EP4652203A2

EP4652203A2 - Ph-selective antibody-based checkpoint inhibitors for conditional antibody-dependent cellular cytotoxicity

Info

Publication number: EP4652203A2
Application number: EP24745184.2A
Authority: EP
Inventors: Michael Kaleko; Jennifer MAYNARD; Annalee Nguyen; Yutong Liu; Yakendra BAJGAIN
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-01-18
Filing date: 2024-01-18
Publication date: 2025-11-26
Also published as: WO2024155778A2; WO2024155778A3

Abstract

Disclosed herein are compositions comprising pH-seiective antibody-based checkpoint inhibitors with modified Fc domains and methods of using the same for the treatment of cancer.

Description

Attorney Docket No.: SYN-061PC/112492-5061 PH-SELECTIVE ANTIBODY-BASED CHECKPOINT INHIBITORS FOR CONDITIONAL ANTIBODY- DEPENDENT CELLULAR CYTOTOXICITY TECHNICAL FIELD [0001] The present disclosure provides, in part, pH-selective antibodies, compositions thereof, and methods of using the same for the treatment of cancer, e.g., in a mammalian subject, such as a human. CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63/480,448, filed January 18, 2024, the entire contents of which are herein incorporated by reference. DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY [0003] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety. A computer readable format copy of the Sequence Listing (filename: Sequence_Listing_SYN-061PC.xml; date recorded January 16, 2024; file size: 29,321 bytes). BACKGROUND [0004] Checkpoint inhibitors (CPIs) have emerged as an effective class of anticancer agents. Nearly half of all patients with metastatic cancer in economically developed countries are eligible to receive CPIs, with eight approved agents available for 17 different malignancies as of 2021. The prototypical mechanism underlying CPIs involve blockade of immune checkpoints, which are receptors expressed by immune cells that enable dynamic regulation of immune homeostasis and are particularly relevant to T cell functionality. PD-1, its primary ligand, PD-L1, and CTLA-4 are among the most studied of druggable CPI targets. [0005] CTLA-4 (CD152) has a role in immune activation, engaging with the dendritic cell ligand B7 (also known as CD80) and functions as a higher affinity competitor to CD28, thus limiting the extent of T cell activation at the priming stage. Expression of CTLA-4 also enhances the function and promotes the expansion of regulatory T (Treg) cells in the tumor microenvironment. CTLA-4 is a critical negative regulator of T cells and its blockade with the fully human monoclonal IgG1 antibody, ipilimumab (Ipi), is an effective treatment for a wide range of cancers. In the tumor microenvironment, inhibition of CTLA-4 restores antitumor immune responses by two separate but complementary actions: 1) the activation and proliferation of T cells including tumor-infiltrating T effector cells, and 2) the reduction of immunosuppressive T regulatory cell (Treg) function. Despite the successes of Ipi in the clinic, including longer overall survival, patients have experienced increased treatment-related adverse events. DB1/ 133359610.3 1 Attorney Docket No.: SYN-061PC/112492-5061 [0006] Abrogation of immune-checkpoint signaling introduces several caveats within the context of cancer treatment. For example, data from preclinical studies demonstrated that genetic ablation of Ctla4 in mice resulted in death in early life (typically at 3–4 weeks of age) owing to lymphoproliferation and profound multiorgan autoimmunity. The clinical experience mimics these findings; CTLA4 inhibition results in a high incidence of dose-dependent toxicities (high-grade toxicities in 38.6% and 57.9% of patients with metastatic melanoma receiving ipilimumab 3ௗmg/kg or 10ௗmg/kg, respectively). [0007] Currently, the dose-limiting toxicity of checkpoint inhibitors, such as Ipi, prevents their maximal anticancer activity potential, prompting the development of next-generation molecules with enhanced therapeutic index. There remains a need for strategies that reduce off-target binding, immunotoxicities, chronic immune-related adverse events (irAEs), and systemic antibody-mediated effects within the context of antibody-based CPIs. SUMMARY [0008] Accordingly, provided herein are compositions of pH-selective antibodies comprising an Fc amino acid sequence comprising a substitution of one or more residues at one or more of position 233- 235, 267-268, 296, and 298, or positions corresponding thereto, relative to a wild-type human IgG1 Fc