and transcription termination sequence.

[0144] The term “control sequences” is intended to include, at a minimum, all componentswhose presence is essential for expression and / or processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences. 28Attorney Docket No: 243735.000427

[0145] The term “vector”, as used herein, means a vehicle capable of transporting a nucleic acidinto a host cell. In some embodiments, the vector is a plasmid, e.g., a circular double stranded DNA loop into which additional DNA segments may be ligated. In some embodiments, the vector is a viral vector, and additional DNA segments may be ligated into the viral genome. In some embodiments, the vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). In other embodiments, the vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”).

[0146] The term “promoter” as used herein is defined as a DNA sequence recognized by thesynthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence. As used herein, the term “regulatory sequence” means a nucleic acid sequence which can regulate expression of a gene product operably linked to the regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter or regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner.

[0147] The term “recombinant host cell” (or simply “host cell”) as used herein means a cell intowhich an exogenous nucleic acid and / or recombinant vector has been introduced. It should be understood that “recombinant host cell” and “host cell” mean not only the particular subject cell but also the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein.

[0148] The term “percent sequence identity” means a ratio, expressed as a percent of the numberof identical residues over the total number of residues compared. Sequence identity for nucleic acid sequences may be analyzed over a stretch of at least about nine nucleotides, usually at least about 18 nucleotides, more usually at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at least about 32 nucleotides, and preferably at least about 36, 48, or 29Attorney Docket No: 243735.000427 more nucleotides. There are a number of different algorithms known in the art which can be used to measure nucleotide sequence identity. For instance, polynucleotide sequences can be compared using FASTA, Gap or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wis. FASTA, which includes, e.g., the programs FASTA2 and FASTA3, provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson, Methods Enzymol.183:63-98 (1990); Pearson, Methods Mol. Biol. 132:185-219 (2000); Pearson, Methods Enzymol. 266:227-258 (1996); Pearson, J. Mol. Biol. 276:71-84 (1998); herein incorporated by reference). Unless otherwise specified, default parameters for a particular program or algorithm are used. For instance, percent sequence identity between nucleic acid sequences can be determined using FASTA with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) or using Gap with its default parameters as provided in GCG Version 6.1, herein incorporated by reference. A reference to a nucleotide sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. Sequence identity for polypeptides, is typically measured using sequence analysis software. Protein analysis software matches sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG contains programs such as “Gap” and “Bestfit” which can be used with default parameters, as specified with the programs, to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild-type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, see GCG Version 6.1. (University of Wisconsin Wis.) FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson, Methods Enzymol.183:63-98 (1990); Pearson, Methods Mol. Biol.132:185-219 (2000)). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially blastp or tblastn, using default parameters, as supplied with the programs. See, e.g., Altschul et al., J. Mol. Biol.215:403-410 (1990); Altschul et al., Nucleic Acids Res.25:3389-402 (1997). 30Attorney Docket No: 243735.000427

[0149] The length of polypeptide sequences compared for homology will generally be at leastabout 16 amino acid residues, usually at least about 20 residues, more usually at least about 24 residues, typically at least about 28 residues, and preferably more than about 35 residues. When searching a database containing sequences from a large number of different organisms, it is preferable to compare amino acid sequences.

[0150] The term “substantial similarity” or “substantial sequence similarity”, when referring toa nucleic acid or fragment thereof, means that when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 85%, preferably at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed above. As applied to polypeptides, the term “substantial identity” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, as supplied with the programs, share at least 70%, 75%, 80% or 85% sequence identity, preferably at least 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98% or 99% sequence identity. In certain embodiments, residue positions that are not identical differ by conservative amino acid substitutions.

[0151] A “conservative amino acid substitution” is one in which an amino acid residue issubstituted by another amino acid residue having a side chain R group with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson, Methods Mol. Biol. 243:307-31 (1994). Examples of groups of amino acids that have side chains with similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine. Conservative amino acids substitution groups include: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine- arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a 31Attorney Docket No: 243735.000427 conservative substitution or replacement, as the terms are used interchangeably herein, is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science 256:1443-45 (1992), herein incorporated by reference. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0152] The terms “treat” or “treatment” of a state, disease, disorder, or condition, or the like,include: (1) preventing, delaying, or reducing the incidence and / or likelihood of the appearance of at least one clinical or sub-clinical symptom of the state, disease, disorder, or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, or condition; or (2) inhibiting the state, disease, disorder, or condition, e.g., by arresting, reducing, or delaying the development of the state, disease, disorder, or condition. or a relapse thereof (in case of maintenance treatment), or at least one clinical or sub-clinical symptom thereof; or (3) relieving the state, disease, disorder, or condition, e.g., by causing regression of the state, disease, disorder, or condition, or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0153] As used herein, the term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Within the context of the present invention, the term “therapeutically effective” refers to that quantity of a compound or pharmaceutical composition that is sufficient to reduce or eliminate at least one symptom of a cancer, inflammation, autoimmune, or related disorder. Note that when a combination of active ingredients is administered the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually.

[0154] As used herein, the phrase “pharmaceutically acceptable” refers to molecular entities andcompositions that are generally regarded as physiologically tolerable.

[0155] As used herein, the term “combination” of a compound or a composition, and at least asecond pharmaceutically active ingredient means at least two, but any desired combination of compound or composition, can be delivered simultaneously or sequentially.

[0156] The terms “patient”, “individual”, “subject”, and “animal” are used interchangeablyherein and refer to mammals, including, without limitation, human and veterinary animals (e.g., 32Attorney Docket No: 243735.000427 cats, dogs, cows, horses, goats, sheep, pigs, etc.) and experimental animal models (e.g., rodents such as mice and rats, rabbits, and non-human primates). In a preferred embodiment, the subject is a human.

[0157] As used herein, the term “healthy subject” refers to a subject that is without knowninfections or autoimmune disorders or cancer by using conventional diagnostic methods. In certain embodiments, a healthy subject is a subject without a known first degree relative with an autoimmune disorder. In certain embodiments, a healthy subject is a subject without a known first degree relative with a cancer. In certain embodiments, a matched healthy subject is matched by age, sex, and / or ethnicity.

[0158] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which thecompound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Alternatively, the carrier can be a solid dosage form carrier including, but not limited to, one or more of a binder (for compressed pills), a glidant, an encapsulating agent, a flavorant, and a colorant. Suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin.

[0159] The term “about” or “approximately” means within a statistically meaningful range of avalue. Such a range can be within an order of magnitude, preferably within 50%, more preferably within 20%, still more preferably within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the term “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

[0160] The terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denotethe presence of “at least one” of the referenced item.

[0161] The practice of the present invention employs, unless otherwise indicated, conventionaltechniques of statistical analysis, molecular biology (including recombinant techniques), microbiology, cell biology, and biochemistry, which are within the skill of the art. Such tools and techniques are described in detail in e.g., Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual.3rded. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York; Ausubel et 33Attorney Docket No: 243735.000427 al. eds. (2005) Current Protocols in Molecular Biology. John Wiley and Sons, Inc.: Hoboken, NJ; Bonifacino et al. eds. (2005) Current Protocols in Cell Biology. John Wiley and Sons, Inc.: Hoboken, NJ; Coligan et al. eds. (2005) Current Protocols in Immunology, John Wiley and Sons, Inc.: Hoboken, NJ; Coico et al. eds. (2005) Current Protocols in Microbiology, John Wiley and Sons, Inc.: Hoboken, NJ; Coligan et al. eds. (2005) Current Protocols in Protein Science, John Wiley and Sons, Inc.: Hoboken, NJ; and Enna et al. eds. (2005) Current Protocols in Pharmacology, John Wiley and Sons, Inc.: Hoboken, NJ. Additional techniques are explained, e.g., in U.S. Patent No.7,912,698 and U.S. Patent Appl. Pub. Nos.2011 / 0202322 and 2011 / 0307437. Antibodies and Antigen-binding Fragments

[0162] The present disclosure provides antibodies, or antigen-binding fragments thereof, thatspecifically bind to phosphoinositide-3-kinase interacting protein 1 (PIK3IP1) protein. In some embodiments, antibodies or antigen-binding fragments thereof may bind to a human PIK3IP1 protein which has the amino acid sequence. MLLAWVQAFLVSNMLLAEAYGSGGCFWDNGHLYREDQTSPAPGLRCLNWLDAQSGL ASAPVSGAGNHSYCRNPDEDPRGPWCYVSGEAGVPEKRPCEDLRCPETTSQALPAFTTE IQEASEGPGADEVQVFAPANALPARSEAAAVQPVIGISQRVRMNSKEKKDLGTLGYVLG ITMMVIIIAIGAGIILGYSYKRGKDLKEQHDQKVCEREMQRITLPLSAFTNPTCEIVDEKT VVVHTSQTPVDPQEGTTPLMGQAGTPGA (SEQ ID NO: 25) (UniProt KB Accession No. [Q96FE7-1]).

[0163] In some embodiments, antibodies, or antigen-binding fragments thereof may bind to amouse PIK3IP1 protein which has the amino acid sequence MLLAWVHTFLLSNMLLAEAYGSGGCFWDNGHLYREDQPSPAPGLRCLNWLAAQGSRE SLTEPSPGNHNYCRNPDQDPRGPWCYISSETGVPEKRPCEDVSCPETTSQAPPPSSAMEL EEKSGAPGDKEAQVFPPANALPARSEAAEVQPVIGISQLVRMNSKEKKDLGTLGYVLGI TMMVIILAIGAGIIVGYTYKRGKDLKEQHEKKACEREMQRITLPLSAFTNPTCETVDENTI IVHSNQTPADVQEGSTLLTGQAGTPGA (SEQ ID NO: 26) (UniProt KB Accession No. [Q7TMJ8-1]).

[0164] The CDR and variable region amino acid sequence identifiers of exemplary anti-PIK3IP1 antibodies of the present disclosure are shown in Table 1. 34Attorney Docket No: 243735.000427 Table 1. Amino Acid Sequence Identifiers for CDRs and Variable Regions of Exemplary Anti- PIK3IP1 Antibodies Antibody HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 clone (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ (SEQ (SEQ (SEQ O.)Rsand LCVRs of the present disclosure are presented in bold text below.

[0166] Antibody clone HM16HCVR: MERHWIFLFLLSVTAGVHSQVQLQQSGAELAKPGASVKMSCKASGYTFTRYWMHWVKQRPGQGL EWIGYINPSSDYTEYSQKFKDKATLTADKSSSTAYMQLSSLTSEDSAIFYCAIQRRKPYWGQGTLVTVSA (SEQ ID NO.: 1)HCDR1: RYWMH (SEQ ID NO.: 2)HCDR2: YINPSSDYTEYSQKFKD (SEQ ID NO.: 3)HCDR3: QRRKPY (SEQ ID NO.: 4)LCVR: MDFHVQIFSFMLISVTVILSSGEIVLTQSPAFMAASPGEKVTITCSVSSSISSSNLHWYQQKSE TSPKPWIYGTSNLASGVPVRFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSYPLTFGAGTKLELK (SEQ ID NO: 5)LCDR1: SVSSSISSSNLH (SEQ ID NO.:6)LCDR2: GTSNLAS (SEQ ID NO.: 7)LCDR3: QQWSSYPLT (SEQ ID NO.: 8)

[0167] Antibody clone HM65HCVR: MEWIWIFLFILSGTAGVQSQVQLQQSGDELARPGASVKLSCKASGYTFTSYGVNWVKQRTGQGL EWIGEIYPGSGNTYHNEKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYFCARRRYYGRSKVMDYWGQGTSVTVSS (SEQ ID NO.: 9)HCDR1: SYGVN (SEQ ID NO.: 10) HCDR2: EIYPGSGNTYHNEKFKG (SEQ ID NO.: 11) 35Attorney Docket No: 243735.000427 HCDR3:RRYYGRSKVMDY (SEQ ID NO.: 12) LCVR: MRPSIQFLGLLLFWLHGAQCDIQMTQSPSSLSASLGGKVTITCKTSQDINKYIAWYQHKPGKGP RLLIHYTSTLQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYYCLQYDNLYTFGGGTKLEIK (SEQ ID NO.: 13) LCDR1: KTSQDINKYIA (SEQ ID NO.: 14) LCDR2: YTSTLQP (SEQ ID NO.: 15) LCDR3: LQYDNLYT (SEQ ID NO.: 16)

[0168] Antibody clone HM69HCVR: MGWSCIILFLVAAATGVHSQVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGL EWIGNIDPSDSETHYNQKFKDKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARWAYGSSYAYAM DYWGQGTSVTVSS (SEQ ID NO.: 17) HCDR1:SYWMH (SEQ ID NO.: 18) HCDR2:NIDPSDSETHYNQKFKD (SEQ ID NO.: 19) HCDR3:WAYGSSYAYAMDY (SEQ ID NO.: 20) LCVR: MDFQVQIFSFLLISASVIMSRGQIVLTQSPAIMSASLGERVTMTCTASSSVSSSYLHWYQQKPG SSPKLWIYSTSNLASGVPARFGGSGSGTSYSLTISSMEAEDAATYYCHQYHRSPFTFGSGTKLE IK (SEQ ID NO.: 21) LCDR1: TASSSVSSSYLH (SEQ ID NO.: 22) LCDR2: STSNLAS (SEQ ID NO.: 23) LCDR3: HQYHRSPFT (SEQ ID NO.: 24)

[0169] In some embodiments, an antibody or antigen binding fragment described hereincomprises a heavy chain complementarity determining region 1 (CDR1), a heavy chain CDR2, a heavy chain CDR3 contained within a heavy chain variable region (VH) comprising the amino acid sequence set forth in SEQ ID NO: 1, 9, or 17. In some embodiments, an antibody or antigen binding fragment described herein comprises a VH comprising an amino acid sequence of SEQ ID NO: 1, 9 or 17, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 95.5%, or 99.9% sequence identity to the amino acid sequence of SEQ ID NO: 1, 9, or 17. 36Attorney Docket No: 243735.000427

[0170] In some embodiments, an antibody or antigen binding fragment described hereincomprises a light chain complementarity determining region 1 (CDR1), a light chain CDR2, a light chain CDR3 contained within a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 5, 13, or 21. In some embodiments, an antibody or antigen binding fragment described herein comprises a VL comprising an amino acid sequence of SEQ ID NO: 5, 13, or 21, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 95.5%, or 99.9% sequence identity to the amino acid sequence of SEQ ID NO: 5, 13, or 21.

[0171] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises aheavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1, 9, or 17, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 5, 13, or 21, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.

[0172] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises aheavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3 of a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1, 9, or 17; and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 5, 13, or 21.

[0173] In some embodiments, the heavy chain CDR1 comprises the amino acid sequence setforth in SEQ ID NO: 2, the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 3, and the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 4.

[0174] In some embodiments, the heavy chain CDR1 comprises the amino acid sequence setforth in SEQ ID NO: 10, the heavy chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 11, and the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 12.

[0175] In some embodiments, the heavy chain CDR1 comprises the amino acid sequence setforth in SEQ ID NO: 18, the heavy chain CDR2 comprises the amino acid sequence set forth in 37Attorney Docket No: 243735.000427 SEQ ID NO: 19, and the heavy chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 20.

[0176] In some embodiments, the light chain CDR1 comprises the amino acid sequence set forthin SEQ ID NO: 6, the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 7, and the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0177] In some embodiments, the light chain CDR1 comprises the amino acid sequence set forthin SEQ ID NO: 14, the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 15, and the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0178] In some embodiments, the light chain CDR1 comprises the amino acid sequence set forthin SEQ ID NO: 22, the light chain CDR2 comprises the amino acid sequence set forth in SEQ ID NO: 23, and the light chain CDR3 comprises the amino acid sequence set forth in SEQ ID NO: 24.

[0179] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising an amino acid sequence of SEQ ID NO: 1, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a VL comprising an amino acid sequence of SEQ ID NO: 5, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.

[0180] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising an amino acid sequence of SEQ ID NO: 9, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a VL comprising an amino acid sequence of SEQ ID NO: 13, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.

[0181] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising an amino acid sequence of SEQ ID NO: 17, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a VL comprising an amino acid sequence of SEQ ID NO: 21, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto. 38Attorney Docket No: 243735.000427

[0182] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising an amino acid sequence of SEQ ID NO: 1; and / or a VL comprising an amino acid sequence of SEQ ID NO: 5.

[0183] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising an amino acid sequence of SEQ ID NO: 9; and / or a VL comprising an amino acid sequence of SEQ ID NO: 13.

[0184] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising an amino acid sequence of SEQ ID NO: 17; and / or a VL comprising an amino acid sequence of SEQ ID NO: 21.

[0185] In some embodiments, an antibody or antigen-binding fragment disclosed hereincomprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3 of a VH comprising the amino acid sequence of SEQ ID NO: 1, and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising the amino acid sequence of SEQ ID NO: 5.

[0186] In some embodiments of the above-described antibody or antigen-binding fragment, theantibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 3, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 6, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 7, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 8.

[0187] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising the amino acid sequence of SEQ ID NO: 1, and a VL comprising the amino acid sequence of SEQ ID NO: 5.

[0188] In some embodiments, an antibody or antigen-binding fragment disclosed hereincomprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3 of a VH comprising the amino acid sequence of SEQ ID NO: 9, and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising the amino acid sequence of SEQ ID NO: 13.

[0189] In some embodiments of the above-described antibody or antigen-binding fragment, theantibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 10, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 12, a 39Attorney Docket No: 243735.000427 light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 14, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 16.

[0190] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising the amino acid sequence of SEQ ID NO: 9, and a VL comprising the amino acid sequence of SEQ ID NO: 13.

[0191] In some embodiments, an antibody or antigen-binding fragment disclosed hereincomprises a heavy chain CDR1, a heavy chain CDR2, a heavy chain CDR3 of a VH comprising the amino acid sequence of SEQ ID NO: 17, and a light chain CDR1, a light chain CDR2, and a light chain CDR3 of a VL comprising the amino acid sequence of SEQ ID NO: 21.

[0192] In some embodiments of the above-described antibody or antigen-binding fragment, theantibody or antigen-binding fragment comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 18, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 19, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 20, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 24.

[0193] In some embodiments, the antibody or antigen-binding fragment comprises a VHcomprising the amino acid sequence of SEQ ID NO: 17, and a VL comprising the amino acid sequence of SEQ ID NO: 21.

[0194] In some embodiments, an antibody or antigen-binding fragment thereof described hereincan compete for binding to PIK3IP1 protein with an antibody or antigen-binding fragment of the present disclosure.

[0195] In some embodiments, an antibody or antigen-binding fragment thereof described hereincan bind to the same epitope of PIK3IP1 protein as an antibody or antigen-binding fragment of the present disclosure.

[0196] In certain embodiments, the antibody or antigen-binding fragment comprises one or moreamino acid substitutions. In certain embodiments, amino acid substitutions of an antibody or portion thereof are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, or (4) confer or modify other physicochemical or functional properties. For example, single or multiple amino acid substitutions 40Attorney Docket No: 243735.000427 (preferably conservative amino acid substitutions) may be made in the naturally occurring sequence.

[0197] A conservative amino acid substitution should not substantially change the structuralcharacteristics of the parent sequence. Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al., Nature 354:105 (1991), which are each incorporated herein by reference.

[0198] As used herein, the twenty naturally occurring amino acids and their abbreviations followconventional usage. See Immunology—A Synthesis (2ndEdition, E. S. Golub and D. R. Green, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference.

[0199] In some embodiments, the antibody or antigen-binding fragment is recombinant. Incertain embodiments, the antibody or antigen-binding fragment is a human antibody, a humanized antibody, a chimeric antibody, a murine antibody, a monoclonal antibody, a single chain antibody, a bispecific antibody or antigen-binding fragment thereof, a bi-epitopic antibody or antigen- binding fragment thereof, a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a VH domain, or a nanobody.

[0200] In some embodiments, the antibodies or antigen-binding fragments described herein arehumanized antibodies.

[0201] In some embodiments, the antibodies or antigen-binding fragments described herein arechimeric antibodies.

[0202] In some embodiments, the antigen-binding fragment is a Fab.

[0203] In some embodiments, the antigen-binding fragment is a scFv.

[0204] In some embodiments, an antibody or antigen-binding fragment thereof can be abispecific antibody or antigen-binding fragment thereof. In some embodiments, the bispecific antibody or antigen-binding fragment thereof can comprise at least one antigen-binding domain. An antigen-binding domain can include any portion of an antigen-binding molecule (i.e., a molecule that is capable of specific binding to an antigen) which can specifically bind to an antigen. As a non-limiting example, an antigen-binding domain may be a portion of an antigen- binding fragment such as, without limitation, a Fab, an scFv, or a VH domain. In some embodiments, the bispecific antibody of antigen-binding fragment can comprise a first antigen- binding domain and a second antigen-binding domain. 41Attorney Docket No: 243735.000427

[0205] In some embodiments, a bispecific antibody or antigen-binding fragment thereof maycomprise a bi-epitopic antibody or antigen-binding fragment. For example, without limitation, in such embodiments a bi-epitopic antibody may comprise a first antigen-binding domain which may bind to a first epitope that is the same as an antibody or antigen-binding fragment thereof disclosed herein (e.g., any of various antibodies or antigen-binding fragments thereof set forth in Table 1 or a substantially similar sequence thereof having at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto), and a second antigen-binding domain which may bind to a second epitope that is the same as an antibody or antigen-binding disclosed herein (e.g., any of various antibodies or antigen-binding fragments thereof set forth in Table 1 or a substantially similar sequence thereof having at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto) but is different from the first epitope.

[0206] In some embodiments, a bispecific antibody or bispecific antigen-binding fragment ofthe present disclosure is a bispecific T-cell engager (BiTE), a bispecific natural killer (NK)-cell engager (BiKE), or a bispecific macrophage engager (BiME). In some embodiments, the BiTE comprises an antigen-binding domain that specifically binds to cluster of differentiation (CD)3 (CD3), alpha beta T cell receptor (TCR), or gamma delta TCR. In some embodiments, the BiKE comprises an antigen-binding domain that specifically binds to Fc gamma receptor III (FcγRIII or CD16), natural killer group 2, member D (NKG2D), or natural cytotoxicity triggering receptor 3 (NCR3). In some embodiments, the BiME comprises an antigen-binding domain that specifically binds to Fc gamma receptor III (FcγRIII or CD16), dendritic cell-associated C-type lectin 1 (Dectin-1), cluster of differentiation (CD47), signal regulatory protein alpha (SIRPA), or Tyro3, Axl, and MerTK (TAM) receptor(s).

[0207] In some embodiments, a bispecific antibody or antigen-binding fragment thereof of thepresent disclosure may comprise a first antigen-binding domain which binds to a first epitope that is the same as an antibody or antigen-binding fragment of the present disclosure (e.g., any of various antibodies or antigen-binding fragments thereof set forth in Table 1 or a substantially similar sequence thereof having at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto), and a second antigen-binding domain which binds to a molecule on the cell surface. In some embodiments, the second antigen-binding domain which binds to a molecule on the cell surface is an immune checkpoint, a cytokine or a receptor thereof, a tumor-associated antigen (TAA), or an immune stimulatory receptor. In some embodiments, the 42Attorney Docket No: 243735.000427 second antigen-binding domain is an immune checkpoint, a cytokine or a receptor thereof, a tumor- associated antigen (TAA), or an immune stimulatory receptor.

[0208] Exemplary cytokines include, but are not limited to, interleukin-2 (IL-2), interleukin-6(IL-6), interleukin-10 (IL-10), interleukin-15 (IL-15), interleukin-21 (IL-21), IFN-α, IFN-β, IFN- γ, CCL19, CCL21, IL-18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), or a receptor thereof, and any combinations thereof.

[0209] In some embodiments, the cytokine is IL-2, IL-6, IL-10, IL-15, IL-21, IFN-α, IFN-β,IFN-γ, CCL19, CCL21, IL-18, MCP-1, TNF, GM-CSF, or G-CSF, or a receptor or a combination thereof.

[0210] In some embodiments, the immune checkpoint is programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), lymphocyte activation gene 3 (LAG-3 or CD223), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), cluster of differentiation 47 (CD47), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), B7 homolog 3 protein (B7- H3 or CD276), B7-H4, V-domain Ig suppressor of T cell activation (VISTA or PD-1H), T cell immunoreceptor with Ig and ITIM Domains (TIGIT), signal regulatory protein alpha (SIRPA), signaling lymphocytic activation molecule family members (SLAMF), poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R), adenosine A2A receptor (A2aR), adenosine A2b receptor (A2bR), G protein-coupled receptor 171 (GPR171), insulin like growth factor binding protein 7 (IGFBP7), cluster of differentiation 93 (CD93), CD96, CD226, natural killer group protein 2A (NKG2A), natural killer group protein 2D (NKG2D), a killer cell lectin like receptor G1 (KLRG1), a human endogenous retrovirus-H long terminal repeat- associating protein 2 (HHLA2), a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3), sialic acid-binding immunoglobulin-like lectin (Sigelac)-15, cluster of differentiation 24 (CD24), sialic acid-binding immunoglobulin-like lectin (Sigelac)-10, P-selectin glycoprotein ligand-1 (PSGL-1), V-set and Ig domain-containing protein 3 (VSIG3 or BT-IgSF or IGSF11), leucine rich repeats and immunoglobulin like domains 1 (LRIG1), fibrinogen-like protein 1 (FGL1), B and T lymphocyte attenuator (BTLA), leukocyte associated immunoglobulin like receptor 1 (LAIR-1), cluster of differentiation 160 (CD160), leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), leukocyte immunoglobulin-like receptor (LILRB4), angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), and 43Attorney Docket No: 243735.000427 any combination thereof. In some embodiments, the immune checkpoint is selected from the immune checkpoint is PD-1, PD-L1, LAG-3, or CTLA-4, and any combination thereof.

[0211] In some embodiments, the second antigen-binding domain which binds to an immunecheckpoint is an immune checkpoint inhibitor. Exemplary immune checkpoint inhibitors include, but are not limited to, a programmed cell death protein 1 (PD-1) inhibitor, a programmed death- ligand 1 (PD-L1) inhibitor, lymphocyte activation gene 3 (LAG-3 or CD223) inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a cluster of differentiation 47 (CD47) inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or PD-1H) inhibitor, a T cell immunoreceptor with Ig and ITIM Domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor- related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a cluster of differentiation 93 (CD93) inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus- H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a cluster of differentiation 24 (CD24) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-10 inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or BT-IgSF or IGSF11) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin like receptor 1 (LAIR-1) inhibitor, a cluster of differentiation 160 (CD160) inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, angiopoietin 2 (Ang2), and vascular endothelial growth factor (VEGF), and any combinations thereof. 44Attorney Docket No: 243735.000427

[0212] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1inhibitor, a LAG-3 inhibitor, or a CTLA-4 inhibitor, or a combination thereof.