antibody domain of SEQ ID NO: 1, and an antigen-binding portion that binds a checkpoint inhibitor target, the target being a checkpoint inhibitor that functions, in part, by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP), wherein the checkpoint inhibitor target is or comprises one or more of CTLA-4, VISTA, TIGIT, LAG-3, TIM-3, B7-H3, CD73, PD- 1, PD-L1, PD-L2, GITR, 4-1BB, CD36, CD25, CCR4, CCR5, CCR8, CCR10, CXCR3, TGF-ȕR, ICOS, CD27, OX40, or CD15. [0009] In embodiments, the checkpoint inhibitor target is CTLA-4. In embodiments, the CTLA-4 is human (hCTLA-4) or murine (mCTLA-4). [0010] In embodiments, the antigen-binding portion comprises an immunoglobulin heavy chain variable region comprising a CDRH1 comprising an amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 5, or SEQ ID NO: 23, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 6, or SEQ ID NO: 24, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 7, or SEQ ID NO: 25, and comprises an immunoglobulin light chain variable region comprising: a CDRL1 comprising an amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO: 26, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 27, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 28. DB1/ 133359610.3 2 Attorney Docket No.: SYN-061PC/112492-5061 [0011] In embodiments, the antigen-binding portion binds CTLA-4 and comprises an immunoglobulin heavy chain variable region comprising a HCDR1 of SEQ ID NO: 23, a HCDR2 of SEQ ID NO: 24, and a HCDR3 of SEQ ID NO: 25 and an amino acid sequence having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 15, and a light chain variable region comprising a LCDR1 of SEQ ID NO: 26, a LCDR2 of SEQ ID NO: 27, and a LCDR3 of SEQ ID NO: 28 and an amino acid sequence having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 16. [0012] In embodiments, the antigen-binding portion binds CTLA-4 and comprises an immunoglobulin heavy chain variable region comprising an amino acid of SEQ ID NO: 15, a light chain variable region comprising an amino acid sequence of SEQ ID NO: 16, and a human IgG1 Fc domain amino acid sequence having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 1 and having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto, e.g., identity calculated outside of positions 233-235, 267-268, 296, and 298, or positions corresponding thereto. [0013] In embodiments, the pH-selective antibody binds CTLA-4 and comprises a heavy chain comprising a HCDR1 of SEQ ID NO: 23, a HCDR2 of SEQ ID NO: 24, and a HCDR3 of SEQ ID NO: 25 and an amino acid sequence of at least about 95%, at least about 98%, or at least about 99% to SEQ ID NO: 17, with a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto, and a light chain comprising a LCDR1 of SEQ ID NO: 26, a LCDR2 of SEQ ID NO: 27, and a LCDR3 of SEQ ID NO: 28 and an amino acid sequence of at least about 95%, at least about 98%, or at least about 99% to SEQ ID NO: 18. [0014] In embodiments, the substitution of the residue at position 233, or the position corresponding thereto, is a negatively charged amino acid. In embodiments, the negatively charged amino acid is selected from aspartic acid or glutamic acid. [0015] In embodiments, the substitution of the residue at position 234, or the position corresponding thereto, is an aliphatic amino acid. In embodiments, the aliphatic amino acid is selected from glycine, alanine, valine, proline, and isoleucine. In embodiments, the aliphatic residue is valine. [0016] In embodiments, the substitution of the residue at position 235, or the position corresponding thereto, is an aliphatic or a negatively charged amino acid. In embodiments, the aliphatic amino acid is selected from glycine, alanine, valine, proline, or isoleucine. In embodiments, the negatively charged amino acid is selected from aspartic acid and glutamic acid. DB1/ 133359610.3 3 Attorney Docket No.: SYN-061PC/112492-5061 [0017] In embodiments, the substitution of the residue at position 267, or the position corresponding thereto, is an aliphatic or a negatively charged amino acid. In embodiments, the aliphatic amino acid is selected from glycine, alanine, valine, proline, isoleucine, and leucine. In embodiments, the negatively charged amino acid is selected from aspartic acid and glutamic acid. [0018] In embodiments, the substitution of the residue at position 268, or the position corresponding thereto, is a negatively charged amino acid. In embodiments, the negatively charged amino acid is selected from aspartic acid and glutamic acid. [0019] In embodiments, the substitution of the residue at position 296, or the position corresponding thereto, is a positively charged amino acid. In embodiments, the positively charged amino acid is selected from histidine, lysine, and arginine. [0020] In embodiments, the substitution of the residue at position 298, or the position corresponding thereto, is a positively charged amino acid. In embodiments, the positively charged amino acid is selected from histidine, lysine, and arginine. [0021] In embodiments, the Fc amino acid sequence comprises one or more of: 1) E233D, L234V, L235V, S267E, H268D, and Y296H, 2) E233D, L234V, L235V, S267E, H268D, and S298R, 3) E233D, L234V, L235D, S267G, H268D, and Y296H, 4) E233D, L234V, L235D, S267E, H268D, and Y296H, 5) S267E, H268D, and Y296H, 6) S267D, H268D, and S298R, or ) S267G, H268D, and Y296H, or positions corresponding thereto. [0022] In embodiments, the Fc amino acid sequence comprises the substitutions S267E and H268D, or positions corresponding thereto. In embodiments, the Fc amino acid sequence comprises the substitutions S267E, H268D, and Y296H, or positions corresponding thereto. [0023] In embodiments, the pH-selective antibody comprises one or more additional Fc amino acid sequence substitutions at one or more positions of S240, A331, and/or I333, or positions corresponding thereto. In embodiments, the pH-selective antibody comprises the additional Fc amino acid sequence substitutions S240D, A331L, and/or I333E, or positions corresponding thereto. In embodiments, the pH- selective antibody comprises S240D/A331L/I333E, or positions corresponding thereto. [0024] In embodiments, the pH-selective antibody binds CTLA-4 and comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 19 further comprising the Fc amino acid substitutions of S240D, A331L, and/or I333E, or positions corresponding thereto, and a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto, and a light chain comprising an amino acid sequence of SEQ ID NO: 20. DB1/ 133359610.3 4 Attorney Docket No.: SYN-061PC/112492-5061 [0025] In embodiments, the pH-selective antibody binds CTLA-4 and comprises a heavy chain amino acid sequence comprising at least 95% sequence identity to SEQ ID NO: 21 further comprising a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto; and a light chain comprising at least 95% sequence identity to SEQ ID NO: 20. [0026] In embodiments, the pH-selective antibody binds CTLA-4 and comprises a heavy chain amino acid sequence comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto; and a light chain comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 18. [0027] In embodiments, the pH-selective antibody is an IgG1 antibody. [0028] In embodiments, the pH-selective antibody exhibits greater affinity for an antibody Fc receptor at a pH less than about 7.0 in comparison to its affinity at a pH greater than about 7.0. In embodiments, the pH-selective antibody has higher affinity for an antibody Fc receptor at: about or at least about pH 7.0 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.9 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.8 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.7 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.6 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.5 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.4 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.3 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.2 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.1 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.0 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.9 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.8 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.7 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.6 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.5 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.4 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.3 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.2 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.1 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.0 relative to its affinity at about or at least about pH 7.4. DB1/ 133359610.3 5 Attorney Docket No.: SYN-061PC/112492-5061 [0029] In embodiments, the pH-selective antibody exhibits greater affinity for an antibody Fc receptor at a pH of about 6.5 in comparison to its affinity at a pH of about 7.4. In embodiments, the pH-selective antibody exhibits about or at least about a 1-fold increase in