[0213] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or PD-L1inhibitor. Non-limiting examples of PD-1 inhibitors or PD-L1 inhibitors include nivolumab, pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

[0214] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. ExemplaryPD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. Exemplary PD-L1 inhibitors include, but are not limited to, durvalumab, avelumab, atezolizumab, bintrafusp alfa, a variant or any combinations thereof.

[0215] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. ExemplaryLAG-3 inhibitors include, but are not limited to, relatlimab (BMS-986016), ABL501, CB213, EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO- 45Attorney Docket No: 243735.000427 7247669), TSR-033, tuparstobart (INCAGN02385), or BGA-1953, or a variant or a combination thereof. In certain specific embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), or a variant thereof.

[0216] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.Exemplary CTLA-4 inhibitors include, but are not limited to, ipilimumab, tremelimumab, XmAb20717, ONC-392, XmAb22841, BMS-986249, ADG116, ATOR-1015, ADG126, YH001, botensilimab, HBM4003, lorigerlimab, SI-B003, AK104, KN046, quavonlimab, BNT316 / ONC- 392 (gotistobart), porustobart (HBM4003), or a variant or combination thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab, BNT316 / ONC- 392 (gotistobart), or porustobart (HBM4003), or a variant or a combination thereof.

[0217] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor. ExemplaryTIGIT inhibitors include, but are not limited to, BMS‐986207, ociperlimab, BGB‐A1217, tiragolumab, domvanalimab, ASP8374, vibostolimab, IBI‐939, etigilimab, COM902, M6223, EOS884448, BAT6021, HLX301, or a variant or any combinations thereof.

[0218] In some embodiments, the immune checkpoint inhibitor is a SLAMF inhibitor. In someembodiments, the SLAMF inhibitor is elotuzumab or a variant thereof. In some embodiments, the immune checkpoint inhibitor is a PVRIG inhibitor. In some embodiments, the PVRIG inhibitor is COM701, JS009, or a variant thereof. In some embodiments, the immune checkpoint inhibitor is a CD96 inhibitor. In some embodiments, the CD96 inhibitor is GSK6097608 or a variant thereof.

[0219] In some embodiments, the immune stimulatory receptor is the immune stimulatoryreceptor is CD28, ICOS, CD28H / TMIGD2, NCR3, NCR1, NCR2, 4-1BB, OX40, CD30, CD40, DR3, CD226, CRTAM, CD27, HVEM, TNFR1, TNFR2, CD2, CD7, TLR4, TLR7, TLR9, or GITR, or a combination thereof.

[0220] In some embodiments, the immune stimulatory receptor is CD28, ICOS, TMIGD2,NCR3, NCR1, NCR2, 4-1BB, OX40, CD30, CD40, DR3, CD226, CRTAM, CD27, HVEM, TNFR1, TNFR2, CD2, CD7, TLR4, TLR7, or TLR9.

[0221] In some embodiments, the tumor-associated antigen is 5T4, Ang2, BCMA, CD123,CD19, CD20, CD22, CD33, CD38, CD47, CEA, CEACAM5, CEACAM6, Claudin 6, Claudin 18.2, Tie2, CLEC12A, DLL3, EGFR, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, Her2, Her3, MAGE-A4, MET, MUC16, MUC17, NY-ESO-1, P-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, TROP2 (TACSTD2), VEGF, VEGFR, γδTCR, KRAS, RAF, or 46Attorney Docket No: 243735.000427 a combination thereof. However, disclosure of immune checkpoints as cell surface on a cell surface is not intended to be limiting. Thus, it is well within the knowledge of one skilled in the art that where anti-cell surface molecule antibodies or antigen-binding fragments thereof may be used, such anti-cell surface antibodies or antigen-binding fragments may target any of various cell surface molecules known to a skilled artisan. In some embodiments, the TAA-targeting agent is a VEGF inhibitor, a VEGFR inhibitor, a CD20 inhibitor, a CD38 inhibitor, a TROP2 inhibitor, a KRAS inhibitor, or a RAF inhibitor.

[0222] In some embodiments, the CD20 inhibitor is rituximab. In some embodiments, the VEGFinhibitor is bevacizumab. In some embodiments, the CD38 inhibitor is daratumumab. In some embodiments, the TROP2 inhibitor is sacituzumab govitecan.

[0223] In some embodiments, an antibody or antigen-binding fragment thereof may comprise aKineTAC such as, e.g., a KineTAC similar to, or the same as, those which are described by Pance, K. et. Al., Nature Biotechnology, 41, 2023, 273-281 (PMID 36138170), the content of which is incorporated herein by reference in its entirety for all purposes. Without wishing to be bound by theory, KineTACs are a modular cytokine receptor-targeting chimera. KineTACs are genetically encoded bispecific antibodies that are used for targeted degradation of both cell surface and extracellular proteins via lysosomal delivery. KineTACs are made of a target-binding arm (e.g., a PIK3IP1-binding Fab), which can be bound to a protein of interest (e.g., PIK3IP1 protein), and a cytokine arm, which can bind its cognate cytokine receptor. The cytokine arm may be, but is not limited to, CXCL12, CXCL11, vMIPII, and / or IL-2 for lysosomal degradation applications. The KineTAC cytokine arm may bind CXCR7 or IL-2R.

[0224] In some embodiments, an antibody or antigen-binding fragment described herein, cancomprise a first antigen-binding domain and a cytokine receptor-targeting molecule (e.g., a cytokine). In some embodiments, the first antigen-binding domain can bind to a first epitope that is the same as an antibody or antigen-binding fragment of the present disclosure (e.g., any of various antibodies or antigen-binding fragments thereof set forth in Table 1 or a substantially similar sequence thereof having at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto), and the cytokine receptor-targeting molecule (e.g., a cytokine) may bind to its cognate cytokine receptor.

[0225] In some embodiments, the anti-PIK3IP1 antibodies disclosed herein, having the heavychain CDRs disclosed herein, contains framework regions derived from a subclass of germline VH 47fragment. Such germline VH regions are well known in the art. See, e.g., the IMGT database (imgt.org) or at vbase2.org / vbstat.php. Examples include the IGHV1 subfamily (e.g., IGHV1-2, IGHV1-3, IGHV1-8, IGHV1-18, IGHV1-24, IGHV1-45, IGHV1-46, IGHV1-58, and IGHV1-69), the IGHV2 subfamily (e.g., IGHV2-5, IGHV2-26, and IGHV2-70), the IGHV3 subfamily (e.g., IGHV3-7, IGHV3-9, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30, IGHV3-33, IGHV3-43, IGHV3- 48, IGHV3-49, IGHV3-53, IGHV3-64, IGHV3-66, IGHV3-72, and IGHV3-73, IGHV3-74), the IGHV4 subfamily (e.g., IGHV4-4, IGHV4-28, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-59, IGHV4-61, and IGHV4-B), the IGHV subfamily (e.g., IGHV5-51, or IGHV6-1), and the IGHV7 subfamily (e.g., IGHV7-4-1).

[0226] Alternatively, or in addition, in some embodiments, the anti-PIK3IPl antibody, having the light chain CDRs disclosed herein, contains framework regions derived from a germline VK fragment. Examples include an IGKV1 framework (e.g., IGKV1-05, IGKV1-12, IGKV1-27, IGKV1-33, or IGKV1-39), an IGKV2 framework (e.g., IGKV2-28), an IGKV3 framework (e.g., IGKV3-11, IGKV3-15, or IGKV3-20), and an IGKV4 framework (e.g., IGKV4-1). In other instances, the anti-PIK3IPl antibody comprises a light chain variable region that contains a framework derived from a germline VZ fragment. Examples include an IgZI framework (e.g., IgZVl-36, IgZVl-40, IgZVl-44, IgZVl-47, IgXVl-51), an IgZ2 framework (e.g., IgXV2-8, IgXV2- 11, IgXV2-14, IgXV2-18, IgXV2-23), an IgX3 framework (e.g., IgXV3-l, IgXV3-9, IgXV3-10, IgZV3-12, IgXV3-16, IgXV3-19, IgXV3-21, IgXV3-25, IgXV3-27), an IgX4 framework (e.g., IgXV4- 3, IgXV4-60, IgXV4-69), an IgX5 framework (e.g., IgXV5-39, IgXV5-45), an IgX6 framework (e.g., IgXV6-57), an IgX7 framework (e.g., IgXV7-43, IgXV7-46), an IgX8 framework (e.g., IgXV8-6 l ), an IgX9 framework (e.g., IgZV9-49), or an IgXIO framework (e.g., IgXV10-54).

[0227] In some embodiments, an anti-PHC3IPl antibody, or antigen-binding fragment thereof, may bind to human PIK3IP1 protein. In some embodiments, the antibody or antigen-binding fragment thereof may bind to mouse PIK3IP1 protein. In some embodiments, an anti-PIK3IPl antibody, or antigen -binding fragment thereof, may bind to both human PIK3IP1 protein and mouse PIK3IP1 protein. In some embodiments, an anti-PIK3IPl antibody, or antigen-binding fragment thereof, may bind to either human PIK3IP1 protein or mouse PIK3IP1 protein.

[0228] In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof as described herein has a suitable binding affinity for the target antigen (e g., PIK3IP1 protein) or antigenic epitopes thereof. As used herein, “binding affinity” refers to the apparent associationconstant or KA. The KA is the reciprocal of the dissociation constant (KD). In various embodiments, the anti-PIK3IPl antibody, or antigen-binding fragment thereof described herein, may have a binding affinity (KD) of at least about 1X10'6M or less, about 1x1 O’7M or less, about 1x1 O’8M or less, about IxlO'9M or less, about lxlO'loM or less, about IxlO'11M or less, about IxlO'12M or less, or about IxlO'13M or less for the target antigen or antigenic epitope. An increased binding affinity corresponds to a decreased KD.

[0229] In various embodiments, the antibodies of the disclosure have the ability to bind to a predetermined antigen (e.g., PIK3IP1 protein) with a dissociation constant (KD) of IxlO'6M or less, 5xl0'7M or less, IxlO'7M or less, 5xl0'8M or less, 4xl0'8M or less, 3xl0'8M or less, 2x10'8M or less, about IxlO'8M or less, 9xl0'9M or less, 8xl0'9M or less, 7xl0'9M or less, 6xl0'9M or less, 5xl0'9M or less, 4xl0'9M or less, 3xl0'9M or less, 2xl0'9M or less, about IxlO'9M or less, 9xlO'10M or less, 8xlO'10M or less, 7xlO'10M or less, 6xlO'10M or less, 5xlO'10M or less, 4xlO'10M or less, 3xlO'10M or less, 2xlO'10M or less, IxlO'10M or less, 5xl0'nM or less, about IxlO'11M or less, 5xl0'12M or less, about IxlO'12M or less, 5xl0'13M or less, or about IxlO'13M or less.

[0230] In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof, described herein may bind to human PIK3IP1 protein at a dissociation constant (KD) of about 1x10'6M or less, 5xl0'7M or less, IxlO'7M or less, 5xl0'8M or less, 4xl0'8M or less, 3xl0'8M or less, 2xl0'8M or less, about IxlO'8M or less, 9xl0'9M or less, 8xl0'9M or less, 7xl0'9M or less, 6xl0'9M or less, 5xl0'9M or less, 4xl0'9M or less, 3xl0'9M or less, 2xl0'9M or less, about 1x10'9M or less, 9xlO'10M or less, 8xl0'10M or less, 7xlO'10M or less, 6xlO'10M or less, 5xl0'10M or less, 4xlO'10M or less, 3xl0'10M or less, 2xlO'10M or less, IxlO10M or less, 5xl0'nM or less, about IxlO'11M or less, 5xl0'13M or less, about IxlO'12M or less, 5xl0'12M or less, or about IxlO'13M or less. As a non-limiting example, the anti-PIK3IPl antibody, or antigen-binding fragment thereof, may bind to human PIK3IP1 protein at a dissociation constant (KD) of about IxlO'8M or less. In some embodiments, the anti-PIK3IPl antibody, or antigen-binding fragment thereof, may bind to human PIK3IP1 protein at a dissociation constant (KD) of about IxlO'7M or less. In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein may bind human PIK3IP1 protein at a KD of about 2xl0'9M or less. In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein may bind human PIK3IP1 protein at a KD of about 5xl0'9M or less.

[0231] In some embodiments, an anti-PIK3TPl antibody or antigen-binding fragment thereof described herein may bind to mouse PIK3IP1 protein at a dissociation constant (KD) of about 1x10'6M or less, 5x1 O’7M or less, 1x1 O’7M or less, 5x1 O’8M or less, 4x1 O’8M or less, 3x1 O’8M or less, 2xl0'8M or less, about IxlO'8M or less, 9xl0'9M or less, 8xl0'9M or less, 7xl0'9M or less, 6xl0'9M or less, 5xl0'9M or less, 4x1 O'9M or less, 3xl0'9M or less, 2xl0'9M or less, about 1x10"9M or less, 9xlO'10M or less, 8xl0'10M or less, 7xlO'10M or less, 6xlO'10M or less, 5xl0'10M or less, 4xlO'10M or less, 3xl0'10M or less, 2xlO'10M or less, IxlO'10M or less, 5xl0'nM or less, about IxlO'11M or less, 5xl0'12M or less, about IxlO'12M or less, 5xl0'13M or less, or about IxlO'13M or less. As a non-limiting example, the anti-PIK3IPl antibody, or antigen-binding fragment thereof, may bind mouse PIK3IP1 protein at a dissociation constant (KD) of about 1x10'8M or less. In some embodiments, the anti-PIK3IP 1 antibody, or antigen-binding fragment thereof, may bind to human PIK3IP1 protein at a dissociation constant (KD) of about IxlO'7M or less. In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein may bind mouse PIK3IP1 protein at a KD of about 2xl0'9M or less. In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein may bind to mouse PIK3IP1 protein at a KD of about 5xl0'9M or less.

[0232] Binding affinity (or binding specificity) can be determined by a variety of methods including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, biolayer interferometry (BLI), surface plasmon resonance (SPR), bead-based assay, radioimmunoassay, or spectroscopy (e.g., using a fluorescence assay). In certain embodiments, a PIK3IP1 antigen, or derivative thereof, is coated onto a bead or onto the surface of an ELISA plate or other solid phase used for measurement. Examples of bead-based binding assays which may be used for measuring KD of the anti-PIK3IPl antibodies and / or antigen-binding fragments herein are described in, e.g., Nishikori et al., J Mol Biol. 2012 Dec 14;424(5):391-9 (PMID 23041298) and Hattori et al., J Immunol Methods. 2021 Mar;490: l 12952 (PMID 33358997), each of which is incorporated herein by reference in its entirety and for all purposes as if fully set forth herein.

[0233] These techniques can be used to measure the concentration of bound antibody or antigenbinding fragment as a function of target antigen concentration. Under certain conditions, the fractional concentration of bound antibody or antigen-binding fragment ([Bound] / [Total]) is generally related to the concentration of total target antigen ([Target]) by the following equation: [Bound] / [Total] = [Target] / (Ko+[Target])

[0234] It is not always necessary to make an exact determination of KD, though, since sometimes it is sufficient to obtain a quantitative measurement of affinity, e.g., determined using a method such as ELISA or FACS analysis, is proportional to KD, and thus can be used for comparisons, such as determining whether a higher affinity is, e.g., 2-fold higher, to obtain a qualitative measurement of affinity, or to obtain an inference of affinity, e.g., by activity in a functional assay, e.g., an in vitro or in vivo assay. In some cases, the in vitro binding assay is indicative of in vivo activity. In other cases, the in vitro binding assay is not necessarily indicative of in vivo activity. In some cases, tight binding is beneficial, but in other cases tight binding is not as desirable in the in vivo setting, and an antibody with lower binding affinity is more desirable.

[0235] In some embodiments, the heavy chain of any of any of the anti-PIK3IPl antibodies as described herein further comprise a heavy chain constant region (CH) or a portion thereof (e.g., CHI, CH2, CH3, or a combination thereof). The heavy chain constant region can be of any suitable origin, e.g., human, mouse, rat, or rabbit. In some embodiments, the heavy chain constant region is from an IgD, IgE, IgG, IgA, or IgM class, or sub-class thereof. In some embodiments, the heavy chain constant region is from a human IgG (a gamma heavy chain) or any IgG subfamily as described herein. In some embodiments, the heavy chain constant region is from an IgGl, IgG2, IgG3, or IgG4 subclass.

[0236] In some embodiments, the heavy chain constant region of the antibodies described herein comprise a single domain (e.g., CHI, CH2, or CH3) or a combination of any of the single domains, of a constant region. In some embodiments, the light chain constant region of the antibodies described herein comprise a single domain (e.g., CL), of a constant region.

[0237] In some embodiments, the anti-PIK3IPl antibody or antigen-binding fragment described herein is of an IgGl subclass.

[0238] In some embodiments, the anti-PIK3IPl antibody or antigen-binding fragment described herein is of an IgG2 subclass.

[0239] In some embodiments, the anti-PIK3IPl antibody or antigen-binding fragment described herein is of an IgG4 subclass.

[0240] In some embodiments, anti-PIK3IPl antibodies or antigen-binding fragments described herein comprises a fragment crystallizable (Fc) region. In some embodiments, anti-PIK3IPl antibodies or antigen-binding fragment described herein comprises a modified Fc region.

[0241] In some embodiments, an Fc region described herein is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody. For example, one or more amino acids selected from the following positions: 234, 235, 236, 237, 297, 318, 320, 322, 330, and / or 331 may be substituted with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigenbinding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. See, e.g., U.S. Pat. Nos. 5,624,821 and 5,648,260, both of which are incorporated herein by reference in their entirety.

[0242] In one embodiment, an Fc region described herein comprises one or more amino acids substitutions at amino acid residues 329, 331 and 322 such that the antibody has altered Clq binding and / or reduced or abolished complement dependent cytotoxicity (CDC). See, e.g., U.S. Pat. No. 6,194,551, which is incorporated herein by reference in its entirety.

[0243] In some examples, an Fc region described herein comprises one or more amino acid residues at amino acid positions 231 and / or 239 to alter the ability of the antibody to fix complement. See, e.g., PCT Publication WO 94 / 29351, which is incorporated herein by reference in its entirety.

[0244] In some examples, an Fc region described herein can be modified to decrease antibody dependent cellular cytotoxicity (ADCC) and / or to decrease the affinity for an Fey receptor by modifying one or more amino acids at the following positions: 234, 235, 236, 238, 239, 240, 241,243, 244, 245, 247, 248, 249, 252, 254, 255, 256, 258, 262, 263, 264, 265, 267, 268, 269, 270,272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 299, 301, 303, 305,307, 309, 312, 313, 315, 320, 322, 324, 325, 326, 327, 329, 330, 331, 332, 333, 334, 335, 337,338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 433, 434, 435, 436, 437, 438 or 439. Exemplary substitutions include but are not limited to 236A, 239D, 239E, 268D, 267E, 268E, 268F, 324T, 332D, and 332E. Exemplary variants include but are not limited to 239D / 332E, 236A / 332E, 236A / 239D / 332E, 268F / 324T, 267E / 268F, 267E / 324T, and 267E / 268F / 324T. In some embodiments, an exemplary variant can comprise L234A / L235A / P329G (LALA-PG), e.g., as described in Lo et al., J Biol Chem. 2017 Mar 3;292(9):3900-3908 (PMID 28077575).

[0245] In some embodiments, an Fc region described herein include modifications that reduce or ablate binding to FcyR and / or complement proteins, thereby reducing or ablating Fc-mediated effector functions such as ADCC, ADCP, and CDC. Exemplary modifications include but are notlimited to substitutions, insertions, and deletions at amino acid residues (EU numbering) 234, 235, 236, 237, 267, 269, 325, 328, 330, and / or 331. Exemplary substitutions include but are not limited to 234A, 235E, 236R, 237A, 267R, 269R, 325L, 328R, 330S, and 33 IS (e.g., 330S, and 33 IS). An exemplary Fc variant can comprise 236R / 328R. Other modifications for reducing FcyR and complement interactions include substitutions 297A, 234A, 235A, 237A, 318A, 228P, 236E, 268Q, 309L, 330S, 33 IS, 220S, 226S, 229S, 238S, 233P, and 234V, as well as removal of the glycosylation at position 297 by e.g., mutational or enzymatic means or by production in organisms such as bacteria that do not glycosylate proteins.

[0246] In one embodiment, an Fc region described herein is a human IgGl .3 Fc constant region comprising L234A, L235E, and G237A substitutions. In one embodiment, an Fc region described herein is a IgGlfa.P238K (or IgGl.P238K) comprising a P238K substitution. In one embodiment, an Fc region described herein is a IgGl. If variant comprising L234A, L235E, G237A, A33OS, and P331S substitutions.

[0247] In some embodiments, an Fc region described herein is modified to enhance affinity for an inhibitory receptor FcyRIIb. Such modification can provide an Fc fusion protein with immunomodulatory activities related to FcyRIIb cells, including for example B cells and monocytes. For example, the Fc variants may provide selectively enhanced affinity to FcyRIIb relative to one or more activating receptors. Modifications that alter binding to FcyRIIb include one or more modifications at a position (EU numbering) selected from the group consisting of 234, 235, 236, 237, 239, 266, 267, 268, 325, 326, 327, 328, 330, 331, and 332. Exemplary substitutions for enhancing FcyRIIb affinity include but are not limited to 234 A, 234D, 234E, 234F, 234W, 235D, 235E, 235F, 235R, 235Y, 236D, 236N, 237A, 237D, 237N, 239D, 239E, 266M, 267D, 267E, 268D, 268E, 327D, 327E, 328F, 328W, 328Y, 330S, 33 IS, and 332E. Exemplary substitutions include 235Y, 236D, 239D, 266M, 267E, 268D, 268E, 328F, 328W, and 328Y. Other Fc variants for enhancing binding to FcyRIIb include 235Y / 267E, 236D / 267E, 239D / 268D, 239D / 267E, 267E / 268D, 267E / 268E, and 267E / 328F.

[0248] Other modifications for enhancing FcyR and complement interactions include but are not limited to substitutions 298A, 333A, 334A, 326A, 2471, 339D, 339Q, 280H, 290S, 298D, 298V, 243L, 292P, 300L, 396L, 3051, and 396L. These and other modifications are reviewed in Strohl, 2009, Current Opinion in Biotechnology 20:685-691. Fc modifications that increase binding to an Fey receptor include amino acid modifications at any one or more of amino acid positions (EUnumbering) 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 279, 280, 283, 285, 298, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 312, 315, 324, 327, 329, 330, 335, 337, 338, 340, 360, 373, 376, 379, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439 of the Fc region (see., Patent Publication No. WO 00 / 42072).

[0249] The affinities and binding properties of an Fc region for its ligand can be determined by a variety of in vitro methods (e.g., biochemical or immunological based assays) known in the art including but not limited to, equilibrium methods (e.g., enzyme-linked immunosorbent assay (ELISA), or radioimmunoassay (RIA)), or kinetics (e.g., BIACORE analysis), and other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography (e.g., gel filtration). These and other methods can utilize a label on one or more of the components being examined and / or employ a variety of detection methods including but not limited to fluorescent, luminescent, chromogenic, or isotopic labels.

[0250] In some embodiments, the glycosylation of an antibody is altered. Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, glycosylation of the constant region on N297 can be prevented or reduced by mutating the N297 residue to another residue, e.g., N297A, or N297D and / or by mutating an adjacent amino acid, e.g., 298. Additionally, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation can increase the affinity of the antibody for antigen. See, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861, both of which are incorporated herein by reference in their entirety.

[0251] In some embodiments, the antibody can be modified to increase its biological half-life. For example, the Fc region can be modified to increase its binding affinity for FcRn, by mutating one or more of following residues: 252, 254, 256, 433, 435, 436 (see, e.g., U.S. Pat. No. 6,277,375, which is incorporated herein by reference in its entirety). Specific exemplary mutations include one or more of the following: T252L, T254S, and / or T256F. In some embodiments, the antibody can be modified within the CHI or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022, each of which is incorporated herein by reference in its entirety.

[0252] Other exemplary variants that increase Fc binding to FcRn include: 250E, 250Q, 428L, 428F, 250Q / 428L (Hinton et al. 2004, J. Biol. Chem. 279(8): 6213-6216; Hinton et al. 2006 Journal of Immunology 176:346-356, each of which is incorporated herein by reference in its entirety), 256A, 272A, 286A, 305A, 307A, 307Q, 311A, 312A, 376A, 378Q, 380A, 382A, 434A (Shields et al., Journal of Biological Chemistry, 2001, 276(9):6591-6604, which is incorporated herein by reference in its entirety), 252F, 252T, 252Y, 252W, 254T, 256S, 256R, 256Q, 256E, 256D, 256T, 309P, 31 IS, 433R, 433S, 4331, 433P, 433Q, 434H, 434F, 434Y, 252Y / 254T / 256E, 433K / 434F / 436H, 308T / 309P / 311S (Dall Acqua et al. Journal of Immunology, 2002, 169:5171- 5180, Dall’ Acqua et al., 2006, Journal of Biological Chemistry 281 :23514-23524, each of which is incorporated herein by reference in its entirety). Additional exemplary variants that increase binding to FcRn and / or improve pharmacokinetic properties include mutations at positions 259, 308, 428, and 434, including for example 2591, 308F, 428L, 428M, 434S, 434H. 434F, 434Y, and 434M. Further modifications for modulating FcRn binding include those described in Yeung et al., 2010, J Immunol, 182:7663-7671, which is incorporated herein by reference in its entirety.

[0253] In some embodiments, antibodies described herein are of hybrid IgG isotypes. In some embodiments, an IgGl / IgG2 hybrid variant can be constructed by substituting IgG2 positions in the CH2 and / or CH3 region with amino acids from IgGl at positions where the two isotypes differ. In some embodiments, a hybrid variant IgG antibody can be constructed that comprises one or more substitutions, e.g., one or more of the following amino acid substitutions: 233E, 234L, 235L, - 236G (referring to an insertion of a glycine at position 236), and 327A. In some embodiments, an IgGl / IgG3 hybrid variant can be constructed by substituting IgGl positions in the CH2 and / or CH3 region with the amino acids from IgG3 at positions where the two isotypes differ. In some embodiments, a hybrid variant IgG antibody can be constructed that comprises one or more substitutions, e.g., 274Q, 276K, 300F, 339T, 356E, 358M, 384S, 392N, 397M, 4221, 435R, and / or 436F.