affinity, about or at least about a 1.5-fold increase in affinity, about or at least about a 2-fold increase in affinity, about or at least about a 2.5-fold increase in affinity, about or at least about a 3-fold increase in affinity, about or at least about a 3.5-fold increase in affinity, about or at least about a 4-fold increase in affinity, about or at least about a 4.5-fold increase in affinity, about or at least about a 5-fold increase in affinity for an antibody Fc receptor at a pH of about 6.5 compared to its affinity for an antibody Fc receptor at pH 7.4. [0030] In embodiments, the pH-selective antibody exhibits greater selectivity for binding an antibody Fc receptor at a pH less than about 7.0 in comparison to a pH greater than about 7.0 relative to an antibody with a wild-type Fc domain. In embodiments, the pH-selective antibody exhibits a selectivity for binding at a pH of about 6.5 versus at a pH of about 7.4 of about or at least about 1.1, about or at least about 1.2, about or at least about 1.3, about or at least about 1.4, about or at least about 1.5, about or at least about 1.6, about or at least about 1.7, about or at least about 1.8, about or at least about 1.9, about or at least about 2.0, about or at least about 2.1, about or at least about 2.2, about or at least about 2.2, about or at least about 2.3, about or at least about 2.4, about or at least about 2.5, about or at least about 2.6, about or at least about 2.7, about or at least about 2.8, about or at least about 2.9, about or at least about 3.0, about or at least about 3.1, about or at least about 3.2, about or at least about 3.3, about or at least about 3.4, about or at least about 3.5, about or at least about 3.6, about or at least about 3.8, or about or at least about 4.0. [0031] In embodiments, the antibody Fc receptor is one or more of an Fc gamma-receptor (FcȖR), FcRn, FcȖRI (CD64), FcȖRII (CD32), and FcȖRIII (CD16). [0032] In embodiments, the pH-selective antibody exhibits pH-selective FcȖRIIIa binding. [0033] In embodiments, the pH-selective antibody exhibits increased binding for the checkpoint inhibitor target in an acidic environment in comparison to an environment at a pH greater than about 7.0. [0034] In embodiments, the pH-selective antibody comprises a variable heavy chain amino acid sequence and a variable light chain amino acid sequence of ipilimumab, wherein the variable heavy chain amino acid sequence has one or more substitutions in a CDR amino acid sequence and/or the variable light chain amino acid sequence has one or more substitutions in a CDR amino acid sequence; and the checkpoint inhibitor target is CTLA-4. [0035] In embodiments, wherein the pH-selective antibody comprises and antigen-binding portion that binds CTLA-4 and comprises an immunoglobulin heavy chain variable region comprising a CDRH1 DB1/ 133359610.3 6 Attorney Docket No.: SYN-061PC/112492-5061 comprising an amino acid sequence of SEQ ID NO: 5, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 6, and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 7, and comprises an immunoglobulin light chain variable region comprising a CDRL1 comprising an amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 10, wherein the pH- selective antibody exhibits an increased level of CTLA-4 binding in an acidic environment in comparison to at a pH of about 7.4. [0036] In embodiments, the pH-selective antibody exhibits increased binding for the checkpoint inhibitor target on T cells within a tumor microenvironment in comparison to T cells outside of the tumor microenvironment. In embodiments, the pH-selective antibody exhibits increased binding for the checkpoint inhibitor target on cancer cells within a tumor microenvironment in comparison to cells outside of the tumor microenvironment. [0037] In embodiments, the pH-selective antibody preferably binds CTLA-4 on T regulatory cells (T regs) within a tumor microenvironment in comparison to T regs outside the tumor microenvironment. [0038] In embodiments, the pH-selective antibody exhibits greater antibody-dependent cellular phagocytosis (ADCP) and/or antibody-dependent cellular cytotoxicity (ADCC) at a pH less than about 7.0 in comparison to a pH greater than about 7.0. In embodiments, the pH-selective antibody exhibits about or at least about a 0.5-fold increase in ADCC, about or at least about a 1-fold increase in ADCC, about or at least about a 1.5-fold increase in ADCC, about or at least about a 2-fold increase in ADCC, about or at least about a 2.5-fold