[0254] Moreover, the binding sites on human IgGl for FcyRI, FcyRII, FcyRIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R. L. et al. (2001) J. Biol. Chem. 276:6591-6604). Specific mutations at positions 256, 290, 298, 333, 334 and 339 were shown to improve binding to FcyRIII. Additionally, the following combination mutants were shown to improve FcyRIII binding: T256A / S298A, S298A / E333A, S298A / K224A and S298A / E333A / K334A, which has been shown to exhibit enhanced FcyRIIIa binding andADCC activity (Shields et al., 2001). Other IgGl variants with strongly enhanced binding to FcyRIIIa have been identified, including variants with S239D / I332E and S239D / I332E / A330L mutations Ih showed the greatest Increase in affinity for FcyRIIIa, a decrease in FcyRIIb binding, and strong cytotoxic activity in cynomolgus monkeys (Lazar et al., 2006). Introduction of the triple mutations into antibodies such as alemtuzumab (CD52-specific), trastuzumab (HER2 / neu- specific), rituximab (CD20-specific), and cetuximab (EGFR-specific) translated into greatly enhanced ADCC activity in vitro, and the S239D / I332E variant showed an enhanced capacity to deplete B cells in monkeys (Lazar et al., 2006).

[0255] In addition, IgGl mutants containing L235V, F243L, R292P, Y300L and P396L mutations which exhibited enhanced binding to FcyRIIIa and concomitantly enhanced ADCC activity in transgenic mice expressing human FcyRIIIa in models of B cell malignancies and breast cancer have been identified (Stavenhagen et al., 2007; Nordstrom et al., 2011). Other Fc mutants that can be used include: S298A / E333A / L334A, S239D / I332E, S239D / I332E / A330L, L235V / F243L / R292P / Y300L / P396L, and M428L / N434S.

[0256] In some embodiments, an Fc region described herein may have reduced binding to FcyRs. For example, the Fc region (e.g., IgGl Fc) with reduced FcyR binding may comprise the following three amino acid substitutions: L234A, L235E and G237A.

[0257] In some embodiments, an Fc region described herein may have reduced complement fixation. For example, the Fc region (e.g., IgGl Fc) with reduced complement fixation may have the following two amino acid substitutions: A33OS and P331S.

[0258] In some embodiments, an Fc region described herein may have essentially no effector function, i.e., it has reduced binding to FcyRs and reduced complement fixation. For example, an “effectorless” Fc region (e.g., IgGl Fc) may comprise the following five mutations: L234A, L235E, G237A, A33OS and P331S.

[0259] In some embodiments, an Fc region described herein may include mutations L234A and / or L235A (EU numbering), which can suppress FcgR binding, and / or a P329G mutation (EU numbering) to abolish complement Clq binding, e.g., to abolish all immune effector functions.

[0260] In some embodiments, an IgG4 Fc region described herein may include a S228P mutation, e.g., to stabilize stabilizes IgG4 molecules and suppress formation of half-antibodies. In some embodiments, an hIgG4 Fab described herein may comprise an exchange mutant sequence which may include a S228P mutation which can suppress Fab arm exchange.

[0261] In some embodiments, the Fc region may comprise a non-naturally occurring amino acid residue at additional and / or alternative positions as described in, e.g., PCT Patent Publications WO 00 / 42072; WO 01 / 58957; WO 02 / 06919; WO 04 / 016750; WO 04 / 029207; WO 04 / 035752; WO 04 / 063351; WO 04 / 074455; WO 04 / 099249; WO 05 / 040217; WO 05 / 070963; WO 05 / 092925 and WO 06 / 020114; and U.S. Pat. Nos. 5,624,821; 6,277,375; 6,737,056; 6,194,551; 7,317,091; 8,101,720; each of which is incorporated herein by reference in its entirety). Other suitable Fc modifications are described in WO 2016 / 081746 or WO 2017 / 087678, both of which are incorporated herein by reference in their entirety.

[0262] In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein is capable of:(i) improving an anti-cancer T cell response(s) upon binding to PHC3IP1 expressed on a T cell;(ii) inhibiting or antagonizing an immune suppressive function(s) of PIK3IP1 on a T cell; and / or(iii) stimulating the release of IFN-y, MCP-1, TNF, IL-2, IL-6, and / or IL- 10 from a T cell.

[0263] In some embodiments of the above-described T cell, the T cell is PD-1 and / or LAG-3 negative. In some embodiments of the above-described T cell, the T cell is a memory T cell.

[0264] In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein is capable of depleting PIK3IP1 protein from a tumor microenvironment of a subject.

[0265] In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein is capable of selectively recognizing PIK3IP1 in the tumor microenvironment (TME), that is, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein has a higher affinity to PHC3IP1 that is present in the TME than PIK3IP1 in healthy tissues. Such anti- PIK3IP1 antibodies or antigen-binding fragments thereof described herein may exhibit higher safety. Reported antibody engineering technologies may be exploited for developing such anti- PIK3IP1 antibodies or antigen-binding fragments thereof described herein.

[0266] In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein may improve anti -cancer T cell response upon binding to PIK3IP1 expressed on a T cell. In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereof described herein may inhibit or antagonize an immune suppressive function of PHC3IP1 on a T cell. In some embodiments, an anti-PIK3IPl antibody or antigen-binding fragment thereofdescribed herein may stimulate the release of one or more cytokines, such as IFN-y, MCP-1 , TNF, IL-2, IL-6, and / or IL- 10 from a T cell.Antibody-drug Conjugates

[0267] In some embodiments, the present disclosure also provides an antibody-drug conjugate comprising the antibody or antigen-binding fragment described herein conjugated to a heterologous moiety. Non-limiting examples of a heterologous moiety include a cytotoxic agent, siRNA, an antisense oligonucleotide, a radionucleotide, a lysosome-targeting chimera (LYTAC), an immune checkpoint inhibitor, a cytokine, a tumor-associated antigen (TAA)- targeting agent, and an immune agonist. In some embodiments, an antibody- drug conjugate is an immune- stimulating antibody conjugate (ISAC) or an antibody-oligonucleotide conjugate (AOC).

[0268] In some embodiments, an antibody-drug conjugate comprising the antibody or antigenbinding fragment described is conjugated to a heterologous moiety selected from an immune checkpoint inhibitor, a cytokine, a tumor-associated antigen (TAA) targeting agent, an immune agonist, a cytotoxic agent, a siRNA, and an antisense oligonucleotide.

[0269] In some embodiments, the heterologous moiety of the present disclosure is an immune checkpoint inhibitor. Exemplary immune checkpoint inhibitors include, but are not limited to, a programmed cell death protein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, lymphocyte activation gene 3 (LAG-3 or CD223) inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a cluster of differentiation 47 (CD47) inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or PD-1H) inhibitor, a T cell immunoreceptor with Ig and ITIM Domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a cluster of differentiation 93 (CD93) inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a cluster of differentiation 24 (CD24) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or BT-IgSF or IGSF11) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin like receptor 1 (LAIR-1) inhibitor, a cluster of differentiation 160 (CD 160) inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, and a vascular endothelial growth factor (VEGF) inhibitor, and any combinations thereof.

[0270] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, or a CTLA-4 inhibitor, or a combination thereof

[0271] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor or PD-L1 inhibitor. Non-limiting examples of PD-1 inhibitors or PD-L1 inhibitors include nivolumab, pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

[0272] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. Exemplary PD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, BAT 1308, acrixolimab, balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, ociperlimab, penpulimab, peresolimab,pidilizumab, pimivalimab, pradu sin Stobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tiragolumab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, zimberelimab, or a variant or any combinations thereof. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. Exemplary PD-L1 inhibitors include, but are not limited to, durvalumab, avelumab, atezolizumab, bintrafusp alfa, or a variant or any combinations thereof. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. Exemplary PD-L1 inhibitors include, but are not limited to, durvalumab, avelumab, atezolizumab, bintrafusp alfa, a variant or any combinations thereof.

[0273] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. Exemplary LAG-3 inhibitors include, but are not limited to, relatlimab (BMS-986016), ABL501, CB213, EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO- 7247669), TSR-033, tuparstobart (INCAGN02385), BGA-1953, or a variant or any combinations thereof. In certain specific embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), or a variant thereof. In certain specific embodiments, the LAG-3 inhibitor is relatlimab (BMS-986016), or a variant thereof.

[0274] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. Exemplary CTLA-4 inhibitors include, but are not limited to, ipilimumab, tremelimumab, XmAb20717, ONC-392, XmAb22841, BMS-986249, ADG116, ATOR-1015, ADG126, YH001, botensilimab, HBM4003, lorigerlimab, SLB003, AK104, KN046, quavonlimab, BNT316 / ONC- 392 (goti Stobart), porustobart (HBM4003), or a variant or combination thereof. In some embodiments, the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab, BNT316 / ONC- 392 (goti Stobart), or porustobart (HBM4003), or a variant or a combination thereof.

[0275] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor. Exemplary TIGIT inhibitors include, but are not limited to, BMS-986207, ociperlimab, BGB-A1217, tiragolumab, domvanalimab, ASP8374, vibostolimab, IBI-939, etigilimab, COM902, M6223, EOS884448, BAT6021, HLX301, or a variant or any combinations thereof.

[0276] In some embodiments, the immune checkpoint inhibitor is a SLAMF inhibitor. In some embodiments, the SLAMF inhibitor is elotuzumab or a variant thereof. In some embodiments, theimmune checkpoint inhibitor is a PVRIG inhibitor. In some embodiments, the PVRIG inhibitor is COM701, JS009, or a variant thereof. In some embodiments, the immune checkpoint inhibitor is a CD96 inhibitor. In some embodiments, the CD96 inhibitor is GSK6097608 or a variant thereof.

[0277] In some embodiments, a heterologous moiety of the present disclosure is an immune agonist. Exemplary immune agonists include, but are not limited to, a 4-1BB agonist, a 0X40 agonist, a CD40 agonist, a CD30 agonist, a GITR agonist, an ICOS agonist, a CD27 agonist, a CD28 agonist, a CD28H / TMIGD2 agonist, a NCR3 agonist, a NCR1 agonist, a NCR2 agonist, a 4-1BB agonist, a DR3 agonist, a CD226 agonist, a CRTAM agonist, a HVEM agonist, a TNFR1 agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, a TLR4 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, and any combinations thereof.

[0278] In some embodiments, the heterologous moiety of the present disclosure is a cytokine. Exemplary cytokines include, but are not limited to, interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin- 10 (IL-10), interleukin- 15 (IL-15), interleukin-21 (IL -21), IFN-a, IFN-P, IFN-y, CCL19, CCL21, interleukin- 18 (IL- 18), monocyte chemoattractant protein- 1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF), a receptor thereof, and any combinations thereof.

[0279] In some embodiments, the cytokine is IL-2, IL-6, IL-10, IL-15, IL-21, IFN-a, IFN-P, IFN-y, CCL19, CCL21, IL-18, MCP-1, TNF, GM-CSF, or G-CSF, or a receptor or a combination thereof.

[0280] In some embodiments, the heterologous moiety of the present disclosure is a TAA- targeting agent. Exemplary TAA-targeting agents include, but are not limited to, 5T4, Ang2, BCMA, CD123, CD19, CD20, CD22, CD33, CD38, CD47, CEA, CEACAM5, CEACAM6, Claudin 6, Claudin 18.2, Tie2, CLEC12A, DLL3, EGFR, EpCAM, FcRH5, FLT3, GD2, Glypican- 3, gpA33, GPRC5D, Her2, Her3, MAGE-A4, MET, MUC16, MUC17, NY-ESO-1, P-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, TROP2 (TACSTD2), VEGF, VEGFR, ybTCR, KRAS, RAF, and any combinations thereof.

[0281] In some embodiments, the TAA-targeting agent is a VEGF inhibitor, a VEGFR inhibitor, a CD20 inhibitor, a CD38 inhibitor, a TROP2 inhibitor, a KRAS inhibitor, or a RAF inhibitor.

[0282] In some embodiments, the CD20 inhibitor is rituximab. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the CD38 inhibitor is daratumumab. In some embodiments, the TROP2 inhibitor is sacituzumab govitecan.

[0283] In some embodiments the heterologous moiety of the present disclosure is an immune agonist such as, but not limited to, a CD28 agonist, an ICOS agonist, a CD28H / TMIGD2 agonist, an NCR3 agonist, an NCR1 agonist, an NCR2 agonist, a 4-1BB agonist, an 0X40 agonist, a CD30 agonist, a CD40 agonist, a DR3 agonist, a CD226 agonist, a CRT AM agonist, a CD27 agonist, an HVEM agonist, a TNFR1 agonist, a TNFR2 agonist, a CD2 agonist, a CD 7 agonist, a TLR4 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a GITR agonist, or any combinations thereof.

[0284] In some embodiments, a cytotoxic agent can include, e.g., an anti-tubulin agent, a tubulin polymerization inhibitor, a DNA synthesis inhibitor, a DNA intercalating agent, a DNA alkylating agent, a DNA cross-linking agent, a DNA cleaving agent, a platinum-based agent, topoisomerase I inhibitor, topoisomerase II inhibitor, an anti-microtubule agent, an anti-mitotic agent, a taxane- related anti-neoplastic agent, an anti-metabolite, an anti-tumor plant alkaloid, and an RNA polymerase II inhibitor.

[0285] Non-limiting examples of cytotoxic agents are doxorubicin, nemorubicin, PNU- 159682, paclitaxel, docetaxel, auristatin E, auristatin F, dolastatin 10, dolastatin 15, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), monomethyl auristatin D (MMAD), maytansine, mertansine (DM1), maytansinoid DM4, calicheamicin, N-acetyl-calicheamicin, vinblastine, vincristine, vindesine, vinorelbine, camptothecin, topotecan, irinotecan, SN-38, duocarmycin A, duocarmycin Bl, duocarmycin B2, duocarmycin CI, duocarmycin C2, duocarmycin D, duocarmycin SA, duocarmycin TM, duocarmycin MB, duocarmycin DM, mitomycin C, rachelmycin, epothilone A, epothilone B, epothilone C, tubulysin B, tubulysin M, pyrrol obenzodiazepine (PBD), bortezomib, ranpimase, hTNF, IL- 12, ranpimase, human ribonuclease (RNAse), Bovine pancreatic Rnase, pokeweed antiviral protein, Pseudomonas exotoxin A, gelonin, ricin-A, interferon-alpha, interferon-lambda, urease, amatoxin, alpha- amanitin, beta-amanitin, gamma-amanitin, epsilon- amanitin, bouganin, and staphylococcal enterotoxin.

[0286] Further non-limiting examples of cytotoxic agents are antiviral drugs (e.g., abacavir, acyclovir, ampligen, cidofovir, delavirdine, didanosine, efavirenz, entecavir, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, inosine, lopinavir, methisazone, nexavir, nevirapine, oseltamivir, penciclovir, stavudine, trifluridine, 54PG EMM, valaciclovir, and zanamivir), daunorubicin hydrochloride, daunoriycin, rubidomycin, cerubidine, idarubicin, doxorubicin,epirubicin and morpholino derivatives, phenoxizone biscyclopeptides (e.g., dactinomycin), basic glycopeptides (e.g., bleomycin), anthraquinone glycosides (e.g., plicamycin and mithramycin), anthracenediones (e.g., mitoxantrone), azirinopyrrolo indolediones (e.g., mitomycin), macrocyclic immunosuppressants (e.g., cyclosporine, FK-506, tacrolimus, prograf, and rapamycin), navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, allocolchicine, Halichondrin B, colchicine and colchicine derivatives, rhizoxin, thiocolchicine, trityl cysterin, vinblastine sulfate, hydroxyurea, N-methylhydrazine, epidophyllotoxin, procarbazine, mitoxantrone, leucovorin, and tegafur, combretatstatin, chalicheamicin, maytansine, DM-I, netropsin, podophyllotoxin (e.g., etoposide and teniposide), baccatin and its derivatives, anti-tubulin agents, cryptophysin, combretastatin, vincristine, vincristine sulfate, vinblastine, vindesine, vinorelbine, VP-16, camptothecin, epothilone A, epothilone B, nocodazole, colchicines, colcimid, estramustine, cemadotin, discodermolide, eleutherobin, mechlorethamine, cyclophosphamide, melphalan, carmustine, lomustine, semustine, streptozocin, chlorozotocin, uracil mustard, chlormethine, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, temozolomide, ytarabine, cytosine arabinoside, fluorouracil, 5 -fluorouracil (5-FU), floxuridine, 6-thioguanine, 6-mercaptopurine, pentostatin, methotrexate, 10-propargyl- 5,8-dideazafolate, 5,8-dideazatetrahydrofolic acid, leucovorin, NCA1, auristatin, auristatin E, DNA minor groove binding agents, DNA minor groove alkylating agents, enediyne, lexitropsin, duocarmycin, taxane, puromycin, dolastatin, maytansinoid, vinca alkaloid, AFP, MMAF, MMAE, AEB, AEVB, 54PG EMM (e.g., paclitaxel and paclitaxel derivatives (TAXOL*, Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (American Pharmaceutical Partners, Schaumberg, Ill.), as well as docetaxel and docetaxel derivatives), CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin- 10, echinomycin, fludarabine phosphate, pentostatine, gemcitabine, Ara-C, deoxy coformycin, mitomycins such as mitomycin-C, L-asparaginase, azathioprine, brequinar, antibiotics (e.g., anthracycline, gentamicin, cefalotin, vancomycin, telavancin, daptomycin, azithromycin, erythromycin, rocithromycin, furazolidone, amoxicillin, ampicillin, carbenicillin, flucioxacillin, methicillin, penicillin, ciprofloxacin, moxifloxacin, ofloxacin, doxycycline, minocycline, oxytetracycline, tetracycline, streptomycin, rifabutin, ethambutol, and rifaximin), enediyne antibiotics (e.g., calicheamicin, calicheamicin gammall and calicheamicin omegall, and dynemicin, including dynemicin A),. “Taxanes” include paclitaxel, as well as any active taxane derivative or pro-drug.Chemotherapeutic agents such as erlotinib (TARCEVA®, Genentech / OSI Pharm.), bortezomib (VELCADE®, Millenium Pharm.), fulvestrant (FASLODEX®, AstraZeneca), sunitinib (Sutent®, Pfizer), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), oxaliplatin (El oxatin®, Sanofi), leucovorin, lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), lonafarnib (SCH 66336), sorafenib (BAY43-9006, Bayer Labs.), and gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; antifolate antineoplastic such as pemetrexed (ALIMTA® Eli Lilly); aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (such as bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); cryptophycins (such as cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including its synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; 54PG EMM55zu; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 55PG EMM, e.g., paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ Cremophor-free, albumin, nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone- Poulenc Rorer, Antony, France); 55PG EMM55zuma; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); mitoxantrone; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, anthramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®) (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-FU; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, 56PGEMM56zum, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; losoxantrone; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- tri chlorotri ethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; and pharmaceutically acceptable salts, esters, acids, prodrugs, or derivatives of any of the above.

[0287] In some embodiments, a heterologous moiety of the present disclosure is a lysosometargeting chimera (LYTAC). In some embodiments, a LYTAC described herein may be used, e.g., to target PIK3IP1 protein for degradation (e.g., via a lysosomal-based degradation pathway). A LYTAC can target membrane proteins and extracellular proteins for degradation, such as is described by Ahn, G. et. Al., Nat Chem Biol, 17(9), 2021, 937-946 (PMID 33767387), Banik, S. M. et. Al., Nature, 584(7820), 2020, 291-297 (PMID 32728216) and Caianiello et al., Nat Chem Biol. 2021 Sep;17(9):947-953 (PMID 34413525), each of which is incorporated herein by reference in its entirety and for all purposes as if fully set forth herein. Without wishing to be bound by theory, LYTACs can bridge the extracellular domain of a target protein (e.g., PIK3IP1 protein) to a cell-surface lysosomal targeting receptor. The motif that binds the lysosomal targetingreceptor may be, e.g., without limitation, N-acetylgalactosamine (GalNAc), galactose (Gal), or mannose-6-phosphonate (M6Pn). The lysosomal targeting receptor be, e.g., without limitation, a cation-independent mannose-6-phosphate receptor (CI-M6PR) or asialoglycoprotein receptor (ASGPR). The lysosomal targeting receptor can allow for degradation of a protein (e.g., PIK3IP1 protein) in a cell type-specific manner. In some embodiments, a heterologous moiety of the present disclosure is ZNFR3. (Marei, H., Tsai, WT.K., Kee, YS. et al. Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature 610, 182-189 (2022).

[0288] In some embodiments, a heterologous moiety of the present disclosure is an oligonucleotide (e.g., siRNA or antisense oligonucleotide). In some embodiments, an oligonucleotide is described herein may be used, e.g., to silence PIK3IP1 protein.

[0289] Methods for making the antibody-drug conjugates disclosed herein is also contemplated as within the scope of this disclosure. In one aspect, provided herein is a method for making an antibody-drug conjugate described herein comprising(a) contacting the antibody or antigen-binding fragment with the heterologous moiety under the conditions favorable for conjugation of the antibody or antigen-binding fragment to the heterologous moiety; and(b) optionally, isolating the antibody-drug conjugate produced in step (a).

[0290] In order to facilitate the coupling between the heterologous moiety and the antibody, it is possible to directly conjugate the two agents, or to introduce a spacer molecule between them. Suitable spacers include poly(alkylene) glycols such as polyethylene glycol, and peptide linkers. Many suitable coupling techniques are well known in the art. Suitable agents allowing covalent, electrostatic or noncovalent binding of the moiety to the antibody include benzoquinone, carbodiimide and more particularly EDC (l-ethyl-3-[3-dimethyl-aminopropyl]-carbodiimide hydrochloride), dimaleimide, dithiobis-nitrobenzoic acid (DTNB), N-succinimidyl S-acetyl thioacetate (SATA), the bridging agents having one or more phenylazide groups reacting with the ultraviolets (U.V.) and preferably N-[-4-(azidosalicylamino)butyl]-3'-(2'-pyridyldithio)- propionamide (APDP), N-succinimid-yl 3 -(2-25 pyridyldithio)propionate (SPDP), 6-hydrazino- nicotinamide (HYNIC). Another form of coupling, especially for the radioelements, includes the use of a bifunctional ion chelator. For example, chelates derived from EDTA or DTPA which have been developed for binding metals, especially radioactive metals, and immunoglobulins. Thus,DTPA and its derivatives can be substituted by different groups on the carbon chain in order to increase the stability and the rigidity of the ligand-metal complex, as is well known in the art.

[0291] In some embodiments, conjugation of a heterologous moiety to an antibody or antigenbinding fragment described herein is carried out via the covalent-nature binding, or binding by the use of adapter molecules or linkers.

[0292] Covalent binding requires prior activation of the heterologous moieties. In some embodiments, covalent strategies occur via carbodiimide chemistry, mal eimide chemistry or “click chemistry”, as discussed in detail below.

[0293] In some embodiments, a heterologous moiety described herein is conjugated to an anti- PIK3IP1 antibody or antigen-binding fragment. In some embodiments, a heterologous moiety described herein is conjugated to an anti-PIK3IPl antibody or antigen-binding fragment directly. In some embodiments, a heterologous moiety described herein is conjugated to an anti-PIK3IPl antibody or antigen-binding fragment via a linker covalently connecting the anti-PIK3IPl antibody or antigen-binding fragment with the heterologous moiety.

[0294] In some embodiments, the heterologous moiety described herein is conjugated to the anti- PIK3IP1 antibody or antigen-binding fragment by a chemical ligation process. In some embodiments, the heterologous moiety described herein is conjugated to the anti-PIK3IPl antibody or antigen-binding fragment by a native ligation. In some embodiments, the conjugation is as described in e.g., Dawson, et al. Science 1994, 266, 776-779; Dawson, et al. J. Am. Chem. Soc. 1997, 119, 4325-4329; Hackeng, et al. Proc. Natl. Acad. Sci. USA 1999, 96, 10068-10073; or Wu, et al. Angew. Chem. Int. Ed. 2006, 45, 4116-4125, each of which is herein incorporated by reference in its entirety. In some embodiments, the conjugation is as described in U.S. Patent No. 8,936,910, which is herein incorporated by reference in its entirety. In some embodiments, the heterologous moiety described herein is conjugated to the anti -PIKA IP 1 antibody or antigenbinding fragment either site-specifically or non-specifically via native ligation chemistry.

[0295] Sortase (SrtA), a transpeptidase from Staphylococcus aureus, catalyzes a cell-wall sorting reaction at an LPXTG (SEQ ID NO: 28) motif by cleaving between threonine and glycine and subsequently joining the carboxyl group of threonine to an amino group of pentaglycine on the cell wall peptidoglycan. In some embodiments, sortase-mediated ligation may be utilized to covalently link an antibody or an antigen-binding fragment thereof according to the present disclosure comprising a sortase recognition sequence (e.g., a LPXT sequence) to a heterologousmoiety comprising a (G), sequence (see, e.g., Proft T. Sortase-mediated protein ligation: an emerging biotechnology tool for protein modification and immobilization. Biotechnol Lett. 2010, 32(1): 1-10). In one embodiment, an antibody or an antigen-binding fragment thereof according to the present disclosure comprising an LPXT motif can be specifically ligated to a linker or linkerpayload comprising an aminoglycine via an amide bond in the presence of sortase.

[0296] Subtiligase is a variant of the serine protease subtilisin BPN’ that has been engineered to catalyze a ligation reaction between a peptide ester donor substrate and the N-terminal a-amine of a peptide or protein (Abrahmsen et al., 1991). Based on its ability to catalyze peptide bond formation with absolute chemoselectivity for N-terminal a-amines over lysine a-amines, subtiligase has been utilized for both site-specific protein bioconjugation and for cellular N- terminomics studies (see, e.g., Weeks, A. M. Subtiligase-Catalyzed Peptide Ligation. Chemical Reviews 2020, 120(6): 3127-3160). In some embodiments, subtiligase-mediated ligation may be utilized to covalently link an antibody or an antigen-binding fragment thereof according to the present disclosure to a linker or linker-payload comprising an ester moiety. In one embodiment, an antibody or an antigen-binding fragment thereof according to the present disclosure can be specifically ligated to a linker or a linker-payload comprising an ester moiety via an amide bond in the presence of subtiligase.

[0297] In some embodiments, the heterologous moiety described herein is conjugated to the anti- PIK3IP1 antibody or antigen-binding fragment by a site-directed method utilizing an enzyme- catalyzed process. In some embodiments, the site-directed method utilizes SMARTagTM technology (Catalent, Inc.). In some embodiments, the SMARTagTM technology comprises generation of a formylglycine (Fgly) residue from cysteine by formylglycine-generating enzyme (FGE) through an oxidation process under the presence of an aldehyde tag and the subsequent conjugation of Fgly to an alkylhydraine-functionalized heterologous moiety described herein (e.g., a cytotoxic agent) via 59PG EMM59z-Pictet-Spengler (HIPS) ligation. (See Wu et al., PNAS 106(9): 3000-3005 (2009); Agarwal, et al., PNAS 110(1): 46-51 (2013), each of which is herein incorporated by reference in its entirety).

[0298] In some embodiments, the heterologous moiety described herein is conjugated to the anti- PIK3IP1 antibody or antigen-binding fragment by a site-directed method utilizing a “traceless” coupling technology (Philochem). In some embodiments, the “traceless” coupling technology utilizes an N-terminal 1,2-aminothiol group on the anti-PIK3IPl antibody or antigen -bindingfragment which is then conjugated with a heterologous moiety described herein (e.g., a cytotoxic agent) containing an aldehyde group. (See Casi et al., JACS 134(13): 5887-5892 (2012), which is herein incorporated by reference in its entirety).

[0299] In some embodiments, the heterologous moiety described herein is conjugated to the anti- PIK3IP1 antibody or antigen-binding fragment by a site-directed method utilizing an unnatural amino acid incorporated into the anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, the unnatural amino acid comprises p-acetylphenylalanine (pAcPhe). In some embodiments, the keto group of pAcPhe is selectively coupled to an alkoxy-amine derivatized conjugating moiety to form an oxime bond. (See Axup et al., PNAS 109(40): 16101-16106 (2012), which is herein incorporated by reference in its entirety).

[0300] In some embodiments, the enzyme-catalyzed process comprises transglutaminase (TG), e g., microbial transglutaminase (mTG). In some cases, the heterologous moiety described herein (e.g., a cytotoxic agent) is conjugated to the anti-PIK3IPl antibody or antigen-binding fragment utilizing a microbial transglutaminase-catalyzed process. In some embodiments, mTG catalyzes the formation of a covalent bond between the amide side chain of a glutamine within the recognition sequence and a primary amine of a functionalized heterologous moiety described herein (In some embodiments, mTG is produced from Streptomyces mobarensis. (See Strop et al., Chemistry and Biology 20(2) 161-167 (2013), which is herein incorporated by reference in its entirety).

[0301] In some embodiments, a sequence of amino acids comprising an acceptor glutamine residue are incorporated into (e.g., appended to) a polypeptide sequence, under suitable conditions, for recognition by a TG. This sequence leads to cross-linking by the TG through a reaction between an amino acid side chain within the sequence of amino acids and a reaction partner. The recognition tag may be a peptide sequence that is not naturally present in the polypeptide comprising the TG recognition tag. In some embodiments, the TG recognition tag comprises at least one Gin.

[0302] In some embodiments, the TGase recognition tag comprises an amino acid sequence XXQX, wherein X is any amino acid (e.g., conventional amino acid Leu, Ala, Gly, Ser, Vai, Phe, Tyr, His, Arg, Asn, Glu, Asp, Cys, Gin, He, Met, Pro, Thr, Lys, or Trp or nonconventional amino acid). In some embodiments, the acyl donor glutamine-containing tag comprises an amino acid sequence selected from the group consisting of LLQ, LLQG (SEQ ID NO: 29), LLQGG (SEQ IDNO: 30), LSLSQG (SEQ ID NO: 31), GGGLLQGG (SEQ ID NO: 32), GLLQ (SEQ ID NO: 33), GLLQG (SEQ ID NO: 34), GLLQGGG (SEQ ID NO: 35), GLLQGG (SEQ ID NO: 36), GSPLAQSHGG (SEQ ID NO: 37), LLQLLQGA (SEQ ID NO: 38), LLQGA (SEQ ID NO: 39), LLQYQGA (SEQ ID NO: 40), LLQGSG (SEQ ID NO: 41), LLQYQG (SEQ ID NO: 42), LLQLLQG (SEQ ID NO: 43), SLLQG (SEQ ID NO: 44), LLQLQ (SEQ ID NO: 45), LLQLLQ (SEQ ID NO: 46), and LLQGR (SEQ ID NO: 47). See, e.g., PCT Publication No. WO20 12 / 059882, which is herein incorporated by reference in its entirety. In some embodiments, the acyl donor glutamine-containing tag is present at the N-terminus of the antibody or antigenbinding fragment. In some embodiments, the acyl donor glutamine-containing tag is present at the C-terminus of the antibody or antigen-binding fragment. In some embodiments, the acyl donor glutamine-containing tag is present both at the N-terminus and the C-terminus of the antibody or antigen-binding fragment.

[0303] In some embodiments, the heterologous moiety described herein (e.g., a cytotoxic agent) is conjugated to the anti-PIK3IPl antibody or antigen-binding fragment by a method which utilizes a sequence-specific transpeptidase (see, e.g., PCT Publication No. W02014 / 140317, which is herein incorporated by reference in its entirety). Other conjugation methods include those described in U.S. Patent Publication Nos. 2015 / 0105539 and 2015 / 0105540, each of which is herein incorporated by reference in its entirety.

[0304] In some embodiments, the heterologous moiety described herein (e.g., a cytotoxic agent) is conjugated to the anti-PIK3IPl antibody or antigen-binding fragment utilizing Azide-Alkyne Cycloaddition (CuAAC) click chemistry. Azides and alkynes can undergo catalyst free [3+2] cycloaddition by a using the reaction of activated alkynes with azides. Such catalyst-free [3+2] cycloaddition can be used in the methods described herein to conjugate an anti-PIK3IPl antibody or antigen-binding fragment and the heterologous moiety described herein (e.g., a cytotoxic agent). Alkynes can be activated by ring strain such as, by way of example only, eight-membered ring structures, or nine-membered, appending electron-withdrawing groups to such alkyne rings, or alkynes can be activated by the addition of a Lewis acid such as, by way of example only, Au(I) or Au(III).

[0305] Alkynes activated by ring strain have been described and used in “copperless” [3+2] cycloaddition. Non-limiting examples include cyclooctynes and difluorocyclooctynes (Agard et al., J. Am. Chem. Soc., 126 (46): 15046-15047 (2004)), dibenzocyclooctynes (PCT InternationalPublication No. WO 2009 / 067663 Al (2009)), aza-dibenzocyclooctynes (Debets et al., Chem. Comm., 46:97-99 (2010)), and cyclononynes (Dommerholt et al., Angew. Chem. 122:9612-9615 (2010)). In some embodiments, a tetrazine (Tzn)-activated anti-PIK3IPl antibody or antigenbinding fragment may be cross-linked to a trans-cyclooctene (TCO)-activated heterologous moiety described herein (e.g., a cytotoxic agent). In some embodiments, a TCO-activated anti-PIK3IPl antibody or antigen-binding fragment may be crosslinked to a Tzn-activated heterologous moiety described herein (e.g., a cytotoxic agent).

[0306] Complexes described herein may comprise a linker that connects an antibody or antigenbinding fragment to a heterologous moiety (e.g., a cytotoxic agent). A linker comprises at least one covalent bond. In some embodiments, a linker may be a single bond, e.g., a disulfide bond or disulfide bridge, that connects an antibody or antigen-binding fragment to a heterologous moiety (e.g., a cytotoxic agent). However, in some embodiments, a linker may connect an antibody or antigen-binding fragment to a heterologous moiety (e.g., a cytotoxic agent) through multiple covalent bonds. A linker is generally stable in vitro and in vivo, and may be stable in certain cellular environments. Additionally, generally a linker does not negatively impact the functional properties of either the antibody or antigen-binding fragment or the heterologous moiety (e.g., a cytotoxic agent).

[0307] A precursor to a linker typically will contain two different reactive species that allow for attachment to both the antibody or antigen-binding fragment and a heterologous moiety (e.g., a cytotoxic agent. In some embodiments, the two different reactive species may be a nucleophile and / or an electrophile. In some embodiments, a linker is connected to an antibody or antigenbinding fragment via conjugation to a lysine residue or a cysteine residue of the antibody or antigen-binding fragment. In some embodiments, a linker is connected to a cysteine residue of an antibody or antigen-binding fragment via a maleimide-containing linker, wherein optionally the maleimide-containing linker comprises a maleimidocaproyl or maleimidomethyl cyclohexane- 1 - carboxylate group. In some embodiments, a linker is connected to a cysteine residue of an antibody or antigen-binding fragment or thiol functionalized heterologous moiety via a 3 -arylpropionitrile functional group. In some embodiments, a linker is connected to an antibody or antigen-binding fragment and / or a heterologous moiety (e.g., a cytotoxic agent) via an amide bond, a hydrazide, a triazole, a thioether or a disulfide bond.

[0308] In some embodiments, a linker described herein is a cleavable linker or a non-cleavable linker. In some embodiments, the linker is a cleavable linker. In other embodiments, the linker is a non-cleavable linker.

[0309] A cleavable linker may be a protease-sensitive linker, a pH-sensitive linker, or a glutathione-sensitive linker. These linkers are generally cleavable only intracellularly and are preferably stable in extracellular environments.

[0310] Protease-sensitive linkers are cleavable by protease enzymatic activity. These linkers typically comprise peptide sequences and may be 2-10 amino acids, about 2-5 amino acids, about 5-10 amino acids, about 10 amino acids, about 5 amino acids, about 3 amino acids, or about 2 amino acids in length. In some embodiments, a peptide sequence may comprise naturally- occurring amino acids, e.g. cysteine, alanine, or non-naturally-occurring or modified amino acids. Non-naturally occurring amino acids include 3-amino acids, homo-amino acids, proline derivatives, 3-substituted alanine derivatives, linear core amino acids, N-methyl amino acids, and others known in the art. In some embodiments, a protease-sensitive linker comprises a valinecitrulline or alanine-citrulline dipeptide sequence. In some embodiments, a protease-sensitive linker can be cleaved by a lysosomal protease, e.g. cathepsin B, and / or an endosomal protease.

[0311] A pH-sensitive linker is a covalent linkage that readily degrades in high or low pH environments. In some embodiments, a pH-sensitive linker may be cleaved at a pH in a range of 4 to 6. In some embodiments, a pH-sensitive linker comprises a hydrazone or cyclic acetal. In some embodiments, a pH-sensitive linker is cleaved within an endosome or a lysosome.

[0312] In some embodiments, a glutathione-sensitive linker comprises a disulfide moiety. In some embodiments, a glutathione-sensitive linker is cleaved by a disulfide exchange reaction with a glutathione species inside a cell. In some embodiments, the disulfide moiety further comprises at least one amino acid, e.g. a cysteine residue.

[0313] In some embodiments, non-cleavable linkers may be used. Generally, a non-cleavable linker cannot be readily degraded in a cellular or physiological environment. In some embodiments, a non-cleavable linker comprises an optionally substituted alkyl group, wherein the substitutions may include halogens, hydroxyl groups, oxygen species, and other common substitutions. In some embodiments, a linker may comprise an optionally substituted alkyl, an optionally substituted alkylene, an optionally substituted arylene, a heteroarylene, a peptide sequence comprising at least one non-natural amino acid, a truncated glycan, a sugar or sugars that’llcannot be enzymatically degraded, an azide, an alkyneazide, a peptide sequence comprising a LPXT sequence, a thioether, a biotin, a biphenyl, repeating units of polyethylene glycol or equivalent compounds, acid esters, acid amides, sulfamides, and / or an alkoxy-amine linker.

[0314] In some embodiments, a linker may comprise a substituted alkylene, an optionally substituted alkenylene, an optionally substituted alkynylene, an optionally substituted cycloalkylene, an optionally substituted cycloalkenylene, an optionally substituted arylene, an optionally substituted heteroarylene further comprising at least one heteroatom selected from N, O, and S; an optionally substituted heterocyclylene further comprising at least one heteroatom selected from N, O, and S; an imino, an optionally substituted nitrogen species, an optionally substituted oxygen species, an optionally substituted sulfur species, or a poly(alkylene oxide), e.g. polyethylene oxide or polypropylene oxide.

[0315] In some cases, the linker is a non-polymeric linker. A non-polymeric linker refers to a linker that does not contain a repeating unit of monomers generated by a polymerization process. Exemplary non-polymeric linkers include, but are not limited to, C1-C30 alkyl group (e.g., a C5, C4, C3, C2, or Cl alkyl group), homobifunctional cross linkers, heterobifunctional cross linkers, peptide linkers, traceless linkers, self-immolative linkers, maleimide-based linkers, or combinations thereof. In some cases, the non-polymeric linker comprises a C1-C30 alkyl group (e.g., a C5, C4, C3, C2, or Cl alkyl group), a homobifunctional cross linker, a heterobifunctional cross linker, a peptide linker, a traceless linker, a self-immolative linker, a maleimide-based linker, or a combination thereof. In additional cases, the non-polymeric linker does not comprise more than two of the same type of linkers, e.g., more than two homobifunctional cross linkers, or more than two peptide linkers. In further cases, the non-polymeric linker optionally comprises one or more reactive functional groups. In some cases, the non-polymeric linker does not encompass a polyalkylene oxide (e.g., PEG). In some cases, the non-polymeric linker does not encompass a PEG.

[0316] In some embodiments, the linker comprises a homobifunctional linker. Exemplary homobifunctional linkers include, but are not limited to, bis(sulfosuccinimidyl)suberate (BS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo DST), ethylene glycobis(succinimidylsuccinate) (EGS), disuccinimidyl glutarate (DSG), N,N’-disuccinimidyl carbonate (DSC), dimethyl adipimidate (DMA), dimethyl pimelimidate (DMP), dimethyl suberimidate (DMS), dimethyl-3, 3’ -dithiobi spropionimidate (DTBP), l,4-di-3’-(2’-pyridyldithio)propionamido) butane (DPDPB), bismaleimidohexane (BMH), aryl halide- containing compound (DFDNB), such as e.g. l,5-difluoro-2,4-dinitrobenzene or l,3-difluoro-4,6- dinitrobenzene, 4,4’-difluoro-3,3’-dinitrophenylsulfone (DFDNPS), bis-113-(4- azidosalicylamido)ethyl]disulfide (BASED), organoazide, organoalkyne, Lomant’s reagent dithiobis (succinimidylpropionate) DSP, 3’3’-dithiobis(sulfosuccinimidyl proprionate (DTSSP), disuccinimidyl suberate (DSS), formaldehyde, glutaraldehyde, 1,4-butanediol diglycidyl ether, adipic acid dihydrazide, carbohydrazide, o-toluidine, 3,3 ’-dimethylbenzidine, benzidine, a,a’-p- diaminodiphenyl, diiodo-p-xylene sulfonic acid, N,N’-ethylene-bis(iodoacetamide), or N,N’- hexamethylene-bis(iodoacetamide).

[0317] In some embodiments, the linker comprises a heterobifunctional linker. Non-limiting examples of heterobifunctional linker include carbonyl-reactive and sulfhydrylreactive crosslinkers such as 4-(4-N-maleimidophenyl) butyric acid hydrazide (MPBH), 4-(N- maleimidom ethyl) cyclohexane-l-carboxyl-hydrazide-8 (M2C2H), 3 -(2- pyridyldithio)propionyl hydrazide (PDPH), amine-reactive and sulfhydryl cross-linkers such as N-succinimidyl 3-(2- pyridyldithio) propionate (sPDP), long-chain N-succinimidyl 3-(2-pyridyldithio) propionate (LC- sPDP), water-soluble-long-chain N-succinimidyl 3 -(2 -pyridyldithio) propionate (sulfo-LCsPDP), succinimidyloxycarbonyl-a-methyl-a-(2-pyridyldithio) toluene (sMPT), sulfosuccinimidyl-6-[a- methyl-a-(2-pyridyldithio)toluamido]hexanoate (sulfo-LC-sMPT), succinimidy 1 -4-(N- maleimidomethyl) cyclohexane-l-car-boxylate (sMCC), sulfosuccinimidyl-4-(N- maleimidomethyl) cyclohexane- 1 -carboxylate (sulfo-sMCC), m-maleimidobenzoyl-N- hydroxysuccinimide ester (MBs), m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sulfo- MB s), N-succinimidyl (4-iodoacteyl)aminobenzoate (sIAB), sulfosuccinimidyl (4- iodoacteyl)aminobenzoate (sulfo-sIAB), succinimidyl-4-(p-maleimidophenyl)butyrate (sMPB), sulfosuccinimidyl-4-(p-maleimidophenyl)butyrate (sulfo-sMPB), N-(y- maleimidobutyryloxy)succinimide ester (GMBs), N-(y-maleimidobutyryloxy)sulfosuccinimide ester (sulfo-GMBs), succinimidyl 6-((iodoacetyl)amino)hexanoate (sIAX), succinimidyl 6-[6- (((iodoacetyl)amino) hexanoyl)amino]hexanoate (sIAXX), succinimidyl 4-(((iodoacetyl) amino)methyl)cyclohexane-l-carboxylate (sIAC), succinimidyl 6-((((4- iodoacetyl)amino)methyl)cyclohexane-l -carbonyl)amino) hexanoate (sIACX), p-nitrophenyl iodoacetate (NPIA), amine-reactive and photoreactive cross-linkers such as N- hydroxysuccinimidyl-4-azidosalicylic acid (NHs-AsA), N-hydroxysulfosuccinimidyl-4-azidosalicylic acid (sulfo-NHs-AsA), sulfosuccinimidyl-(4-azidosalicylamido)hexanoate (sulfo- NHs-LC-AsA), sulfosuccinimidyl-2-(p-azidosalicylamido)ethyl 1,3 ’-di thiopropionate (sAsD), N- hydroxysuccinimidyl-4-azidobenzoate (HsAB), N-hydroxysulfosuccinimidyl-4-azidobenzoate (sulfo-HsAB), N-succinimidyl-6-(4’-azido2’-nitrophenylamino)hexanoate (sANPAH), sulfo succinimidyl- 6- (4’ -azido-2’-nitrophenylamino)hexanoate (sulfo-sANPAH), N-5-azido-2- nitrobenzoyloxy succinimide (ANB-NOs), sulfosuccinimidy 1 -2-(m-azido-o-nitrobenzamido)- ethyl-1 ,3 ’-dithiopropionate (sAND), N-succinimidyl-4(4-azidopheny 1)1,3’ -dithiopropi onate (sADP), N-sulfosuccinimidyl(4-azidophenyl)-l, 3 ’-di thiopropionate (sulfo-sADP), sulfosuccinimidyl 4-(p-azidophenyl) butyrate (sulfo-sAPB), sulfosuccinimidyl 2-(7-azido-4- methylcoumarin-3-acetamide)ethyl-l,3’-dithiopropionate (sAED), sulfosuccinimidyl 7-azido-4- methylcoumain-3 -acetate (sulfo-sAMCA), p-nitrophenyl diazopyruvate (pNPDP), p-nitrophenyl- 2-diazo-3,3,3-trifluoropropionate (PNP-DTP), carboxylate-reactive and photoreactive crosslinkers such as 4-(p-azidosalicylamido) butylamine (AsBA), and arginine-reactive and photoreactive cross-linkers such as p-azidophenyl glyoxal (APG); sulfhydryl-reactive and photoreactive crosslinkers such as l-(p-Azidosalicylamido)-4-(iodoacetamido) butane (AsIB), N- [4-(p-azidosalicylamido)butyl]-3’-(2’-pyridyldithio)propionamide (APDP), benzophenone-4- iodoacetamide, benzophenone-4-mal eimide carbonylreactive and photoreactive cross-linkers such as p-azidobenzoyl hydrazide (ABH).

[0318] In some embodiments, the linker comprises a reactive functional group. In some cases, the reactive functional group comprises a nucleophilic group that is reactive to an electrophilic group present on an anti-PIK3IPl antibody or antigen-binding fragment. Exemplary electrophilic groups include carbonyl groups such as aldehyde, ketone, carboxylic acid, ester, amide, enone, acyl halide or acid anhydride. In some embodiments, the reactive functional group is aldehyde. Exemplary nucleophilic groups include hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.

[0319] In some embodiments, the linker comprises a maleimide group. In some embodiments, the maleimide group is also referred to as a maleimide spacer. In some embodiments, the maleimide group further encompasses a caproic acid, forming maleimidocaproyl (me). In some cases, the linker comprises maleimidocaproyl (me). In some cases, the linker is maleimidocaproyl (me). In other embodiments, the maleimide group comprises a maleimidomethyl group, such assuccinimidyl-4-(N-maleimidomethyl)cyclohexane-l-carboxylate (sMCC) or sulfosuccinimidyl - 4-(N-maleimidomethyl)cyclohexane-l -carboxylate (sulfo-sMCC) described above.

[0320] In some embodiments, the maleimide group is a self-stabilizing maleimide. In some embodiments, the self-stabilizing maleimide utilizes di ami nopropionic acid (DPR) to incorporate a basic amino group adjacent to the maleimide to provide intramolecular catalysis of tiosuccinimide ring hydrolysis, thereby eliminating maleimide from undergoing an elimination reaction through a retro-Michael reaction. In some embodiments, the self-stabilizing maleimide is a maleimide group described in Lyon, et al., Nat. Biotechnol. 32(10): 1059-1062 (2014). In some embodiments, the linker comprises a self-stabilizing maleimide. In some embodiments, the linker is a self-stabilizing maleimide.

[0321] In some embodiments, the linker is a traceless linker or a linker in which after cleavage does not leave behind a linker moiety (e g., an atom or a linker group) to an anti-PIK3IPl antibody or antigen-binding fragment or a polynucleotide B. Exemplary traceless linkers include, but are not limited to, aryl-triazene linkers, germanium linkers, silicium linkers, sulfur linkers, selenium linkers, nitrogen linkers, phosphorus linkers, boron linkers, chromium linkers, or phenylhydrazide linker. In some embodiments, the linker is a traceless linker described in Blaney, et al., Chem. Rev. 102: 2607-2024 (2002) or U.S. Patent No. 6,821,783.

[0322] In some embodiments, the linker is a linker described in U.S. Pat. Nos. 6,884,869; 7,498,298; 8,288,352; 8,609,105; or 8,697,688; U.S. Patent Publication Nos. US2014 / 0127239; US2013 / 028919; US2014 / 286970; US2013 / 0309256; US2015 / 037360; and US2014 / 0294851; or International Application Publication Nos. WO2015 / 057699; W02014 / 080251;WO2014 / 197854; W02014 / 145090; WO2014 / 177042, W02022 / 015656, each of which is herein incorporated by reference in its entirety.

[0323] In some embodiments, a linker is absent. In some cases, a linker is a non-polymeric linker. In some cases, a linker is a polymeric linker.

[0324] In some embodiments, the linker comprises an alkyl group. In some embodiments, the linker comprises a C1-C30 alkyl group, or a C1-C24 alkyl group, or a C1-C20 alkyl group, or a C1-C16 alkyl group, or a C1-C12 alkyl group, or a C1-C10 alkyl group, or a C1-C8 alkyl group, or a C1-C6 alkyl group, or a C1-C4 alkyl group. In some cases, a linker is a C1-C6 alkyl group, such as for example, a C3, C4, C3, C2, or Cl alkyl group. In some cases, the C1-C6 alkyl group is an unsubstituted C1-C6 alkyl group. As used in the context of a linker, alkyl means a saturatedstraight or branched hydrocarbon radical containing up to six carbon atoms. In some embodiments, the linker comprises a homobifunctional linker or a heterobifunctional linker described herein.[003251 In some cases, a linker is an oligomeric or a polymeric linker. In some embodiments, a linker is a natural or synthetic oligomer or polymer, consisting of branched or unbranched monomers, and / or cross-linked network of monomers in two or three dimensions. In some embodiments, the linker comprises a polysaccharide, lignin, rubber, or polyalkylen oxide (e.g., polyethylene glycol).

[0326] In some embodiments, polymeric linker includes, but is not limited to, alpha-, omega- dihydroxylpolyethyleneglycol, biodegradable lactone-based polymer, e.g. polyacrylic acid, polylactide acid (PLA), poly(glycolic acid) (PGA), polypropylene, polystyrene, polyolefin, polyamide, polycyanoacrylate, polyimide, polyethylene terephthalate (also known as poly(ethylene terephthalate), PET, PETG, or PETE), polytetramethylene glycol (PTG), or polyurethane as well as mixtures thereof. In some embodiments, the linker comprises polyalkylene oxide. In some embodiments, the linker comprises PEG. In some embodiments, the linker comprises polyethylene imide (PEI) or hydroxy ethyl starch (HES).

[0327] In some embodiments, the linker comprises a polyalkylene oxide (e.g., PEG) comprising discrete ethylene oxide units. In some cases, the linker comprises between about 2 and about 48 ethylene oxide units. In some cases, the polymer linker comprises about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 24, about 30, about 36, about 42, or about 48 ethylene oxide units.

[0328] In some embodiments, the anti-PIK3IPl antibody or antigen-binding fragment is conjugated to the heterologous moiety described herein (e.g., a cytotoxic agent) using a protamine linker (see, e.g., U.S. Patent Application Publication Nos. US2002 / 0132990, US2004 / 0023902, US2007 / 012152, and US2010 / 0209440, each of which is herein incorporated by reference in its entirety). In some embodiments, a protamine linker encompassed for use in the antibody-drug conjugates described herein comprises a sequence disclosed in US 2010 / 0209440, which is herein incorporated by reference in its entirety.

[0329] Acid cleavable linkers can also be used in the antibody-drug conjugates described herein and include, but are not limited to, bismaleimideothoxy propane, adipic acid dihydrazide linkers and acid labile transferrin conjugates that contain a sufficient portion of transferrin to permit entryinto the intracellular transferrin cycling pathway. Conjugates linked via acid cleavable linkers should be preferentially cleaved in acidic intracellular compartments, such as the endosome.

[0330] Photocleavable linkers can also be used with in the antibody-drug conjugates described herein. Photocleavable linkers are cleaved upon exposure to light, thereby releasing the targeted agent upon exposure to light. Example photocleavable linkers may comprise nitrobenzyl group as a photocleavable protective group for cysteine; water soluble photocleavable copolymers, including hydroxypropylmethacrylamide copolymer, glycine copolymer, fluorescein copolymer and methylrhodamine copolymer; and nitrobenzyloxy carbonyl chloride cross linking reagents that produce photocleavable linkages. Such linkers are particularly useful in treating dermatological or ophthalmic conditions. In addition, other tissues, such as blood vessels that can be exposed to light using fiber-optics during angioplasty in the prevention or treatment of restenosis may benefit from the use of photocleavable linkers. After administration of the conjugate, the body part is exposed to light, resulting in release of the targeted moiety from the conjugate. Heat sensitive linkers would also have similar applicability.

[0331] In some embodiments, antibodies can be conjugated or recombinantly fused to a diagnostic, detectable or therapeutic agent or any other molecule. The conjugated or recombinantly fused antibodies can be useful, e.g., for monitoring or prognosing the onset, development, progression and / or severity of a disease as part of a clinical testing procedure, such as determining the efficacy of a particular therapy. Such diagnosis and detection can be accomplished by coupling the antibody to detectable substances including, but not limited to, various enzymes, such as, but not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; prosthetic groups, such as, but not limited to, streptavidin / biotin and avidin / biotin; fluorescent materials, such as, but not limited to, umbelliferone, fluorescein, fluorescein isothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; luminescent materials, such as, but not limited to, luminol; bioluminescent materials, such as but not limited to, luciferase, luciferin, and aequorin; radioactive materials, such as, but not limited to, iodine (1311, 1251, 1231, and 1211,), carbon (14C), sulfur (35 S), tritium (3H), indium (115In, 113In, 112In, and l l lln,), technetium (99Tc), thallium (201Ti), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 187Re, 142Pr, 105Rh, 97Ru, 68Ge, 57Co, 65Zn, 85Sr, 32P, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, and 117Sn; and positronemitting metals using various positron emission tomographies, and non-radioactive paramagnetic metal ions.

[0332] Encompassed herein are antibodies recombinantly fused or chemically conjugated (including both covalent and non-covalent conjugations) to a heterologous protein or polypeptide (or fragment thereof, preferably to a polypeptide of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100 amino acids) to generate fusion proteins. In particular, provided herein are fusion proteins comprising an antigen-binding fragment of a monoclonal antibody (e.g., a Fab fragment, Fd fragment, Fv fragment, F(ab)2 fragment, a VH domain, a 68PG EM, a VL domain or a VL CDR) and a heterologous protein, polypeptide, or peptide. In a specific embodiment, the heterologous protein, polypeptide, or peptide that the antibody is fused to is useful for targeting the antibody to a particular cell type.

[0333] In one embodiment, a fusion protein provided herein comprises an anti-PIK3IPl antibody described herein, or an antigen-binding fragment thereof, and a heterologous polypeptide. In another embodiment, a fusion protein provided herein comprises one, two, or more VH domains having the amino acid sequence of any one of the VH domains of an anti-PIK3IPl antibody described herein or one or more VL domains having the amino acid sequence of any one of the VL domains of an anti-PIK3IPl antibody described herein and a heterologous polypeptide. In another embodiment, a fusion protein provided herein comprises one, two, or more VH CDRs having the amino acid sequence of any one of the VH CDRs of an anti-PIK3IPl antibody described herein and a heterologous polypeptide. In another embodiment, a fusion protein comprises one, two, or more 68PG EMM having the amino acid sequence of any one of the 68PG EMM of an anti-PIK3IPl antibody described herein and a heterologous polypeptide. In another embodiment, a fusion protein provided herein comprises at least one VH domain and at least one VL domain of an anti-PIK3IPl antibody described herein and a heterologous polypeptide. In yet another embodiment, a fusion protein provided herein comprises at least one 68PG EM and at least one VL CDR of an anti-PIK3IPl antibody described herein and a heterologous polypeptide. In certain embodiments, the above-referenced antibodies comprise a modified IgG (e.g., IgGl) constant domain, or FcRn binding fragment thereof (e.g., the Fc domain or hinge-Fc domain), described herein.

[0334] Moreover, antibodies can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide(SEQ ID NO: 48) (z.e., His-tag), such as the tag provided in a pQE vector (QIAGEN, Inc.), among others, many of which are commercially available. As described in Gentz et al., 1989, Proc. Natl. Acad. Sci. USA 86:821-824, for instance, hexa-histidine (SEQ ID NO: 49) provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the hemagglutinin (“HA”) tag, which corresponds to an epitope derived from the Influenza hemagglutinin protein (Wilson et al., 1984, Cell 37:767), and the “flag” tag.

[0335] Methods for fusing or conjugating therapeutic moieties (including polypeptides) to antibodies are well known, see, e.g., Amon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in Monoclonal Antibodies 84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), Thorpe et al., 1982, Immunol. Rev. 62: 119-58; — C — U.S. Pat. Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, 5,723,125, 5,783,181, 5,908,626, 5,844,095, and 5,112,946; EP 307,434; EP 367,166; EP 394,827; PCT publications WO 91 / 06570, WO 96 / 04388, WO 96 / 22024, WO 97 / 34631, and WO 99 / 04813; Ashkenazi et al., Proc. Natl. Acad. Sci. USA, 88: 10535-10539, 1991; Traunecker et al., Nature, 331 :84-86, 1988; Zheng et al., J. Immunol., 154:5590-5600, 1995; Vil et al., Proc. Natl. Acad. Sci. USA, 89: 11337- 11341, 1992; which are incorporated herein by reference in their entireties.

[0336] In particular, fusion proteins may be generated, for example, through the techniques of gene-shuffling, motif-shuffling, exon-shuffling, and / or codon-shuffling (collectively referred to as “DNA shuffling”). DNA shuffling may be employed to alter the activities of the monoclonal antibodies described herein or generated in accordance with the methods provided herein (e.g., antibodies with higher affinities and lower dissociation rates). See, e.g., U.S. Pat. Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten et al., 1997, Curr. Opinion Biotechnol. 8:724-33; Harayama, 1998, Trends Biotechnol. 16(2):76-82; Hansson, et al., 1999, J. Mol. Biol. 287:265-76; and Lorenzo and Blasco, 1998, Biotechniques 24(2):308-313 (each of these patents and publications are hereby incorporated by reference in its entirety). Antibodies, or the encodedantibodies, may be altered by being subjected to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. A polynucleotide encoding a monoclonal antibody described herein or generated in accordance with the methods provided herein may be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.

[0337] An antibody can also be conjugated to a second antibody to form an antibody heteroconjugate as described in U.S. Pat. No. 4,676,980, which is incorporated herein by reference in its entirety.

[0338] An antibody can also be linked directly or indirectly to one or more antibodies to produce bispecific / multispecific antibodies.

[0339] An antibody can also be attached to solid supports, which are particularly useful for immunoassays or purification of an antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.

[0340] In some embodiments, one or more heterologous moieties is conjugated to an anti- PIK3IP1 antibody or antigen-binding fragment. In some embodiments, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 20, 24, 30, 36 or more heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 1 heterologous moiety is conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 2 heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 3 heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 4 heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 5 heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 6 heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigenbinding fragment. In some embodiments, 7 heterologous moieties are conjugated to one anti- PIK3IP1 antibody or antigen-binding fragment. In some embodiments, 8 heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 9 heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment. In some embodiments, 10 or more heterologous moieties are conjugated to one anti-PIK3IPl antibody or antigen-binding fragment.Polynucleotides and Vectors

[0341] In one aspect, the present disclosure provides one or more polynucleotides encoding an antibody or antigen-binding fragment as described herein. The isolated polynucleotides capable of encoding the variable domain segments provided herein may be included on the same, or different, vectors to produce antibodies or antigen-binding fragments.

[0342] In some embodiments, an isolated polynucleotide encoding an anti-PIK3IPl antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 1, 9, or 17, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a nucleotide sequence encoding a VL amino acid sequence of SEQ ID NO: 5, 13, or 21, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.

[0343] In some embodiments, an isolated polynucleotide encoding an anti-PIK3IPl antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 1, 9, or 17; and / or a nucleotide sequence encoding a VL amino acid sequence of SEQ ID NO: 5, 13, or 21.

[0344] In some embodiments, an isolated polynucleotide encoding an anti-PIK3IPl antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 1, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a nucleotide sequence encoding a VL amino acid sequence of SEQ ID NO: 5, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.

[0345] In some embodiments, an isolated polynucleotide encoding an anti- PIK3IP1 antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 1; and a nucleotide sequence encoding a VL amino acid sequence of SEQ ID NO: 5.

[0346] In some embodiments, an isolated polynucleotide encoding an anti-PIK3IPl antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 9, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a nucleotide sequenceencoding a VL amino acid sequence of SEQ ID NO: 13, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.

[0347] In some embodiments, an isolated polynucleotide encoding an anti-PIK3IPl antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 9; and a nucleotide sequence encoding a VL amino acid sequence of SEQ ID NO: 13.

[0348] In some embodiments, an isolated polynucleotide encoding an anti-PIK3IPl antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 17, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto; and / or a nucleotide sequence encoding a VL amino acid sequence of SEQ ID NO: 21, or a sequence having at least 70%, 75%, 80%, 85%, 90%, preferably 95% or more, such as 95%, 96%, 97%, 98%, or 99% identity thereto.

[0349] In some embodiments, an isolated polynucleotide encoding an anti-PIK3IPl antibody or antigen-binding fragment comprises a nucleotide sequence encoding a VH amino acid sequence of SEQ ID NO: 17; and a nucleotide sequence encoding a VL amino acid sequence of SEQ ID NO: 21.

[0350] In some embodiments, the polynucleotide is a DNA molecule or a derivative thereof.

[0351] In some embodiments, the polynucleotide is an RNA molecule (e.g., mRNA) or a derivative thereof.

[0352] Also provided are vectors comprising the polynucleotides described herein. The vectors can be expression vectors. Recombinant expression vectors containing a sequence encoding a polypeptide of interest are thus contemplated as within the scope of this disclosure. The expression vector may contain one or more additional sequences such as but not limited to regulatory sequences (e g., promoter, enhancer), a selection marker, and a polyadenylation signal. Vectors for transforming a wide variety of host cells are well known and include, but are not limited to, plasmids, phagemids, cosmids, baculoviruses, bacmids, bacterial artificial chromosomes (BACs), yeast artificial chromosomes (YACs), as well as other bacterial, yeast and viral vectors. In some embodiments, the vector is a viral vector.

[0353] Recombinant expression vectors within the scope of the description include synthetic, genomic, or cDNA-derived nucleic acid fragments that encode at least one recombinant protein which may be operably linked to suitable regulatory elements. Such regulatory elements mayinclude a transcriptional promoter, sequences encoding suitable mRNA ribosomal binding sites, and sequences that control the termination of transcription and translation. Expression vectors, especially mammalian expression vectors, may also include one or more nontranscribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, other 5’ or 3’ flanking nontranscribed sequences, 5’ or 3’ nontranslated sequences (such as necessary ribosome binding sites), a polyadenylation site, splice donor and acceptor sites, or transcriptional termination sequences. An origin of replication that confers the ability to replicate in a host may also be incorporated.

[0354] Vectors described herein may contain one or more Internal Ribosome Entry Site(s) (IRES). Inclusion of an IRES sequence into fusion vectors may be beneficial for enhancing expression of some proteins. In some embodiments the vector system will include one or more polyadenylation sites (e.g., SV40), which may be upstream or downstream of any of the aforementioned nucleic acid sequences. Vector components may be contiguously linked, or arranged in a manner that provides optimal spacing for expressing the gene products (i.e., by the introduction of “spacer” nucleotides between the ORFs), or positioned in another way. Regulatory elements, such as the IRES motif, may also be arranged to provide optimal spacing for expression.

[0355] The vectors may comprise selection markers, which are well known in the art. Selection markers include positive and negative selection markers, for example, antibiotic resistance genes (e.g., neomycin resistance gene, a hygromycin resistance gene, a kanamycin resistance gene, a tetracycline resistance gene, a penicillin resistance gene, a puromycin resistance gene, a blasticidin resistance gene), glutamate synthase genes, HSV-TK, HSV-TK derivatives for ganciclovir selection, or bacterial purine nucleoside phosphorylase gene for 6-methylpurine selection (Gadi et al., 7 Gene Ther. 1738-1743 (2000)). A nucleic acid sequence encoding a selection marker or the cloning site may be upstream or downstream of a nucleic acid sequence encoding a polypeptide of interest or cloning site.

[0356] Non-limiting examples of additional vectors that can be used in accordance with the present disclosure include Moloney murine leukemia viruses (MLV), Moloney murine leukemia viruses pseudotyped with vesicular stomatitis virus G protein (MLV-VSV-G), murine stem cell viruses (MSCV), lentiviruses, lentiviruses pseudotyped with vesicular stomatitis virus G protein (LV-VSV-G), adenoviruses (e.g., Ad5, Ad41), adeno-associated viruses (such as AAV1, AAV2, AAV5, AAV8, AAV9, AAV10, AAV6), and variants and derivatives thereof. Additional suitablevectors include those described in Buckinx and Timmermans, Histochem Cell Biol (2016) 146:709-720, which is incorporated herein by reference in its entirety.

[0357] In some embodiments, bacteriophages may be engineered to incorporate a nucleotide sequence encoding an antibody described herein into the genetic material of the phage so that the antibody may be exposed on the surface of the phage.

[0358] The vectors described herein may be used to transform various cells with the genes encoding the described antibodies or antigen-binding fragments. For example, the vectors may be used to generate PIK3 IP 1 -specific antibody or antigen-binding fragment-producing cells. Thus, in another aspect is provided host cells transformed with vectors comprising a nucleic acid sequence encoding an antibody or antigen-binding fragment thereof that specifically binds a PIK3IP1 protein, such as the antibodies or antigen-binding fragments described and exemplified herein.

[0359] In some embodiments, a host cell comprising a polynucleotide described herein or a vector described herein can express an antibody or an antigen-binding fragment of the present disclosure. Any of a wide variety of host cells within the knowledge of one of skill in the art may be used in the practice of the present disclosure. A non-limiting example of a host cell is a hybridoma. In some embodiments, the antibody or antigen-binding fragment is recombinantly produced.

[0360] Numerous techniques are known in the art for the introduction of foreign genes into cells and may be used to construct the recombinant cells for purposes of carrying out the described methods, in accordance with the various embodiments described and exemplified herein. The technique used should provide for the stable transfer of the heterologous gene sequence to the host cell, such that the heterologous gene sequence is heritable and expressible by the cell progeny, and so that the necessary development and physiological functions of the recipient cells are not disrupted. Techniques which may be used include but are not limited to chromosome transfer (e.g., cell fusion, chromosome mediated gene transfer, micro cell mediated gene transfer), physical methods (e.g., transfection, spheroplast fusion, microinjection, electroporation, liposome carrier), viral vector transfer (e.g., recombinant DNA viruses, recombinant RNA viruses) and the like (described in Cline, 29 Pharmac. Ther. 69-92 (1985)). Calcium phosphate precipitation and polyethylene glycol (PEG)-induced fusion of bacterial protoplasts with mammalian cells may also be used to transform cells.Preparation of Antibodies or Antigen-Binding Fragments

[0361] Antibodies or antigen-binding fragments capable of binding PIK3IP1 protein as described herein can be made by any method known in the art, including but not limited to, recombinant technology.

[0362] For example, nucleic acids encoding the heavy and light chain of an anti-PIK3IPl antibody as described herein can be cloned into one expression vector, each nucleotide sequence being in operable linkage to a suitable promoter. In one example, each of the nucleotide sequences encoding the heavy chain and light chain is in operable linkage to a distinct promoter.

[0363] Alternatively, the nucleotide sequences encoding the heavy chain and the light chain can be in operable linkage with a single promoter, such that both heavy and light chains are expressed from the same promoter. When necessary, an internal ribosomal entry site (IRES) can be inserted between the heavy chain and light chain encoding sequences.

[0364] In some examples, the nucleotide sequences encoding the two chains of the antibody are cloned into two vectors, which can be introduced into the same or different cells. When the two chains are expressed in different cells, each of them can be isolated from the host cells expressing such and the isolated heavy chains and light chains can be mixed and incubated under suitable conditions allowing for the formation of the antibody.

[0365] Generally, a nucleic acid sequence encoding one or all chains of an antibody can be cloned into a suitable expression vector in operable linkage with a suitable promoter using methods known in the art. For example, the nucleotide sequence and vector can be contacted, under suitable conditions, with a restriction enzyme to create complementary ends on each molecule that can pair with each other and be joined together with a ligase. Alternatively, synthetic nucleic acid linkers can be ligated to the termini of a gene. These synthetic linkers contain nucleic acid sequences that correspond to a particular restriction site in the vector. The selection of expression vectors / promoter would depend on the type of host cells for use in producing the antibodies.

[0366] A variety of promoters can be used for expression of the antibodies described herein, including, but not limited to, cytomegalovirus (CMV) intermediate early promoter, a viral LTR such as the Rous sarcoma virus LTR, HIV-LTR, HTLV-1 LTR, the simian virus 40 (SV40) early promoter, E. coli lac UV5 promoter, and the herpes simplex tk virus promoter.

[0367] Regulatable promoters can also be used. Such regulatable promoters include those using the lac repressor from E. coli as a transcription modulator to regulate transcription from lacoperator-bearing mammalian cell promoters [Brown, M. et al., Cell, 49:603-612 (1987)], those using the tetracycline repressor (tetR) [Gossen, M., and Bujard, H., Proc. Natl. Acad. Sci. USA 89:5547-5551 (1992); Yao, F. et al., Human Gene Therapy, 9: 1939-1950 (1998); Shockelt, P„ et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)]. Other systems include FK506 dimer, VP16 or p65 using astradiol, RU486, diphenol murislerone, or rapamycin. Inducible systems are available from Invitrogen, Clontech and Ariad.

[0368] Regulatable promoters that include a repressor with the operon can be used. In one embodiment, the lac repressor from E. coli can function as a transcriptional modulator to regulate transcription from lac operator-bearing mammalian cell promoters (M. Brown et al., Cell, 49:603- 612 (1987); Gossen and Bujard (1992); M. Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551 (1992)) combined the tetracycline repressor (tetR) with the transcription activator (VP 16) to create a tetR-mammalian cell transcription activator fusion protein, tTa (tetR-VP 16), with the tetO- bearing minimal promoter derived from the human cytomegalovirus (hCMV) major immediate- early promoter to create a tetR-tet operator system to control gene expression in mammalian cells. In one embodiment, a tetracycline inducible switch is used. The tetracycline repressor (tetR) alone, rather than the tetR-mammalian cell transcription factor fusion derivatives can function as potent trans-modulator to regulate gene expression in mammalian cells when the tetracycline operator is properly positioned downstream for the TATA element of the CMVIE promoter (Yao et al., Human Gene Therapy, 10(16): 1392-1399 (2003)). One particular advantage of this tetracycline inducible switch is that it does not require the use of a tetracycline repressor-mammalian cells transactivator or repressor fusion protein, which in some instances can be toxic to cells (Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551 (1992); Shockett et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)), to achieve its regulatable effects.

[0369] Additionally, the vector can contain, for example, some or all of the following: a selectable marker gene, such as the neomycin gene for selection of stable or transient transfectants in mammalian cells; enhancer / promoter sequences from the immediate early gene of human CMV for high levels of transcription; transcription termination and RNA processing signals from SV40 for mRNA stability; SV40 polyoma origins of replication and ColEl for proper episomal replication; internal ribosome binding sites (IRESes), versatile multiple cloning sites; and T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNA. Suitable vectors and methods for producing vectors containing transgenes are well known and available in the art.

[0370] Examples of polyadenyl tion signals useful to practice the methods described herein include, but are not limited to, human collagen I polyadenylation signal, human collagen II polyadenylation signal, and SV40 polyadenylation signal.

[0371] One or more vectors (e.g., expression vectors) comprising nucleic acids encoding any of the antibodies may be introduced into suitable host cells for producing the antibodies. The host cells can be cultured under suitable conditions for expression of the antibody or any polypeptide chain thereof. Such antibodies or polypeptide chains thereof can be recovered by the cultured cells (e.g., from the cells or the culture supernatant) via a conventional method, e.g., affinity purification. If necessary, polypeptide chains of the antibody can be incubated under suitable conditions for a suitable period of time allowing for production of the antibody.

[0372] In some embodiments, methods for preparing an antibody described herein involve a recombinant expression vector that encodes both the heavy chain and the light chain of an anti- PIK3IP1 antibody, as also described herein. The recombinant expression vector can be introduced into a suitable host cell by a conventional method, e.g., calcium phosphate-mediated transfection. Positive transformant host cells can be selected and cultured under suitable conditions allowing for the expression of the two polypeptide chains that form the antibody, which can be recovered from the cells or from the culture medium. When necessary, the two chains recovered from the host cells can be co-incubated under suitable conditions allowing for the formation of the antibody.

[0373] In one example, two recombinant expression vectors are provided, one encoding the heavy chain of the anti-PIK3IPl antibody and the other encoding the light chain of the anti- PIK3IP1 antibody. Both of the two recombinant expression vectors can be introduced into a suitable host cell by a conventional method, e.g., calcium phosphate-mediated transfection. Alternatively, each of the expression vectors can be introduced into suitable host cells. Positive transformants can be selected and cultured under suitable conditions allowing for the expression of the polypeptide chains of the antibody. When the two expression vectors are introduced into the same host cells, the antibody produced therein can be recovered from the host cells or from the culture medium. If necessary, the polypeptide chains can be recovered from the host cells or from the culture medium and then incubated under suitable conditions allowing for formation of the antibody. When the two expression vectors are introduced into different host cells, each of them can be recovered from the corresponding host cells or from the corresponding culture media. Thetwo polypeptide chains can then be incubated under suitable conditions for formation of the antibody.

[0374] In some embodiments, the antibody or antigen-binding fragment described herein are produced by a method comprising culturing a host cell described herein (e.g., a host cell expressing an antibody or antigen binding fragment described herein comprising a polynucleotide described herein or a vector described herein) and isolated the antibody or antigen-binding fragment.

[0375] Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells and recovery of the antibodies from the culture medium. For example, some antibodies can be isolated by affinity chromatography with a Protein A or Protein G coupled matrix.

[0376] Any of the nucleic acids encoding the heavy chain, the light chain, or both of an anti- PIK3IP1 antibody as described herein, vectors (e g., expression vectors) containing such; and host cells comprising the vectors are within the scope of the present disclosure.

[0377] In some embodiments, the antibody or antigen-binding fragment described herein are isolated from an animal immunized with a PIK3IP1 -containing antigen, or genetically modified to produce the antibody or antigen-binding fragment. The animal may be genetically modified with the polynucleotide or the vector described herein.

[0378] In some embodiments, the animal is a dairy animal, such as, but not limited to, a goat, a cow, a buffalo, a sheep, or a camel. In such cases, the antibody or antigen-binding fragment may be isolated from milk produced by the dairy animal.

[0379] Anti-PIK3IP1 antibodies prepared as described herein can be characterized using methods known in the art, whereby reduction, amelioration, or neutralization of biological activity associated with the target PIK3IP1 protein is detected and / or measured. For example, in some embodiments, an ELISA-type assay is suitable for qualitative or quantitative measurement of binding of the antibody to the target PIK3IP1 protein.Pharmaceutical Compositions

[0380] Any of the antibodies or antigen-binding fragments, antibody-drug conjugates, polynucleotides, or vectors described herein can be present in a pharmaceutical composition (such as a formulation) that can includes other agents, excipients, or stabilizers. In various embodiments, a pharmaceutical composition described herein may comprise (i) an antibody or antigen-bindingfragment described herein, (ii) an antibody-drug conjugate described herein, (iii) a polynucleotide described herein, and / or (iv) a recombinant vector described herein, and a pharmaceutically acceptable carrier or adjuvant.

[0381] It is understood that the compounds of the present disclosure can use amino acids independently selected from L and D forms (e.g., the peptide may contain two serine residues, each serine residue having the same or opposite absolute stereochemistry), etc., are intended for the use of both L- and D-form amino acids.

[0382] Accordingly, the compounds of the present disclosure also include substantially pure stereoisomeric form of the specific compound with respect to the asymmetric center of the amino acid residue, for example about 90% de, such as greater than about 95% to 97% de, or 99% de. For larger compounds, as well as mixtures thereof (such as racemic mixtures). Such diastereomers may be prepared, for example, by asymmetric synthesis using chiral intermediates, or the mixture may be divided by conventional methods, such as chromatography or the use of dividing agents.

[0383] If the compounds of the disclosure require purification, chromatographic techniques such as high-performance liquid chromatography (HPLC) and reverse phase HPLC can be used. Peptides may be characterized by mass spectrometry and / or other suitable methods.

[0384] If the compound contains one or more functional groups that can be protonated or deprotonated (e.g., at physiological pH), the compound can be prepared and / or isolated as a pharmaceutically acceptable salt. It will be appreciated that the compound can be zwitterion at a given pH. As used herein, the expression “pharmaceutically acceptable salt” refers to a salt of a given compound, which salt is suitable for pharmaceutical administration. Such salts can be formed, for example, by reacting an acid or base with an amine or carboxylic acid group, respectively.

[0385] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of organic acids include acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartrate acid, citrate, benzoic acid, cinnamic acid, mandelic acid, Examples thereof include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

[0386] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Corresponding counterions derived from inorganic bases include salts of sodium, potassium, lithium, ammonium, calcium and magnesium. Organic bases include isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, prokine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, Substituted amines such as primary, secondary and tertiary amines such as N-alkylglucamine, theobromine, purines, piperazine, piperazine and N-ethylpiperidine, substituted amines such as natural substituted amines and cyclic amines can be mentioned.

[0387] Acid / base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid / base forms.

[0388] In some embodiments, it is envisioned that two or more combinations of the compounds of the disclosure will be administered to the subject. It is believed that the compound (s) may also be administered in combination with one or more additional therapeutic agents. This combination can allow separate, continuous or simultaneous administration with the other active ingredients of the above compounds. This combination may be provided in the form of a pharmaceutical composition.

[0389] Combination agents can be administered, for example, simultaneously or staggered in time (z.e., at different times and at equal or different time intervals for any part of a kit). The ratio of the total amount of combination agents administered in a combination can vary, e.g., to address the needs of a subpopulation of patients to be treated or the needs of a single patient, and different needs are the age of the patient, it can be due to gender, weight, etc.

[0390] In some embodiments, the pharmaceutical composition further comprises one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include, but are not limited to, a programmed cell death protein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD- Ll) inhibitor, lymphocyte activation gene 3 (LAG-3 or CD223) inhibitor, a cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a cluster of differentiation 47 (CD47) inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or PD-1H) inhibitor, a T cell immunoreceptor with Ig and ITEM Domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signalinglymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor- related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a cluster of differentiation 93 (CD93) inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus- H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a cluster of differentiation 24 (CD24) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO inhibitor, a P-selectin glycoprotein ligand- 1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 also BT-IgSF and IGSF11) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) inhibitor, a cluster of differentiation 160 (CD 160) inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, and a vascular endothelial growth factor (VEGF) inhibitor, and any combinations thereof.

[0391] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. Exemplary PD-1 inhibitors include, but are not limited to, nivolumab, pembrolizumab, BAT1308, acrixolimab, balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, fmotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, ociperlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tiragolumab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, zimberelimab, a variant or any combinations thereof. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. Exemplary PD-L1 inhibitorsinclude, but are not limited to, durvalumab, avelumab, atezolizumab, bintrafusp alfa, a variant or any combinations thereof.[003921 In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. Exemplary LAG-3 inhibitors include, but are not limited to, relatlimab (BMS-986016), ABL501, CB213, EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO- 7247669), TSR-033, tuparstobart (INCAGN02385), BGA-1953, or a variant or any combinations thereof.

[0393] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. Exemplary CTLA-4 inhibitors include, but are not limited to, ipilimumab, tremelimumab, XmAb20717, ONC-392, XmAb22841, BMS-986249, ADG116, ATOR-1015, ADG126, YH001, botensilimab, HBM4003, lorigerlimab, SI-B003, AK104, KN046, quavonlimab, BNT316 / ONC- 392 (goti Stobart), porustobart (HBM4003), or a variant or combination thereof.

[0394] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor. Exemplary TIGIT inhibitors include, but are not limited to, BMS-986207, ociperlimab, BGB-A1217, tiragolumab, domvanalimab, ASP8374, vibostolimab, IBI-939, etigilimab, COM902, M6223, EOS884448, BAT6021, HLX301, or a variant or any combinations thereof.

[0395] In some embodiments, the SLAMF inhibitor is elotuzumab or a variant thereof. In some embodiments, the PVRIG inhibitor is COM701, JS009, or a variant thereof. In some embodiments, the CD96 inhibitor is GSK6097608 or a variant thereof.

[0396] In some embodiments, the pharmaceutical composition further comprises one or more cytokines, tumor-associated antigen (TAA)-targeting agents, immune agonists, cytotoxic agents, siRNAs, or antisense oligonucleotides.

[0397] Exemplary cytokines include, but are not limited to, interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin- 10 (IL-10), interleukin- 15 (IL-15), interleukin-21 (IL-21), IFN-a, IFN-P, IFN- y, CCL19, CCL21, IL- 18, monocyte chemoattractant protein- 1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), or a receptor thereof, and any combinations thereof.

[0398] Exemplary tumor-associated antigen-targeting agents include, but are not limited to, 5T4, Ang2, BCMA, CD123, CD19, CD20, CD22, CD33, CD38, CD47, CEA, CEACAM5,CEACAM6, Claudin 6, Claudin 18.2, Tie2, CLEC12A, DLL3, EGFR, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, Her2, Her3, MAGE-A4, MET, MUC16, MUC17, NY-ESO- 1, P-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, TROP2 (TACSTD2), VEGF, VEGFR, ySTCR, KRAS, RAF, and any combinations thereof. In some embodiments, the TAA-targeting agent is a VEGF inhibitor, a VEGFR inhibitor, a CD20 inhibitor, a CD38 inhibitor, a TR0P2 inhibitor, a KRAS inhibitor, or a RAF inhibitor.

[0399] In some embodiments, the CD20 inhibitor is rituximab. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the CD38 inhibitor is daratumumab. In some embodiments, the TROP2 inhibitor is sacituzumab govitecan.

[0400] Exemplary immune agonists include, but are not limited to, a 4-1BB agonist, a 0X40 agonist, a CD40 agonist, a CD30 agonist, a GITR agonist, an ICOS agonist, a CD27 agonist, a CD28 agonist, a CD28H / TMIGD2 agonist, a NCR3 agonist, a NCR1 agonist, a NCR2 agonist, a 4-1BB agonist, a DR3 agonist, a CD226 agonist, a CRTAM agonist, a HVEM agonist, a TNFR1 agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, a TLR4 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, and any combinations thereof.

[0401] The route of administration and the type of pharmaceutically acceptable carrier will depend on the condition being treated and the type of mammal. Formulations containing the active compound may be prepared such that the activity of the compound is not disrupted during the process and the compound can reach its site of action without disruption. In some cases, it may be necessary to protect the compound by means known in the art, such as microencapsulation. Similarly, the route of dosing selected should be such that the compound reaches its site of action.

[0402] In some embodiments, the composition further comprises a targeting agent or a carrier that promotes the delivery of the inhibitors of endocytosis to an area affected by the chronic pain. Exemplary carriers include liposomes, micelles, nanodisperse albumin and its modifications, polymer nanoparticles, dendrimers, inorganic nanoparticles of different compositions.

[0403] The appropriate formulation for the compound of the disclosure can be adjusted for pH. Buffer systems are routinely used to provide pH values in the desired range and include carboxylic acid buffers such as acetates, citrates, lactates and succinates. In some embodiments, the composition is formulated to have a pH range of about 4.5 to about 9.0, including for example pH ranges of about any of 5.0 to about 8.0, about 6.5 to about 7.5, and about 6.5 to about 7.0. In some embodiments, the pH of the composition is formulated to no less than about 6, including forexample no less than about any of 6.5, 7, or 8 (such as about 8). The composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol.

[0404] The formulation may also include suitable excipients, such as antioxidants. Examples of antioxidants include phenolic compounds such as BHT or Vitamin E, reducing agents such as methionine or sulfites, and metal chelating agents such as EDTA.

[0405] The compounds or pharmaceutically acceptable salts thereof described herein can be prepared in parenteral dosage forms such as those suitable for, e.g., intravascular (intravenous or intraarterial), subcutaneous, intraperitoneal, intratumoral, intraventricular, intrapleural or intramuscular administration delivery. Suitable pharmaceutical forms for injectable use include sterile injectable or dispersions and sterile powders for the immediate preparation of sterile injectable solutions. They must be stable under manufacturing and storage conditions and protected from reduction or oxidation and the contaminating effects of microorganisms such as bacteria or fungi.

[0406] The solvent or dispersion medium for the injectable solution or dispersion may include either conventional solvents or carrier systems for the active compound, e.g., water, ethanol, polyols (e.g., glycerol, propylene glycol and). Liquid polyethylene glycol, etc., suitable mixtures thereof, and vegetable oils may be included. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. Prevention of the action of microorganisms can be performed as needed by incorporating various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it may be preferable to include agents that regulate osmotic pressure, such as sugar or sodium chloride. Preferably, the injectable formulation is isotonic with blood. Sustained absorption of the injectable composition can be brought about by the use of agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition. Suitable pharmaceutical forms for injection can be delivered by any suitable route, including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.

[0407] Sterilized injectable solutions are prepared by adding the required amount of the compounds of the disclosure to a suitable solvent containing various other components, such as those listed above, as needed, followed by filtration sterilization. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basicdispersion medium and other required ingredients from those described above. For sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying or lyophilization of the pre-sterile fdtered solution of the active ingredient plus any additional desired ingredients.

[0408] Other pharmaceutical forms include the oral and enteral formulations, where the active compound can be formulated with an inert diluent or an assimilated edible carrier, or encapsulated in hard or softshell gelatin capsules. The formulations can also be tableted, or it can be incorporated directly into diet foods. For oral therapeutic administration, the active compound is taken up with excipients and used in the form of ingestible tablets, buccal or sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. The amount of active compound in such a therapeutically useful composition is such that an appropriate dose can be obtained.

[0409] Tablets, lozenges, pills, capsules, etc. may also contain the ingredients listed below: binders such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; corn starch, Disintegrants such as potato starch, arginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose or saccharin, or flavors such as peppermint, winter green oil, or cherry flavor may be added. If the dosage unit form is a capsule, it may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as a coating or in other ways to alter the physical form of the dosage unit. For example, tablets, pills, or capsules can be coated with shellac, sugar, or both. The syrup or elixir may contain active compounds, sucrose as a sweetener, methyl and propylparabens as preservatives, pigments and flavors such as cherry or orange flavors. Of course, any substance used to prepare the dosage unit form must be pharmaceutically pure and substantially non-toxic in the amount used. In addition, the compounds of the disclosure may be incorporated into sustained release formulations and formulations comprising those that specifically deliver the active peptide to a particular region of the intestine.

[0410] Liquid formulations can also be administered enterally via the stomach or esophageal canal. The enteral preparation can be prepared in the form of a suppository by mixing with a suitable base such as an emulsifying base or a water-soluble base. It is possible, but not necessary, to administer the compound of the present disclosure topically, intranasally, intravaginally, intraocularly or the like.

[0411] Pharmaceutically acceptable vehicles and / or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarders,and the like. The use of such vehicles and agents for pharmaceutically active substances is well known in the art. Its use in therapeutic compositions is intended unless any conventional vehicle or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the composition.

[0412] It is particularly advantageous to formulate the composition in unit dosage form for ease of administration and uniformity of dosage. As used herein, a dosage unit form means a physically distinct unit suitable as a unit dosage for a mammalian subject to be treated; each unit is a required pharmaceutically acceptable vehicle. A dosage unit form may contain a predetermined amount of active substance calculated to produce a desired therapeutic effect described herein. Details of the novel dosage unit forms of the disclosure include (a) the unique properties of the active substance and the particular therapeutic effect to be achieved, and (b) physical health as disclosed in detail herein. It is determined by and directly dependent on the technology-specific limitations of the active substances formulated for the treatment of the disease in living subjects with impaired disease states.

[0413] As mentioned above, the main active ingredient may be formulated for convenient and effective administration in therapeutically effective amounts using a suitable pharmaceutically acceptable vehicle in the form of a dosage unit. The unit dosage form can contain, for example, the major active compound in an amount ranging from 0.25 pg to about 2000 mg. Expressed in proportion, the active compound may be present in a carrier of about 0.25 pg to about 1000 mg / mL. In the case of a composition containing an auxiliary active ingredient, the dose is determined with reference to the usual dosage and mode of administration of the ingredient.

[0414] In some embodiments, the composition is suitable for administration to a human. In some embodiments, the composition is suitable for administration to a mammal such as, in the veterinary context, domestic pets and agricultural animals. There are a wide variety of suitable formulations of the composition comprising the inhibitor of endocytosis. The following formulations and methods are merely exemplary and are in no way limiting. Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions. Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal91silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.

[0415] Examples of suitable carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline solution, syrup, methylcellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate, and mineral oil. In some embodiments, the composition comprising the inhibitor of endocytosis with a carrier as discussed herein is present in a dry formulation (such as lyophilized composition). The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.

[0416] Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation compatible with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.Kits

[0417] The present disclosure further provides a kit which may contain any of various compositions of the present disclosure, including antibodies or antigen-binding fragments thereof, antibody-drug conjugates, polynucleotides, or vectors of the disclosure.

[0418] In one aspect, a kit may comprise an antibody or antigen-binding fragment described herein, an antibody-drug conjugate described herein, a polynucleotide described herein, or a vector described herein, and (ii) optionally, packaging for the same and / or instructions for use.

[0419] In some embodiments, a kit can comprise: (a) a container that contains a pharmaceutical composition described herein, for example, a pharmaceutical composition in solution or in lyophilized form; (b) optionally, a second container containing a diluent or reconstituting solution for the lyophilized formulation; and / or (c) optionally, instructions for (i) use of the solution or (ii) reconstitution and / or use of the lyophilized formulation.

[0420] In some embodiments, a kit may further comprise, one or more of (i) a diluent, (ii) a buffer, (iii) a fdter (iv) a syringe, and / or (v) a needle.

[0421] In some embodiments, the components of the kit may be provided in one or more liquid solutions. A liquid solutions described herein may be an aqueous solution such as a sterile aqueous solution. The components of the kit may also be provided as solids, which may be converted into liquids such as by addition of suitable solvents, which may be provided in another distinct container.

[0422] In some a pharmaceutical composition described herein may be lyophilized.

[0423] In some embodiments, kits may comprise a lyophilized formulation described herein in a suitable container and instructions for its reconstitution and / or use. Non-limiting examples of suitable containers include, e.g., syringes (such as dual chamber syringes), vials (such as dual chamber vials), bottles, and test tubes. In various embodiments, a container may be a multi-use container. The container may be formed from a variety of materials such as plastic or glass. The kit and / or container may contain instructions upon or accompanying the container which can denote directions for reconstitution of, e.g., a lyophilized formulation and / or use of the kit. In some embodiments, a label may denote that the lyophilized formulation is to be reconstituted to an appropriate concentration. The label may denote that the formulation is useful or intended for any route of administration disclosed herein.

[0424] The container containing the formulation may be a multi-use vial, which may allow for repeat administrations (e.g., from 2-6 administrations) of a reconstituted formulation. The kit may further comprise a second container comprising a suitable diluent (e.g., sodium bicarbonate solution).

[0425] Upon mixing of the diluent and a lyophilized formulation, a final concentration in the reconstituted formulation can reached. The kit may further include other materials desirable from a commercial and / or user perspective, including, e.g., other filters, needles, syringes, buffers, diluents, and / or package inserts which may comprise, e.g., instructions for use.

[0426] Kits may contain a single container that contains the formulation of the pharmaceutical composition with or without other components (e.g., other compounds or pharmaceutical compositions of such other compounds) or may have a separate container for each component.

[0427] Kits may include a formulation of the disclosure packaged for use in combination with the co-administration of a second compound (such as adjuvants (e.g., GM-CSF, a natural product, a hormone or antagonist, an anti-angiogenesis agent or inhibitor, an apoptosis-inducing agent or a chelator a chemotherapeutic agent) or a pharmaceutical composition thereof. The components of the kit may pre-mixed and / or pre-complexed or each component of the kit may be in a separate distinct container prior to administration to a patient.

[0428] In some embodiments, the container of a therapeutic kit may be a vial, flask, test tube, bottle, syringe, or any other means of enclosing a solid or liquid. When there is more than one component, the kit may contain a second vial or other container, which may allow for separate dosing. The kit may also contain another container for a pharmaceutically acceptable liquid. In some embodiments, a kit may contain an apparatus (e.g., syringes, one or more needles, pipettes, eye droppers, etc.) which may permit administration of agents of the disclosure which are components of the kit.Methods of Use

[0429] The pharmaceutical compositions comprising, e.g., antibodies and antigen-binding fragments, antibody-drug conjugates, polynucleotides, and / or vectors of the present disclosure, and e.g., a pharmaceutically acceptable carrier and / or diluent disclosed herein, may be used for various therapeutic applications (in vivo and ex vivo) and as research tools.

[0430] In one aspect, the present disclosure provides a method of inhibiting a function of PIK3IP1 protein and / or depleting PIK3IP1 protein from a bodily fluid of a subject in need thereof, the method comprising administering to the subject an effective amount of an PIK3IP1 inhibitor. In some embodiments, the bodily fluid may be, without limitation, blood, saliva, bronchoalveolar fluid and / or urine. Examples of administering which may be used in the practice of the presentdisclosure include via intratumoral, intravenous, intradermal, intraperitoneal, subcutaneous, intramuscular delivery, inhalation, oral delivery, lipid nanoparticle (LNP)-based delivery, cellular delivery, viral and / or non-viral delivery, or gene editing, or as a cargo in a cell, or any combination thereof. Exemplary dosing and administration regimens are set forth in further detail below.

[0431] In another aspect, the present disclosure provides a method of inhibiting a function of PIK3IP1 protein and / or depleting PIK3IP1 protein from a tumor microenvironment of a subject in need thereof, the method comprising administering to the subject an effective amount of an PIK3IP1 inhibitor.

[0432] In yet another aspect, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that targets PIK3IP1 (e.g., an PIK3IP1 inhibitor).

[0433] In some embodiments, the agent that targets PIK3IP1 protein is selected from a small molecule, a protein, a protein-drug conjugate, a nucleotide molecule, a gene editing system, an engineered cell system, and any combination thereof. In some embodiments, the protein is selected from a peptide; an antibody or antigen-binding fragment thereof; a monobody; engineered, low-density-lipoprotein-receptor-derived, A domain (LDLR-A) (e.g., Avimers™); a designed ankyrin repeat protein (DARPin) lipocalin (e.g., anticalins); an affibody; engineered, Protein- A-derived, Z domain (Affibodies™) CTLD3 (e.g., Tetranectin); C-type lectin-like domain scaffolds; Sac7d-derived polypeptides (e g., Nanoffitins® or affitins); engineered, tenascin-derived, tenascin type III domain (e.g., Centyrin™), thioredoxin (e.g., peptide aptamer); KALBITOR®; the P-sandwich (e.g., iMab); gamma-B crystallin-derived scaffold or engineered, ubiquitin-derived scaffold (e.g., Affilins); engineered, protease inhibitor-derived, Kunitz domain (e.g., EETI-IVAGRP, BPTI / LACI-D1 / ITI-D2); engineered antibody mimics; miniproteins; engineered, Fyn-derived, SH2 domain (e.g., Fynomers®); genetically manipulated counterparts of the foregoing that retains its binding functionality, and any combination thereof. In some embodiments, the antibody or antigen-binding fragment thereof is selected from an intact antibody, an antigen-binding (Fab) fragment, an Fab’ fragment, an (Fab’)2 fragment, an Fd, an Fv, a dAb, a single domain fragment or single monomeric variable antibody domain, a singlechain Diabody (scDb), a single-chain variable fragment (scFv), a VH domain, a nanobody, a Bispecific T-cell engager (BiTE), a bispecific killer cell engager (BiKE), a bi-specific macrophage engager (BiME), a CrossMab, a tri-specific binding partner, and any combination thereof. In someembodiments, the nucleotide molecule is selected from an antisense oligonucleotide, a micro RNA (miRNA), a small interfering RNA (siRNA), a short hairpin RNA (shRNA), a single guide RNA (sgRNA), and any combination thereof. In some embodiments, the gene editing system comprises a CRISPR-associated protein (Cas) nuclease, a zinc finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a meganuclease, any endo- or exonuclease, variants thereof, fragments thereof, or any combination thereof. In some embodiments, the engineered cell system comprises a chimeric antigen receptor (CAR) modified cell comprising a fragment that targets PIK3IP1. In some embodiments, CAR-modified cell is include a CAR- modified T cell (CAR-T cell), a CAR-modified natural killer (NK) cell (CAR-NK cell), or a CAR- macrophage (CAR-M). In some embodiments, the agent is conjugated to a detectable label, a chemotherapeutic agent, a radioisotope, an affinity tag, or a toxin.

[0434] In some embodiments, the present disclosure provides a method for improving an anticancer T cell response in a subject in need thereof comprising administering to the subject an effective amount of an agent that targets PHC3IP1 such that the anti-cancer T cell response of the T cells is improved, and wherein the T cells are PD-1 and / or LAG-3 negative, or are beyond the exhausted T cells (i.e., memory T cells).

[0435] In some embodiments, the agent that targets PIK3IP1 comprises an antibody or antigenbinding fragment described herein, an antibody-drug conjugate described herein, a polynucleotide described herein, a vector of described herein, or a pharmaceutical composition described herein.

[0436] In some embodiments, the cancer is resistant to an immunotherapy and the immunotherapy does not comprise the use of an PIK3IP1 inhibitor.

[0437] The present disclosure also provides a method of sensitizing a cancer to an immunotherapy in a subject in need thereof, the method comprising administering to the subject an effective amount of an PIK3IP1 inhibitor and the immunotherapy does not comprise the use of an PIK3 IP 1 inhibitor.

[0438] The present disclosure also provides a method of increasing effectiveness and / or reducing toxicity of an immunotherapy in a subject in need thereof, the method comprising coadministering to the subject the immunotherapy with an effective amount of an PIK3IP1 inhibitor, and the immunotherapy does not comprise the use of an PIK3IP1 inhibitor.

[0439] In some embodiments, the immunotherapy is administered to subject simultaneously or sequentially with the PIK3IP1 inhibitor. As a non-limiting example, the immunotherapy can beadministered to the subject simultaneously with the PIK3TP1 inhibitor in one composition. As another non-limiting example, the immunotherapy can be administered to the subject simultaneously with the PIK3IP1 inhibitor in separate compositions. As yet another non-limiting example, the immunotherapy can be administered to the subject sequentially with the PIK3IP1 inhibitor in separate compositions.

[0440] In some embodiments, when immunotherapy and the PIK3IP1 inhibitor are administered to the subject sequentially (e.g., in separate compositions), the immunotherapy may be administered as a first component of a dosing regimen and the PIK3IP1 inhibitor may be administered as a second component of a dosing regimen (i.e., the immunotherapy may be administered before the PIK3IP1 inhibitor).

[0441] In some embodiments, when the immunotherapy and the PIK3IP1 inhibitor are administered to subject sequentially (e g., in separate compositions), the PIK3IP1 inhibitor may be administered as a first component of a dosing regimen and the immunotherapy may be administered as a second component of a dosing regimen (z.e., the PIK3IP1 inhibitor may be administered before the immunotherapy).

[0442] In some embodiments, the cancer may be characterized by an increased level of PIK3IP1 protein in a tumor microenvironment.

[0443] In some embodiments, the cancer is a hematologic cancer or solid cancer.

[0444] In some embodiments, the hematologic cancer is leukemia. Non-limiting examples of leukemia are acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute leukemias of ambiguous lineage, chronic myeloid neoplasms (e.g., myeloproliferative or myelodysplastic neoplasms), non-Hodgkin and Hodgkin lymphomas, chronic leukemias (both myeloid and lymphoid), dendritic / histiocytic neoplasms, and other lymphoproliferative disorders.

[0445] A solid cancer may include, without limitation, a lung cancer (e.g., a non-small cell lung cancer [NSCLC] such as a lung adenocarcinoma [LU AD]), a glioma, a thyroid cancer, a colorectal cancer, a head and neck cancer (e.g., head and neck squamous cell carcinoma), a gastric cancer, a stomach cancer, a liver cancer, a pancreatic cancer, a renal cancer, a urothelial cancer, a prostate cancer, a testis cancer, a breast cancer, a cervical cancer, an endometrial cancer, an ovarian cancer, a gallbladder cancer, a sarcoma (e.g., fibrosarcoma), or melanoma.

[0446] In some embodiments, the solid cancer is a lung cancer, a colorectal cancer or a melanoma. In some embodiments, the lung cancer is a non-small cell lung cancer (NSLC). In some embodiments, the non-small cell lung cancer (NSCLC) is lung adenocarcinoma (LU AD).

[0447] In some embodiments, the hematologic cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage, hairy cell leukemia, multiple myeloma, chronic myeloid neoplasm, non-Hodgkin lymphoma, Hodgkin lymphoma, chronic leukemia, dendritic / histiocytic neoplasm, or lymphoproliferative disorder.

[0448] In some embodiments, the PIK3IP1 inhibitor is an antibody or an antigen-binding fragment or a small molecule, an aptamer, or a combination thereof.

[0449] In some embodiments, the PIK3IP1 inhibitor can be, without limitation, any of various antibodies or antigen-binding fragments thereof described herein, any of various antibody-drug conjugates described herein, any of various polynucleotides described herein, or any of various vectors described herein.

[0450] In some embodiments of any of the above-described methods, the immunotherapy may comprise one or more immune checkpoint inhibitors. Non-limiting examples of an immune checkpoint inhibitor include, a T cell immunoreceptor with Ig and ITIM Domains (TIGIT) inhibitor, a programmed cell death protein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD- Ll) inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a lymphocyte activation gene 3 (LAG-3 or CD223) inhibitor, a cluster of differentiation 47 (CD47) inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a (B7-H4) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA or PD-1H) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein-coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a cluster of differentiation 93 (CD93) inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor,a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a cluster of differentiation 24 (CD24) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO inhibitor, a P- selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 also BT-IgSF and IGSF11) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) inhibitor, a cluster of differentiation 160 (CD 160) inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, and a vascular endothelial growth factor (VEGF) inhibitor, and any combination thereof.

[0451] In some embodiments, the PD-1 inhibitor may comprise an antibody or antigen-binding fragment which is capable of specifically targeting PD-1. In some embodiments, the PD-1 targeting antibody is BAT1308, acrixolimab, balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nivolumab, nofazinlimab, pembrolizumab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, zimberelimab, or a variant or combination thereof.

[0452] In some embodiments, the TIGIT inhibitor may comprise an antibody or antigen-binding fragment which is capable of specifically targeting TIGIT (see, e.g., Rui et al., MedComm - Oncology; Volume 1, Issue 2 el8, which is incorporated by reference in its entirety). In some embodiments, the TIGIT inhibitor is BMS-986207, domvanalimab, ociperlimab, BGB-A1217, tiragolumab, ASP8374, vibostolimab, IBI-939, etigilimab, COM902, M6223, EOS884448, BAT6021, HLX301, or a variant or any combinations thereof.

[0453] In some embodiments, the PD-L1 inhibitor may comprise an antibody or antigen-binding fragment which is capable of specifically targeting PD-L1. In some embodiments, the PD-1 targeting antibody is durvalumab, avelumab, atezolizumab, bintrafusp alfa, a variant or any combinations thereof.

[0454] In some embodiments, the LAG-3 inhibitor may comprise an antibody or antigen-binding fragment which is capable of specifically targeting LAG-3. In some embodiments, the LAG-3 targeting antibody is relatlimab (BMS-986016), ABL501, CB213, EMB-02, favezelimab (MK- 420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO-7247669), TSR-033, tuparstobart (INCAGN02385), BGA-1953, or a variant or any combinations thereof.

[0455] In certain embodiments, the CTLA-4 inhibitor may comprise an antibody or antigenbinding fragment which is capable of specifically targeting CTLA-4. In some embodiments, the CTLA-4 targeting antibody is ipilimumab, tremelimumab, XmAb20717, ONC-392, XmAb22841, BMS-986249, ADG116, ATOR-1015, ADG126, YH001, botensilimab, HBM4003, lorigerlimab, SI-B003, AK104, KN046, quavonlimab, BNT316 / ONC-392 (gotistobart), porustobart (HBM4003), or a variant or combination thereof.

[0456] In some embodiments, the TIGIT inhibitor may comprise an antibody or antigen-binding fragment which is capable of specifically targeting TIGIT. In some embodiments, the TIGIT targeting antibody is BMS-986207, ociperlimab, BGB-A1217, tiragolumab, domvanalimab, ASP8374, vibostolimab, IBI-939, etigilimab, COM902, M6223, EOS884448, BAT6021, HLX301, or a variant or any combinations thereof.

[0457] In some embodiments, the SLAMF inhibitor may comprise an antibody or antigenbinding fragment which is capable of specifically targeting SLAMF. In some embodiments, the SLAMF inhibitor is elotuzumab or a variant thereof. In some embodiments, the PVRIG inhibitor may comprise an antibody or antigen-binding fragment which is capable of specifically targeting PVRIG. In some embodiments, the PVRIG inhibitor is COM701, JS009, or a variant thereof. In some embodiments, the CD96 inhibitor may comprise an antibody or antigen-binding fragment which is capable of specifically targeting CD96. In some embodiments, the CD96 inhibitor is GSK6097608 or a variant thereof.

[0458] In some embodiments of any of the above-described methods, the immunotherapy may comprise one or more cytokines. Exemplary cytokines include, but are not limited to, interleukin- 2 (IL-2), interleukin-6 (IL-6), interleukin- 10 (IL-10), interleukin- 15 (IL-15), interleukin-21 (IL- 21), IFN-a, IFN-P, IFN-y, CCL19, CCL21, IL- 18, monocyte chemoattractant protein- 1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF),granulocyte colony stimulating factor (G-CSF), or a receptor thereof, and any combinations thereof.

[0459] In some embodiments of any of the above-described methods, the immunotherapy may comprise one or more tumor-associated antigen -targeting agents. Exemplary tumor-associated antigen -targeting agents include, but are not limited to, 5T4, Ang2, BCMA, CD123, CD19, CD20, CD22, CD33, CD38, CD47, CEA, CEACAM5, CEACAM6, Claudin 6, Claudin 18.2, Tie2, CLEC12A, DLL3, EGFR, EpCAM, FcRH5, FLT3, GD2, Glypican-3, gpA33, GPRC5D, Her2, Her3, MAGE-A4, MET, MUC16, MUC17, NY-ESO-1, P-cadherin, PRAME, PSCA, PSMA, SSTR2, STEAP1, TROP2 (TACSTD2), VEGF, VEGFR, ySTCR, KRAS, RAF, and any combinations thereof. In some embodiments, the TAA-targeting agent is a VEGF inhibitor, a VEGFR inhibitor, a CD20 inhibitor, a CD38 inhibitor, a TROP2 inhibitor, a KRAS inhibitor, or a RAF inhibitor.

[0460] In some embodiments, the CD20 inhibitor is rituximab. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the CD38 inhibitor is daratumumab. In some embodiments, the TROP2 inhibitor is sacituzumab govitecan.

[0461] In some embodiments, the CD20 inhibitor is rituximab. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the CD38 inhibitor is daratumumab. In some embodiments, the TROP2 inhibitor is sacituzumab govitecan.

[0462] In some embodiments of any of the above-described methods, the immunotherapy may comprise one or more immune agonists. Exemplary immune agonists include, but are not limited to, a 4-1BB agonist, a 0X40 agonist, a CD40 agonist, a CD30 agonist, a GITR agonist, an ICOS agonist, a CD27 agonist, a CD28 agonist, or a CD28H / TMIGD2 agonist, aNCR3 agonist, aNCRl agonist, a NCR2 agonist, a 4-1BB agonist, a DR3 agonist, a CD226 agonist, a CRTAM agonist, a HVEM agonist, a TNFR1 agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, a TLR4 agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, and any combinations thereof.

[0463] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agents (e.g., one more additional anti-cancer therapies). Non-limiting examples of additional anti-cancer therapies include immunotherapies, chemotherapeutic agents, targeted therapies, stem cell transplantation, radiotherapy, or a combination thereof.

[0464] In some embodiments, the one or more chemotherapeutic agents comprises an anthracycline, cytarabine, all-trans-retinoic acid, arsenic trioxide, a hypomethylating agent, a BH-3 mimetic (e.g. venetoclax), temozolamide, hydroxyurea, 6-thioguanine, cyclophosphamide, gemtuzumab ozogamicin, midostaurin, ivosidenib, enasidenib, gilteritinib, glasdegib, quizartinib, olutasidenib, vincristine, or a combination thereof.

[0465] In some embodiments, the anthracycline comprises daunorubicin and / or idarubicin.

[0466] In some embodiments, the hypomethylating agent comprises azacytidine, decitabine and / or guadecitabine.

[0467] In some embodiments, the targeted therapy is a KRAS inhibitor. Non-limiting examples of a KRAS inhibitor include adagrasib (MRTX-849), divarasib (GDC-6036), opnurasib (JDQ- 443), garsorasib (D-1553), sotorasib (AMG510), MRTX1133, ARS1620, BI-1701963, N-(I-l-(3- amino-5-(trifluoromethyl)phenyl)-ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3- yl)oxy)quinazolin-4-amine, compound 0375-0604, LY3537982, (3S,4S)-8-(6-amino-5-((2- amino-3-chloroyridin-4-yl)thio)pyrazin-2-yl)-3-methyl)2-oxa-8-azaspiro[4.5]decan-4-amine, or (S)-l-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-l-yl)prop-2- en-l-one, ARS-3248 / JNJ-74699157, JDQ443, MK1084, Compound B, LY3499446, ARS-853, ARS-1620, BI-2852, BI-1823911, BAY-293, GDC-6036, BI-2493, BI-2865, RMC-6236, RMC- 6291, RMC-9805, RMC-5127, RMC-0708, RMC-8839, LUNA18, RM-018, ASP3082, LC-2, JAB-21822, JAB-23400, D-1553, AZD4625, JNJ-74699157 (ARS-3248), BBO-8520, FMC-376, G12D inhibitor, RAS(On)inhibitors, BBP-454, pharmaceutically acceptable salts thereof, and any combinations thereof.

[0468] In various embodiments, the KRAS inhibitor is a KRAS G12C inhibitor. In some embodiments, the KRAS inhibitor is the KRAS G12C inhibitor is adagrasib (MRTX-849), divarasib (GDC-6036), LY3537982, opnurasib (JDQ-443), garsorasib (D-1553) or sotorasib (AMG510). In some embodiments, the KRAS G12C inhibitor is any KRAS inhibitor described herein.

[0469] In various embodiments, the KRAS inhibitor is a KRAS G12D inhibitor. In some embodiments the KRAS G12D inhibitor is MRTX1133. In some embodiments, the KRAS G12D inhibitor may any pan-KRAS inhibitor known to those of skill in the art. In some embodiments, the KRAS G12D inhibitor is any KRAS inhibitor described herein.

[0470] In some embodiments, the targeted therapy is a RAF inhibitor.

[0471] In some embodiments, the subject is human or veterinary animal.Agents that Target PIK3IP1

[0472] Provided herein are methods comprising administering to the subject an effective amount of an agent that targets PIK3IP1. These methods may include, but are not limited to, a method of treating or preventing an autoimmune / autoinflammatory disease as described herein, and a method of increasing effectiveness of an immunotherapy as described herein.

[0473] In some embodiments, the agent that targets PIK3IP1 is selected from a small molecule, a protein, a protein-drug conjugate, a nucleotide molecule, a gene editing system, an engineered cell system, and any combination thereof.

[0474] In some embodiments, the protein is selected from a peptide, an antibody or antigenbinding fragment thereof, an alternative scaffold to immunoglobulin such as, but not limited to, a monobody; engineered, low-density -lipoprotein-receptor-derived, A domain (LDLR-A) (e.g., Avimers™); a designed ankyrin repeat protein (DARPin) lipocalin (e.g., anticalins); an affibody; engineered, Protein-A-derived, Z domain (Affibodies™) CTLD3 (e.g., Tetranectin); C-type lectin- like domain scaffolds; Sac7d-derived polypeptides (e.g., Nanoffitins® or affitins); engineered, tenascin-derived, tenascin type III domain (e.g., Centyrin™), thioredoxin (e.g., peptide aptamer); KALBITOR®; the |3-sandwich (e.g., iMab); gamma-B crystallin-derived scaffold or engineered, ubiquitin-derived scaffold (e.g., Affilins); engineered, protease inhibitor-derived, Kunitz domain (e.g., EETI-II / AGRP, BPTI / LACI-D1 / ITI-D2); engineered antibody mimics; miniproteins; engineered, Fyn-derived, SH2 domain (e.g., Fynomers®); genetically manipulated counterparts of the foregoing that retains its binding functionality, and any combination thereof.

[0475] In some embodiments, the present disclosure provides an antibody that decreases the activity and / or function of its target receptor or protein is conjugated to a diagnostic or therapeutic agent. The diagnostic agent may comprise a radioactive or non -radioactive label, a contrast agent (such as for magnetic resonance imaging, computed tomography or ultrasound), and the radioactive label can be a gamma-, beta-, alpha-, Auger electron-, or positron-emitting isotope. A diagnostic agent is a molecule which is administered conjugated to an antibody moiety, i.e., antibody or antibody fragment, or sub-fragment, and is useful in diagnosing or detecting a disease by locating the cells containing the antigen.

[0476] In certain embodiments, the antibody or antigen-binding fragment comprises one or more amino acid substitutions. In certain embodiments, amino acid substitutions of an antibody or portion thereof are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibilityto oxidation, (3) alter binding affinity for forming protein complexes, or (4) confer or modify other physicochemical or functional properties. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally occurring sequence.

[0477] A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence. Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al., Nature 354: 105 (1991), which are each incorporated herein by reference.

[0478] As used herein, the twenty naturally occurring amino acids and their abbreviations follow conventional usage. See Immunology — A Synthesis (2ndEdition, E. S. Golub and D. R. Green, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference.

[0479] In some embodiments, the antibody or antigen-binding fragment is recombinant. In certain embodiments, the antibody or antigen-binding fragment is a human antibody, a humanized antibody, a chimeric antibody, a murine antibody, a monoclonal antibody, a single chain antibody, a bispecific antibody or antigen-binding fragment thereof, a bi-epitopic antibody or antigenbinding fragment thereof, a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a VH domain, or a nanobody.

[0480] In some embodiments, the antibodies or antigen-binding fragments described herein are humanized antibodies. In some embodiments, the antibodies or antigen-binding fragments described herein are chimeric antibodies. In some embodiments, the antigen-binding fragment is a Fab. In some embodiments, the antigen-binding fragment is an scFv.

[0481] In some embodiments, an antibody or antigen-binding fragment thereof can be a bispecific antibody or antigen-binding fragment thereof. In some embodiments, the bispecific antibody or antigen-binding fragment thereof can comprise at least one antigen-binding domain. An antigen-binding domain can include any portion of an antigen-binding molecule (i.e., a molecule that is capable of specific binding to an antigen) which can specifically bind to an antigen. As a non-limiting example, an antigen-binding domain may be a portion of an antigenbinding fragment such as, without limitation, a Fab, an scFv, or a VH domain. In some embodiments, the bispecific antibody of antigen-binding fragment can comprise a first antigenbinding domain and a second antigen-binding domain.

[0482] In some embodiments, the antibody or antigen-binding fragment thereof as an agent is as described in the section “Antibodies and Antigen-binding Fragments”.

[0483] In some embodiments, the peptide-drug conjugate as an agent is an antibody-drug conjugate.

[0484] In some embodiments, the antibody-drug conjugate as an agent is as described in the section “Antibody-drug conjugates”.

[0485] In some embodiments, the peptide described herein inhibits PIK3IP1.

[0486] In some embodiments, the isolated peptides of the present disclosure can be further modified to improve affinity of the peptides and / or metabolic stability. In some embodiments, the isolated peptides of the present disclosure may also be synthesized with additional chemical groups present at their N- and / or C-termini, to enhance the affinity, bioavailability, and / or stability of the peptides.

[0487] In some embodiments, N-terminal modifications can include, but not limited to, acetylation (e.g., with acetic acid or a halogenated derivative thereof such as a-chloroacetic acid, a-bromoacetic acid, or a-iodoacetic acid), methylation (e.g., — NHCH3 or — N(CH3)2), adding a benzyloxycarbonyl (Cbz) group, or blocking the amino terminus with any blocking group containing a carboxylate functionality defined by RCOO — or sulfonyl functionality defined by R — SO2 — , where R is selected from alkyl, aryl, heteroaryl, and the like, and similar groups. One can also incorporate a desamino acid at the N-terminus (so that there is no N-terminal amino group) to decrease susceptibility to proteases or to restrict the conformation of the peptide. Alternatively or additionally, hydrophobic groups such as carbobenzoxyl, dansyl, or t-butyloxycarbonyl groups can be added to the N-terminus. Similarly, an acetyl group or a 9-fluorenylmethoxy-carbonyl group can be placed at the N-terminus.

[0488] In some embodiments, C-terminal modifications can include, but not limited to, replacing the free acid with a carboxamide group or forming a cyclic lactam at the carboxy terminus to introduce structural constraints. The peptide inhibitors of the present disclosure can be cyclized, or a desamino or descarboxy residue can be incorporated at the termini of the peptide, so that there is no terminal amino or carboxyl group, to decrease susceptibility to proteases or to restrict the conformation of the peptide. C-terminal functional groups of the peptide inhibitors of the present disclosure include amide, amide lower alkyl, amide di(lower alkyl), lower alkoxy, hydroxy, and carboxy, and the lower ester derivatives thereof, and the pharmaceutically acceptable salts thereof.IllIn some embodiments, the hydrophobic group, t-butyl oxy carbonyl, or an amido group can be added to the C-terminus of the peptide inhibitors.

[0489] Non-limiting examples of non-natural modifications include incorporation of nonencoded a-amino acids, retroinversion by using D-amino acids, P-amino acids, backbone reduction, photoreactive cross-linking amino acids, N-methylated amino acids, and C-terminal amidation and PEGylation.

[0490] Non-limiting examples of amino acid replacements include stereoisomers (e.g., D-amino acids) and unnatural amino acids such as, L-citrulline, L-homocysteine, L-homoserine, L- ornithine, 3-sulfino-L-alanine, N-(L-arginino)succinate, 3,4-dihydroxy-L-phenylalanine, 3-iodo- L-tyrosine, 3,5-diiodo-L-tyrosine, triiodothyronine, L-selenocysteine, L-thyroxine, N-(L- arginino)taurine, 4-aminobutylate, (R,S)-3-amino-2-methylpropanoate, a, a-di substituted amino acids, N-alkyl amino acids, lactic acid, -alanine, 3-pyridylalanine, 4-hydroxyproline, O- phosphoserine, N-acetyl serine, N-formylmethionine, N-methylglycine, 3-methylhistidine, 5- hydroxylysine, nor-leucine, and other similar amino acids and imino acids.

[0491] In some embodiments, the peptides of the present disclosure may comprise one or more amino acid substitutions and / or insertions and / or deletions. Amino acid substitution encompasses a substitution of the amino acid residue for a replacement amino acid residue at the same position. Inserted amino acid residues can be inserted at any position and can be inserted such that some or all of the inserted amino acid residues are immediately adjacent one another or can be inserted such that none of the inserted amino acid residues is immediately adjacent another inserted amino acid residue.

[0492] In some embodiments, the peptides of the present disclosure may be about 10-50 amino acids in length. For example, the peptides of the present disclosure may be 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, or 30 amino acids in length. In some embodiments, the peptides of the present disclosure are 25 amino acids in length. In some embodiments, the peptides of the present disclosure are 24 amino acids in length.

[0493] In some embodiments, the peptides of the present disclosure are fused or conjugated to one or more heterologous moieties. Non-limiting examples of heterologous moieties suitable for chemical conjugation and / or genetical fusion with the isolated peptides of the disclosure include,but are not limited to, nucleic acids, lipids, sugars, peptides, polypeptides, small molecules, polymers, etc. The heterologous moieties may be fused at the N- and / or C-terminus of the peptide.

[0494] In some embodiments, the peptide of the present disclosure is fused to carbohydrate, protein, and / or lipid moiety. In some embodiments, the isolated peptide of the present disclosure is fused to lipid moiety. The fusion of the peptide of the present disclosure to lipids may enhance concentration of said isolated peptide at the cell surface.

[0495] Non-limiting examples of heterologous peptides and polypeptides include, but are not limited to, an epitope (such as FLAG) or a tag sequence (such as hexa histidine, and the like) to allow for the detection and / or isolation of a fusion protein; a polypeptide or peptide which increases stability, such as an immunoglobulin constant region (e.g., an Fc domain); a half-life- extending sequence comprising a combination of two or more naturally occurring or non-naturally occurring charged and / or uncharged amino acids designed to form hydrophilic or hydrophobic fusion partner for a fusion protein; a ligand or a portion thereof which binds to a transmembrane receptor protein; an enzyme or portion thereof which is catalytically active; a polypeptide or peptide which promotes oligomerization, for example, a leucine zipper domain; a transmembrane receptor protein or a portion thereof, for example, an extracellular domain or a transmembrane and intracellular domain; a functional or non-functional antibody (e.g., an antibody that is specific for dendritic cells), or a heavy or light chain thereof; and a polypeptide which has an activity, such as a therapeutic activity, different from fusion proteins of the present disclosure. In some embodiments, the one or more heterologous moieties enhances an isolated peptide-specific immune response in a subject. In some embodiments, the one or more heterologous moieties mediates isolated peptide delivery to a specific site within a subject.

[0496] The term “monobody” as used herein encompasses a polypeptide which includes a P- strand domain lacking in disulfide bonds and containing a plurality of P-strands, two or more loop regions each connecting one P-strand to another P-strand, and optionally an N-terminal tail, a C- terminal tail, or both, wherein at least one of the two or more loop regions, the N-terminal tail, or the C-terminal tail is characterized by activity in binding a target protein or molecule. More specifically, such monobodies of the present disclosure can include three or more loop regions or, even more specifically, four or more loop regions.

[0497] In some embodiments, the size of a monobody is less than about 30 kDa. In some embodiments, the size of a monobody is less than about 20 kDa.

[0498] To achieve the specificity in the binding of a monobody to an intracellular target, the amino acid sequence of the monobody may be modified relative to the scaffold used for its construction. Scaffolds for formation of a monobody should be highly soluble and stable. An ideal scaffold for formation of a monobody should be small enough for structural analysis, yet large enough to accommodate multiple binding domains so as to achieve tight binding and / or high specificity for its target.

[0499] An exemplary scaffold for formation of a monobody is the fibronectin type III domain (Fn3). Fibronectin is a large protein which plays essential roles in the formation of extracellular matrix and cell-cell interactions; it consists of many repeats of three types (types I, II, and Ill) of small domains (Baron et al., 1991).

[0500] Fn3 itself is the paradigm of a large subfamily (Fn3 family or s-type Ig family) of the immunoglobulin superfamily. The Fn3 family includes cell adhesion molecules, cell surface hormone and cytokine receptors, chaperonins, and carbohydrate-binding domains (for reviews, see Bork Doolittle, 1992; Jones, 1993; Bork et al., 1994; Campbell Spitzfaden, 1994; Harpez Chothia, 1994).

[0501] Fn3 is small (about 94 residues), monomeric, soluble, and stable. It is one of few members of IgSF that do not have disulfide bonds and, therefore, is stable under reducing conditions. The tenth type III module of fibronectin has a fold similar to that of immunoglobulin domains, with seven p strands forming two antiparallel sheets, which pack against each other. The structure of the type H module includes seven P strands, which form a sandwich of two antiparallel sheets, one containing three strands (ABE) and the other four strands (C’CFG) (Williams Barclay, 1988). The P sheet contains residues Glu-9-Thr-14 Ser-17-Asp-23 and Thr-56- Ser-60 The majority of the conserved residues contribute to the hydrophobic core, with the invariant hydrophobic residues Trp-22 and Try-68 lying toward the N-terminal and C-terminal ends of the core, respectively. The P strands are much less flexible and appear to provide a rigid framework upon which functional, flexible loops can be built. The topology is similar to that of immunoglobulin C domains.

[0502] In some embodiments, monobodies described herein are fibronectin type III (Fn3)- derived polypeptide monobodies. In some embodiments, the Fn3 -derived monobodies include at least two Fn3 P-strand domain sequences with a loop region sequence linked between adjacent P-strand domain sequences and optionally, an N-terminal tail of at least about 2 amino acids, a C- terminal tail of at least about 2 amino acids, or both.

[0503] The loop region sequence, the N-terminal tail, or the C-terminal tail, or combinations thereof include an amino acid sequence which has binding specificity for an intracellular target. To render a loop region sequence, N-terminal tail, or C-terminal tail capable of binding to an intracellular target, either the loop region sequence, the N-terminal tail, the C-terminal tail, or a combination thereof varies by deletion, insertion, or replacement of...

Claims

Claims1. An antibody, or antigen-binding fragment thereof, that specifically binds to phosphoinositide-3 -kinase interacting protein 1 (PIK3IP1) comprising:(i) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, 9, or 17, or a variant thereof; and / or(ii) a light chain variable region (LCVR) comprising the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, 13, or 21, or a variant thereof.

2. The antibody or antigen-binding fragment of claim 1, comprising(a) an HCVR that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, or a variant thereof, and an LCVR that comprises the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, or a variant thereof;(b) an HCVR that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 9, or a variant thereof, and an LCVR that comprises the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 13, or a variant thereof; and / or(c) an HCVR that comprises the HCDR1, HCDR2, and HCDR3 of an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 17, or a variant thereof, and an LCVR that comprises the LCDR1, LCDR2, and LCDR3 of an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 21, or a variant thereof.

3. The antibody or antigen-binding fragment of any one of claims 1-2, comprising(a) an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 2, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 3, and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 4, and an LCVR that comprises an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 6, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 7, and an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 8;(b) an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 10, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 11, and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 12, and a LCVR that comprises an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 14, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 15, and an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16; and / or(c) an HCVR that comprises an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 18, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 19, and an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 20, and an LCVR that comprises an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 22, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 23, and an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 24.

4. The antibody or antigen-binding fragment of any one of claims 1-3, comprising:(i) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, 9, or 17, or a variant thereof; and(ii) an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, 13, or 21, or a variant thereof.

5. The antibody or antigen-binding fragment of any one of claims 1-4, comprising:(a) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, or a variant thereof;(b) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 9, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 13, or a variant thereof; and / or(c) an HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 17, or a variant thereof, and an LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 21, or a variant thereof.

6. An antibody or antigen-binding fragment thereof that competes for binding to PIK3IP 1 with the antibody or antigen-binding fragment of any one of claims 1-5.

7. An antibody or antigen-binding fragment thereof that binds to the same epitope of PIK3IP1 as the antibody or antigen-binding fragment of any one of claims 1-6.

8. The antibody or antigen-binding fragment of any one of claims 1-7, wherein the antibody or antigen-binding fragment binds to human PIK3IP1 and / or mouse PIK3IP1.

9. The antibody or antigen-binding fragment of any one of claims 1-8, wherein the antibody or antigen-binding fragment is recombinant.

10. The antibody or antigen-binding fragment of any one of claims 1-9, wherein the antibody or antigen-binding fragment is a human antibody, a humanized antibody, a chimeric antibody, a murine antibody, a monoclonal antibody, a single chain antibody, a bispecific antibody or antigen-binding fragment thereof, a bi-epitopic antibody or antigen-binding fragment thereof, a Fab, a Fab’, a F(ab’)2, a Fv, a scFv, a VH domain, or a nanobody.

11. The antibody or antigen-binding fragment of claim 10, wherein the bispecific antibody or antigen-binding fragment thereof is a bispecific T-cell engager (BiTE), a bispecific natural killer (NK)-cell engager (BiKE), or a bispecific macrophage engager (BiME).

12. The antibody or antigen-binding fragment of claim 11, wherein the BiTE comprises an antigen-binding domain that specifically binds to cluster of differentiation (CD)3 (CD3), alpha beta T cell receptor (TCR), or gamma delta TCR.

13. The antibody or antigen-binding fragment of claim 11, wherein the BiKE comprises an antigen-binding domain that specifically binds to Fc gamma receptor III (FcyRIII or CD16), natural killer group 2, member D (NKG2D), or natural cytotoxicity triggering receptor 3 (NCR3).

14. The antibody or antigen-binding fragment of claim 11, wherein the BiME comprises an antigen-binding domain that specifically binds to Fc gamma receptor III (Fey RI II or CD 16), dendritic cell-associated C-type lectin 1 (Dectin-1), cluster of differentiation (CD47), signal regulatory protein alpha (SIRPA), or Tyro3, Axl, and MerTK (TAM) receptor(s).

15. The antibody or antigen-binding fragment of claim 10, wherein the bispecific antibody or antigen-binding fragment thereof comprises an antigen-binding domain that specifically binds to an immune checkpoint, a cytokine or a receptor thereof, a tumor-associated antigen (TAA), or an immune stimulatory receptor.

16. The antibody or antigen-binding fragment of claim 15, wherein the immune checkpoint is programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223), cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4), CD47, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), B7 homolog 3 protein (B7-H3 or CD276), B7-H4, V-domain Ig suppressor of T cell activation (VISTA or programmed death-1 homolog (PD- 1H)), T cell immunoreceptor with Ig and ITIM Domains (TIGIT), signal regulatory protein alpha (SIRPA), signaling lymphocytic activation molecule family members (SLAMF), poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R), adenosine A2A receptor (A2aR), adenosine A2b receptor (A2bR), G protein- coupled receptor 171 (GPR171), insulin like growth factor binding protein 7 (IGFBP7), CD93, CD96, CD226, natural killer group protein 2 A (NKG2A), natural killer group protein 2D (NKG2D), a killer cell lectin like receptor G1 (KLRG1), a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2), a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3), sialic acid-binding immunoglobulin-like lectin (Sigelac)-15, CD24, sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO, P-selectin glycoprotein ligand-1 (PSGL-1), V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domaincontaining superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)), leucine rich repeats and immunoglobulin like domains 1 (LRIG1), fibrinogen-like protein 1 (FGL1), B and T lymphocyte attenuator (BTLA), leukocyte associated immunoglobulin like receptor 1 (LAIR-1), CD160, leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), leukocyte immunoglobulin-like receptor (LILRB4), angiopoietin 2 (Ang2), or vascular endothelial growth factor (VEGF), or a combination thereof.

17. The antibody or antigen-binding fragment of claim 16, wherein the immune checkpoint is PD-1, PD-L1, LAG-3, or CTLA-4, or a combination thereof.

18. The antibody or antigen-binding fragment of claim 15, wherein the cytokine is interleukin (IL)-2 (IL-2), IL-6, IL- 10, IL- 15, IL-21, interferon alpha (IFN-a), interferon beta (fFN- ), interferon gamma (IFN-y), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL- 18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF), or a receptor thereof, or a combination thereof.

19. The antibody or antigen-binding fragment of claim 15, wherein the tumor-associated antigen (TAA) is oncofetal antigen 5T4 (5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD123), CD19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms-like tyrosine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein-coupled receptor class C group 5 member D (GPRC5D), human epidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal-epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor- associated calcium signal transducer 2 (TROP2 or TACSTD2), vascular endothelial growthfactor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (ybTCR), Kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibrosarcoma (RAF), CD22, carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5 (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

20. The antibody or antigen-binding fragment of claim 15, wherein the immune stimulatory receptor is cluster of differentiation (CD) 28 (CD28), inducible T-cell costimulatory (ICOS), CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2), natural cytotoxicity receptor (NCR) 3 (NCR3), NCR1, NCR2, tumor necrosis factor receptor superfamily member 9 (4-1BB), tumor necrosis factor receptor superfamily member 4 (0X40), CD30, CD40, death receptor (DR) 3 (DR3), CD226, class I restricted T cell-associated molecule (CRTAM), CD27, herpes virus entry mediator (HVEM), tumor necrosis factor receptor (TNFR) 1 (TNFR1), TNFR2, CD2, CD7, toll-like receptor (TLR) 4 (TLR4), TLR7, TLR9, or glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), or a combination thereof.

21. The antibody or antigen-binding fragment of any one of claims 1-20, wherein the antibody or antigen-binding fragment is an IgG antibody.

22. The antibody or antigen-binding fragment of claim 21, wherein the antibody or antigenbinding fragment is of IgGl, IgG2, IgG3, or IgG4 subclass.

23. The antibody or antigen-binding fragment of claim 22, wherein the antibody or antigenbinding fragment is of IgGl subclass.

24. The antibody or antigen-binding fragment of any one of claims 1-23, wherein the antibody or antigen-binding fragment:(i) improves anti-cancer T cell response upon binding to PIK3IP1 expressed on a T cell;(ii) inhibits or antagonizes an immune suppressive function of PIK3IP1 on a T cell; and / or(iii) stimulates the release of IFN-y, MCP-1, TNF, IL-2, IL-6, and / or IL-10 from a T cell.

25. The antibody of antigen-binding fragment thereof of claim 24, wherein the T cell is PD-1 and / or LAG-3 negative, or is a memory T cell.

26. An antibody-drug conjugate comprising the antibody or antigen-binding fragment of any one of claims 1-25, conjugated to a heterologous moiety.

27. The antibody-drug conjugate of claim 26, wherein the heterologous moiety is an immune checkpoint inhibitor, a cytokine, a tumor-associated antigen (TAA) targeting agent, an immune agonist, a cytotoxic agent, a siRNA, or an antisense oligonucleotide.

28. The antibody-drug conjugate of claim 27, wherein the immune checkpoint inhibitor is a programmed cell death protein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V- domain Ig suppressor of T cell activation (VISTA or programmed death- 1 homolog (PD- 1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD122R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein- coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO inhibitor, a P-selectin glycoproteinligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR-1) inhibitor, a CD 160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, or a vascular endothelial growth factor (VEGF) inhibitor, or a combination thereof.

29. The antibody-drug conjugate of claim 28, wherein the immune checkpoint inhibitor is a PD- 1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, or a CTLA-4 inhibitor, or a combination thereof.

30. The antibody-drug conjugate of claim 29, wherein the PD-1 inhibitor or PD-L1 inhibitor is nivolumab, pembrolizumab, BAT 1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

31. The antibody-drug conjugate of claim 28, wherein the immune checkpoint inhibitor is a LAG-3 inhibitor.

32. The antibody-drug conjugate of claim 31, wherein the LAG-3 inhibitor is relatlimab (BMS- 986016), ABL501, CB213, EMB-02, favezelimab (MK-420 / 22D2), fianlimab(REGN3767), FS118, GSK2831781 (IMP731), IB 1323, ieramilimab(LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO-7247669), TSR-033, tuparstobart (INCAGN02385), or BGA-1953, or a variant or a combination thereof.

33. The antibody -drug conjugate of claim 32, wherein the LAG-3 inhibitor is relatlimab (BMS- 986016), or a variant thereof.

34. The antibody-drug conjugate of claim 28, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

35. The antibody-drug conjugate of claim 34, wherein the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab, BNT316 / ONC-392 (goti Stobart), or porustobart (HBM4003), or a variant or a combination thereof.

36. The antibody-drug conjugate of claim 27, wherein the cytokine is interleukin (IL)-2 (IL-2), IL-6, IL-10, IL-15, IL-21, interferon alpha (IFN-a), interferon beta (IFN- ), interferon gamma (IFN-y), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL- 18, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF), granulocytemacrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF), or a receptor or a combination thereof.

37. The antibody-drug conjugate of claim 27, wherein the tumor-associated antigen (TAA)- targeting agent targets oncofetal antigen 5T4 (5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD123), CD19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms- like tyrosine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein-coupled receptor class C group 5 member D (GPRC5D), humanepidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal-epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor- associated calcium signal transducer 2 (TR0P2 or TACSTD2), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (ydTCR), kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibrosarcoma (RAF), CD22, carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5 (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

38. The antibody-drug conjugate of claim 27, wherein the immune agonist is a cluster of differentiation (CD) 28 (CD28) agonist, an inducible T-cell costimulatory (ICOS) agonist, a CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2) agonist, a natural cytotoxicity receptor (NCR) 3 (NCR3) agonist, a NCR1 agonist, a NCR2 agonist, a tumor necrosis factor receptor superfamily member 9 (4- 1BB) agonist, a tumor necrosis factor receptor superfamily member 4 (0X40) agonist, a CD30 agonist, a CD40 agonist, a death receptor (DR) 3 (DR3) agonist, a CD226 agonist, a class I restricted T cell-associated molecule (CRTAM) agonist, a CD27 agonist, a herpes virus entry mediator (HVEM) agonist, a tumor necrosis factor receptor (TNFR) 1 (TNFR1) agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, a toll-like receptor (TLR) 4 (TLR4) agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a glucocorticoid- induced tumor necrosis factor receptor-related protein (GITR) agonist, or a combination thereof.

39. A polynucleotide encoding the antibody or antigen-binding fragment of any one of claims 1-25.

40. A vector comprising the polynucleotide of claim 39.

41. A host cell expressing the antibody or antigen-binding fragment of any one of claims 1-25, or comprising the polynucleotide of claim 39 or the vector of claim 40.

42. The host cell of claim 41, wherein the antibody or antigen-binding fragment is recombinantly produced.

43. A method of producing the antibody or antigen-binding fragment of any one of claims 1- 25, comprising culturing the host cell of claim 41 or 42, and isolating the antibody or antigen-binding fragment.

44. A pharmaceutical composition comprising the antibody or antigen-binding fragment of any one of claims 1-25, the antibody-drug conjugate of any one of claims 26-38, the polynucleotide of claim 39, or the vector of claim 40, and a pharmaceutically acceptable carrier or diluent.

45. The pharmaceutical composition of claim 44, further comprising one or more immune checkpoint inhibitors, cytokines, tumor-associated antigen (TAA)-targeting agents, immune agonists, cytotoxic agents, siRNAs, or antisense oligonucleotides, or combination thereof.

46. The pharmaceutical composition of claim 45, wherein the immune checkpoint inhibitor is a programmed cell death protein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V- domain Ig suppressor of T cell activation (VISTA or programmed death- 1 homolog (PD- 1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD122R) inhibitor, an adenosineA2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein- coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR-1) inhibitor, a CD 160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, or a vascular endothelial growth factor (VEGF) inhibitor, or a combination thereof.

47. The pharmaceutical composition of claim 46, wherein the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, and / or a CTLA-4 inhibitor, or a combination thereof.

48. The pharmaceutical composition of claim 47, wherein the PD-1 inhibitor or PD-L1 inhibitor is nivolumab, pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab,rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

49. The pharmaceutical composition of claim 46, wherein the immune checkpoint inhibitor is a LAG-3 inhibitor.

50. The pharmaceutical composition of claim 49, wherein the LAG-3 inhibitor is relatlimab(BMS-986016), ABL501, CB213, EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab(LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO-7247669), TSR-033, tuparstobart (INCAGN02385), or BGA-1953, or a variant or a combination thereof.

51. The pharmaceutical composition of claim 50, wherein the LAG-3 inhibitor is relatlimab (BMS-986016), or a variant thereof.

52. The pharmaceutical composition of claim 46, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

53. The pharmaceutical composition of claim 52, wherein the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab, BNT316 / ONC-392 (goti Stobart), or porustobart (HBM4003), or a variant or a combination thereof.

54. The pharmaceutical composition of claim 45, wherein the cytokine is interleukin (IL) 2 (IL- 2), IL-6, IL- 10, IL- 15, IL-21, interferon alpha (IFN-a), interferon beta (fFN-0), interferon gamma (IFN-y), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL- 18, monocyte chemoattractant protein- 1 (MCP-1), tumor necrosis factor (TNF), granulocytemacrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF), or a receptor thereof, or a combination thereof.

55. The pharmaceutical composition of claim 45, wherein the tumor-associated antigen (TAA)- targeting agent targets oncofetal antigen 5T4 (5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD 123), CD 19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms- like tyrosine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein-coupled receptor class C group 5 member D (GPRC5D), ), human epidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal-epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor- associated calcium signal transducer 2 (TR0P2 or TACSTD2), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (ySTCR), kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibrosarcoma (RAF), CD22, carcinoembryonic antigen-related cell adhesion molecule (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

56. The pharmaceutical composition of claim 45, wherein the immune agonist is a cluster of differentiation (CD28) agonist, an inducible T-cell costimulatory (ICOS) agonist, a CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2) agonist, a natural cytotoxicity receptor (NCR) 3 (NCR3) agonist, a NCRl agonist, a NCR2 agonist, a tumor necrosis factor receptor superfamily member 9 (4-1BB agonist), , a tumor necrosis factor receptor superfamily member 4 (0X40) agonist, a CD30 agonist, a CD40 agonist, a death receptor (DR) 3 (DR3) agonist, a CD226 agonist, a class I restricted T cell- associated molecule (CRTAM) agonist, a CD27 agonist, a herpes virus entry mediator (HVEM) agonist, a tumor necrosis factor receptor (TNFR) 1 (TNFR1) agonist, a TNFR2agonist, a CD2 agonist, a CD7 agonist, a toll-like receptor (TLR) 4 (TLR4) agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist, or a combination thereof.

57. A kit comprising (i) the antibody or antigen-binding fragment of any one of claims 1-25, the antibody-drug conjugate of any one of claims 26-38, the polynucleotide of claim 39, or the vector of claim 40, and (ii) optionally, packaging for the same and / or instructions for use.

58. A method for improving an anti-cancer T cell response in a subject in need thereof, the method comprising administering to the subject an effective amount of an agent that targets PIK3IP1 such that the anti-cancer T cell response of the T cells is improved.

59. The method of claim 58, wherein the T cell is PD-1 and / or LAG-3 negative, or is a memory T cell.

60. A method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject an effective amount of an agent that targets PIK3IP1.

61. The method of claim 60, wherein the cancer is resistant to an immunotherapy comprising one or more immune checkpoint inhibitors.

62. The method of claim 61, wherein the immune checkpoint inhibitor is a programmed cell death protein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a B7-H4 inhibitor, a V- domain Ig suppressor of T cell activation (VISTA or programmed death- 1 homolog (PD- 1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activationmolecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein- coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO inhibitor, a P-selectin glycoprotein ligand-1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a Leukocyte associated immunoglobulin like receptor 1 (LAIR-1) inhibitor, a CD 160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, or a leukocyte immunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, or a vascular endothelial growth factor (VEGF) inhibitor, or a combination thereof.

63. The method of claim 62, wherein the immune checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor, or a combination thereof.

64. The method of claim 63, wherein the PD-1 inhibitor or PD-L1 inhibitor is nivolumab, pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab,reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

65. The method of claim 62, wherein the immune checkpoint inhibitor is a LAG-3 inhibitor.

66. The method of claim 65, wherein the LAG-3 inhibitor is relatlimab (BMS-986016), ABL501, CB213, EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BL754111 / 496G6), pavunalimab (XmAb841), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO-7247669), TSR-033, tuparstobart (INCAGN02385), or BGA- 1953, or a variant or a combination thereof.

67. The method of claim 66, wherein the LAG-3 inhibitor is relatlimab (BMS-986016), or a variant thereof.

68. The method of claim 62, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

69. The method of claim 68, wherein the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab, BNT316 / ONC-392 (gotistobart), porustobart (HBM4003), or a variant or combination thereof.

70. The method of any one of claims 60-69, wherein the method further comprises administering to the subject one or more additional anti-cancer therapies.

71. The method of claim 70, wherein the one or more additional anti -cancer therapies comprise an immunotherapy, a chemotherapy, a targeted therapy, or a radiotherapy, or a combination thereof.

72. The method of claim 71, wherein the one or more additional anti-cancer therapies comprise an immunotherapy.

73. A method of increasing effectiveness of an immunotherapy in a subject in need thereof, comprising co-administering to the subject an immunotherapy with an effective amount of an agent that targets PIK3IP1.

74. The method of any one of claims 58-73, wherein the agent that targets PIK3IP1 is selected from a small molecule, a protein, a protein-drug conjugate, a nucleotide molecule, a gene editing system, an engineered cell system, and any combination thereof.

75. The method of claim 74, wherein the protein is selected from a peptide; an antibody or antigen-binding fragment thereof; a monobody; engineered, low-density-lipoprotein- receptor-derived, A domain (LDLR-A) (e.g., Avimers™); a designed ankyrin repeat protein (DARPin) lipocalin (e.g., anticalins); an affibody; engineered, Protein-A-derived, Z domain (Affibodies™) CTLD3 (e.g., Tetranectin); C-type lectin-like domain scaffolds; Sac7d- derived polypeptides (e.g., Nanoffitins® or affitins); engineered, tenascin-derived, tenascin type III domain (e.g., Centyrin™), thioredoxin (e.g., peptide aptamer); KALBITOR®; the P-sandwich (e g., iMab); gamma-B crystallin-derived scaffold or engineered, ubiquitinderived scaffold (e.g., Affilins); engineered, protease inhibitor-derived, Kunitz domain (e.g., EETI-II / AGRP, BPTI / LACI-D1 / ITI-D2); engineered antibody mimics; miniproteins; engineered, Fyn-derived, SH2 domain (e.g., Fynomers®); genetically manipulated counterparts of the foregoing that retains its binding functionality, and any combination thereof.

76. The method of claim 74, wherein the antibody or antigen-binding fragment thereof is selected from an intact antibody, an antigen-binding (Fab) fragment, an Fab’ fragment, an (Fab’)2 fragment, an Fd, an Fv, a dAb, a single domain fragment or single monomeric variable antibody domain, a single-chain Diabody (scDb), a single-chain variable fragment (scFv), a VH domain, a nanobody, a Bi-specific T-cell engager (BiTE), a bispecific killer cell engager (BiKE), a bi-specific macrophage nano-engager (BiME), a CrossMab, a tri- specific binding partner, and any combination thereof.

77. The method of claim 74, wherein the nucleotide molecule is selected from an antisense oligonucleotide, a miRNA, an siRNA, an shRNA, an sgRNA, and any combination thereof.

78. The method of claim 74, wherein the gene editing system comprises a CRISPR-associated protein (Cas) nuclease, a zinc finger nuclease (ZFN), a transcription activator-like effector nuclease (TALEN), a meganuclease, any endo- or exo-nuclease, variants thereof, fragments thereof, or any combination thereof.

79. The method of claim 74, wherein the engineered cell system comprises a chimeric antigen receptor (CAR) modified cell comprising a fragment that targets PIK3IP1.

80. The method of claim 79, wherein the CAR-modified cell is a CAR-modified T cell (CAR- T cell), a CAR-modified natural killer (NK) cell (CAR-NK cell), or a CAR-macrophage (CAR-M).

81. The method of any one of claims 73-80, wherein the agent is conjugated to a detectable label, a chemotherapeutic agent, a radioisotope, or a toxin.

82. The method of any one of claims 58-76, wherein the agent that targets PIK3IP1 comprises the antibody or antigen-binding fragment of any one of claims 1-25, the antibody-drug conjugate of any one of claims 26-38, the polynucleotide of claim 39, the vector of claim 40, or the pharmaceutical composition of any one of claims 44-56.

83. The method of any one of claims 73-82, wherein the immunotherapy and the agent that targets PIK3IP1 are administered sequentially.

84. The method of any one of claims 71-82, wherein the immunotherapy and the agent that targets PIK3IP1 are administered simultaneously in one composition or in separate compositions.

85. The method of any one of claims 71 -84, wherein the immunotherapy comprises one or more immune checkpoint inhibitors, cytokines, tumor-associated antigen (TAA)-targeting agents, or immune agonists.

86. The method of claim 85, wherein the immune checkpoint inhibitor is a programmed cell death protein 1 (PD-1) inhibitor, a programmed death-ligand 1 (PD-L1) inhibitor, a lymphocyte activation gene 3 (LAG-3 or cluster of differentiation (CD) 223 (CD223)) inhibitor, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, a CD47 inhibitor, a T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) inhibitor, a B7 homolog 3 protein (B7-H3 or CD276) inhibitor, a (B7-H4) inhibitor, a V- domain Ig suppressor of T cell activation (VISTA or programmed death- 1 homolog (PD- 1H)) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a signal regulatory protein alpha (SIRPA) inhibitor, a signaling lymphocytic activation molecule family members (SLAMF) inhibitor, a poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG or CD112R) inhibitor, an adenosine A2A receptor (A2aR) inhibitor, an adenosine A2b receptor (A2bR) inhibitor, a G protein- coupled receptor 171 (GPR171) inhibitor, an insulin like growth factor binding protein 7 (IGFBP7) inhibitor, a CD93 inhibitor, a CD96 inhibitor, a CD226 inhibitor, a natural killer group protein 2A (NKG2A) inhibitor, a natural killer group protein 2D (NKG2D) inhibitor, a killer cell lectin like receptor G1 (KLRG1) inhibitor, a human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) inhibitor, a killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 3 (KIR3DL3) inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-15 inhibitor, a CD24 inhibitor, a sialic acid-binding immunoglobulin-like lectin (Sigelac)-lO inhibitor, a P-selectin glycoprotein ligand- 1 (PSGL-1) inhibitor, a V-set and Ig domain-containing protein 3 (VSIG3 or or B7 and T cell immunoglobulin domain-containing superfamily member (BT-IgSF) or immunoglobulin superfamily member 11 (IGSF11)) inhibitor, a leucine rich repeats and immunoglobulin like domains 1 (LRIG1) inhibitor, a fibrinogen-like protein 1 (FGL1) inhibitor, a B and T lymphocyte attenuator (BTLA) inhibitor, a leukocyte associated immunoglobulin-like receptor 1 (LAIR-1) inhibitor, a CD 160 inhibitor, a leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) inhibitor, a leukocyteimmunoglobulin-like receptor (LILRB4) inhibitor, an angiopoietin 2 (Ang2) inhibitor, or a vascular endothelial growth factor (VEGF) inhibitor, or a combination thereof.

87. The method of claim 86, wherein the immune checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, and / or a CTLA-4 inhibitor.

88. The method of claim 87, wherein the PD-1 inhibitor or PD-L1 inhibitor is nivolumab, pembrolizumab, BAT1308, durvalumab, avelumab, atezolizumab, acrixolimab, balstilimab, budigalimab, bintrafusp alfa, cadonilimab, camrelizumab, cemiplimab, cetrelimab, danvilostomig, dostarlimab, eciskafusp alfa, enlonstobart, ezabenlimab, fanastomig, fidasimtamab, finotonlimab, geptanolimab, iparomlimab, ivonescimab, izuralimab, lipustobart, lodapolimab, lomvastomig, lorigerlimab, nofazinlimab, penpulimab, peresolimab, pidilizumab, pimivalimab, pradusinstobart, prolgolimab, pucotenlimab, reozalimab, retifanlimab, rilvegostomig, rosnilimab, rulonilimab, sabestomig, sasanlimab, serplulimab, sintilimab, spartalizumab, tebotelimab, tislelizumab, tobemstomig, toripalimab, volrustomig, vudalimab, zeluvalimab, or zimberelimab, or a variant or a combination thereof.

89. The method of claim 86, wherein the immune checkpoint inhibitor is a LAG-3 inhibitor.

90. The method of claim 89, wherein the LAG-3 inhibitor is ABL501, CB213, EMB-02, favezelimab (MK-420 / 22D2), fianlimab (REGN3767), FS118, GSK2831781 (IMP731), IBI323, ieramilimab (LAG525 / IMP701 / BAP050), miptenalimab (BI-754111 / 496G6), pavunalimab (XmAb841), relatlimab (BMS-986016), Sym022, tebotelimab (MGD013), tobemstomig (RG-6139 / RO-7247669), TSR-033, tuparstobart (INCAGN02385), or BGA- 1953, or a variant or a combination thereof.

91. The method of claim 90, wherein the LAG-3 inhibitor is relatlimab (BMS-986016), or a variant thereof.

92. The method of claim 86, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

93. The method of claim 92, wherein the CTLA-4 inhibitor is ipilimumab, tremelimumab, quavonlimab, BNT316 / ONC-392 (goti Stobart), or pomstobart (HBM4003), or a variant or a combination thereof.

94. The method of claim 85, wherein the cytokine is interleukin (IL) 2 (IL-2), IL-6, IL- 10, IL- 15, IL-21, interferon alpha (IFN-a), interferon beta (IFN-P), interferon gamma (IFN-y), chemokine (C-C motif) ligand (CCL) 19 (CCL19), CCL21, IL- 18, monocyte chemoattractant protein- 1 (MCP-1), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony stimulating factor (G-CSF) or a receptor or a combination thereof.

95. The method of claim 85, wherein the tumor-associated antigen (TAA) targeting agent targets oncofetal antigen 5T4 (5T4), angiopoietin 2 (Ang2), B-cell maturation antigen (BCMA), cluster of differentiation (CD) 123 (CD123), CD19, CD20, CD33, CD38, CD47, carcinoembryonic antigen (CEA), C-type lectin domain family 12 member A (CLEC12A), delta-like ligand 3 (DLL3), epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), Fc receptor homolog 5 (FcRH5), fms-like tyrosine kinase 3 (FLT3), disialoganglioside (GD2), Glypican-3, glycoprotein A33 (gpA33), G protein- coupled receptor class C group 5 member D (GPRC5D), human epidermal growth factor receptor (Her) 2 (Her2), Her3, melanoma antigen family A4 (MAGE-A4), mesenchymal- epithelial transition factor (MET), mucin (MUC) 16 (MUC16), MUC17, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), placental cadherin (P-cadherin), preferentially expressed antigen in melanoma (PRAME), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), somatostatin receptor 2 (SSTR2), six transmembrane epithelial antigen of the prostate 1 (STEAP1), tumor-associated calcium signal transducer 2 (TROP2 orTACSTD2), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), gamma delta T-cell receptor (ySTCR), kirsten rat sarcoma viral oncogene homolog (KRAS), rapidly accelerated fibrosarcoma (RAF), CD22, carcinoembryonic antigen-related cell adhesion molecule(CEACAM) 5 (CEACAM5), CEACAM6, Claudin 6, Claudin 18.2, or TEK tyrosine kinase (Tie2), or a combination thereof.

96. The method of claim 85, wherein the immune agonist is a cluster of differentiation (CD) 28 (CD28) agonist, an inducible T-cell costimulatory (ICOS) agonist, a CD28 homolog / transmembrane and immunoglobulin domain containing 2 (CD28H / TMIGD2) agonist, a natural cytotoxicity receptor (NCR3) agonist, a NCR1 agonist, a NCR2 agonist, a tumor necrosis factor receptor superfamily member 9 (4- IBB) agonist, a tumor necrosis factor receptor superfamily member 4 (0X40) agonist, a CD30 agonist, a CD40 agonist, a death receptor (DR) 3 (DR3) agonist, a CD226 agonist, a class I restricted T cell-associated molecule (CRTAM) agonist, a CD27 agonist, a herpes virus entry mediator (HVEM) agonist, a tumor necrosis factor receptor (TNFR) 1 (TNFR1) agonist, a TNFR2 agonist, a CD2 agonist, a CD7 agonist, or, a toll-like receptor (TLR) 4 (TLR4) agonist, a TLR7 agonist, a TLR8 agonist, a TLR9 agonist, or a glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist, or a combination thereof.

97. The method of any one of claims 58-96, wherein the subject has a solid cancer.

98. The method of claim 97, wherein the solid cancer is a lung cancer, a glioma, a thyroid cancer, a colorectal cancer, a head and neck cancer, a gastric cancer, a stomach cancer, a liver cancer, a pancreatic cancer, a renal cancer, a urothelial cancer, a prostate cancer, a testis cancer, a breast cancer, a cervical cancer, an endometrial cancer, an ovarian cancer, a gallbladder cancer, a sarcoma, or a melanoma.

99. The method of claim 98, wherein the solid cancer is a colorectal cancer or a melanoma.

100. The method of any one of claims 58-96, wherein the subject has a hematologic cancer.

101. The method of claim 100, wherein the hematologic cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage, hairy cell leukemia, multiple myeloma, chronic myeloid neoplasm, non-Hodgkin lymphoma,Hodgkin lymphoma, chronic leukemia, dendritic / histiocytic neoplasm, or lymphoproliferative disorder.

102. The method of claim 101, wherein the hematologic cancer is acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

103. The method of any one of claims 58-102, wherein the method further comprises administering to the subject one or more additional anti-cancer therapies.

104. The method of claim 103, wherein the one or more additional anti-cancer therapies comprise a chemotherapy, a targeted therapy, a radiotherapy, or a combination thereof.

105. The method of any one of claims 58-104, wherein the administering is via intratumoral, intravenous, intradermal, intraperitoneal, subcutaneous, intramuscular, inhalation, oral delivery, lipid nanoparticle (LNP)-based delivery, cellular delivery, viral and / or non-viral delivery, or gene editing, or as a cargo in a cell, or a combination thereof.

106. The method of any one of claims 58-105, wherein the subject is human or veterinary animal.

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