increase in ADCC, about or at least about a 3-fold increase in ADCC, about or at least about a 3.5-fold increase in ADCC, about or at least about a 4-fold increase in ADCC, about or at least about a 4.5-fold increase in ADCC, about or at least about a 5-fold increase in ADCC, about or at least about a 10-fold increase in ADCC, about or at least about a 20-fold increase in ADCC, or about or at least about a 30-fold increase in ADCC at about pH 6.5 compared to its level of ADCC at about pH 7.4. [0039] In embodiments, the pH-selective antibody exhibits about or at least about a 1-fold decrease in ADCC, about or at least about a 1.5-fold decrease in ADCC, about or at least about a 2-fold decrease in ADCC, about or at least about a 2.5-fold decrease in ADCC, about or at least about a 3-fold decrease in ADCC, about or at least about a 3.5-fold decrease in ADCC, about or at least about a 4-fold decrease in ADCC, about or at least about a 4.5-fold decrease in ADCC, about or at least about a 5-fold decrease in ADCC, about or at least about a 10-fold decrease in ADCC, about or at least about a 20-fold decrease DB1/ 133359610.3 7 Attorney Docket No.: SYN-061PC/112492-5061 in ADCC, or about or at least about a 30-fold decrease in ADCC at about pH 7.4 compared to a level of ADCC for a wild-type antibody Fc receptor at about pH 7.4. [0040] In embodiments, the pH-selective antibody exhibits greater selectivity for ADCC at a pH less than about 7.0 in comparison to a pH greater than about 7.0 relative to an antibody with a wild-type Fc domain. In embodiments, the pH-selective antibody exhibits a selectivity for ADCC at a pH of about 6.5 versus at a pH of about 7.4 of about or at least about 2.0, about or at least about 3.0, about or at least about 4.0, about or at least about 5.0, about or at least about 6.0, about or at least about 7.0, about or at least about 8.0, about or at least about 9.0, about or at least about 10.0, about or at least about 11.0, about or at least about 12.0, about or at least about 13.0, about or at least about 14.0, about or at least about 15.0, about or at least about 16.0, about or at least about 17.0, about or at least about 18.0, about or at least about 19.0, about or at least about 20.0, about or at least about 21.0, about or at least about 22.0, about or at least about 23.0, about or at least about 24.0, about or at least about 25.0, about or at least about 26.0, about or at least about 27.0, about or at least about 28.0, about or at least about 29.0, or about or at least about 30.0. [0041] In embodiments, the pH-selective antibody exhibits an increased level of activity at a pH less than about 7.0 in comparison to its activity at a pH greater than about 7.0. In embodiments, the pH- selective antibody exhibits an increased level of activity at a pH of about 6.5 in comparison to its activity at a pH of about 7.4. [0042] In embodiments, the pH-selective antibody exhibits a reduced level of activity at a pH greater than about 7.0 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution at positions 233-235, 267-268, 296, and 298, or positions corresponding thereto. In embodiments, the pH-selective antibody exhibits a reduced level of activity at a pH of about 7.4 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [0043] In embodiments, the pH-selective antibody exhibits an improved safety profile in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [0044] In embodiments, the pH-selective antibody has an in vivo half-life that is at least as long as an in vivo half-life of an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. In embodiments, the pH-selective antibody exhibits an in vivo half-life that is about DB1/ 133359610.3 8 Attorney Docket No.: SYN-061PC/112492-5061 or at least about 0.5-fold, about or at least about 1-fold, about or at least about 1.5-fold, about or at least about 2-fold, about or at least about 2.5-fold, or about or at least about 3-fold longer than a half-life of an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [0045] In embodiments, the pH-selective antibody further comprises one or more amino acid substitutions in the Fc domain that increase the half-life, optionally wherein the Fc domain comprises one or more amino acids substitutions at residues 252, 254, or 256, or positions corresponding thereto, relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. In embodiments, the pH-selective antibody further comprises M252Y, S254T, and T256E (YTE) substitutions, or positions corresponding thereto, in the Fc domain relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. [0046] In embodiments, the pH-selective antibody is humanized or fully human. [0047] In embodiments, the pH-selective antibody has one or more post-translational modifications (PTMs). In embodiments, the pH-selective antibody lacks one or more post-translational modifications (PTMs). In embodiments, the one or more PTMs is a glycan, glycosylation, fucosylation, phosphorylation, carbamylation, deamidation, and/or N-terminal pyroglutamate. In embodiments, the pH-selective antibody is non-fucosylated. [0048] In embodiments, the pH-selective antibody is conjugated to one or more linkers and/or drugs. [0049] In embodiments, wherein the pH-selective antibody is bispecific and/or chimeric. [0050] In embodiments, the pH-selective antibody is an anti-CTLA-4 antibody comprising heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25, light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28, and a human IgG1 Fc domain comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 1 and having variants S267E, H268D, and Y296H, or equivalent positions corresponding thereto. [0051] In embodiments, the pH-selective antibody is an anti-CTLA-4 antibody comprising heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a variable heavy domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 15, light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a variable light domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 16, and a human IgG1 Fc domain comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid DB1/ 133359610.3 9 Attorney Docket No.: SYN-061PC/112492-5061 sequence of SEQ ID NO: 1 and having variants S267E, H268D, and Y296H, or equivalent positions corresponding thereto. [0052] In embodiments, the pH-selective antibody is an anti-CTLA-4 antibody comprising heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a heavy chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ IS NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto, and light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a light chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 18. [0053] In aspects, provided herein are nucleic acid constructs encoding a pH-selective IgG1 Fc antibody domain comprising a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto, relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. In embodiments, the nucleic acid construct is DNA or RNA. In embodiments, the RNA is an mRNA or a modified mRNA. [0054] In aspects, provided herein are host cell comprising nucleic acid constructs, as described herein. [0055] Provided herein, in embodiments, are methods of treating cancer comprising administering a pH-selective antibody, a nucleic acid, or a host cell, as described herein, to a subject in need thereof. [0056] In embodiments, the pH-selective antibody binds a checkpoint inhibitor target, the target being a checkpoint inhibitor that functions, in part, by antibody-dependent cell-mediated cytotoxicity (ADCC), optionally wherein the checkpoint inhibitor target is or comprises one or more of CTLA-4, VISTA, TIGIT, LAG-3, TIM-3, B7-H3, CD73, PD-1, PD-L1, PD-L2, GITR, 4-1BB, CD36, CD25, CCR4, CCR5, CCR8, CCR10, CXCR3, TGF-ȕR, ICOS, CD27, OX40, or CD15. In embodiments, the checkpoint inhibitor target is CTLA-4. [0057] In embodiments, the antigen-binding portion comprises an immunoglobulin heavy chain variable region comprising a heavy chain variable region comprising an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 15, and a light chain variable region comprising an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 16. [0058] In embodiments, the pH-selective antibody is an anti-CTLA-4 antibody comprising heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a variable heavy domain having at least about 95%, at least about 97%, at least about DB1/ 133359610.3 10 Attorney Docket No.: SYN-061PC/112492-5061 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 15, light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a variable light domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 16, and a human IgG1 Fc domain having variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto. [0059] In embodiments, the pH-selective antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 17 with a substitution of one or more residues at one or more of position 233- 235, 267-268, 296, and 298, or positions corresponding thereto; and a light chain comprising an amino acid sequence of SEQ ID NO: 18. [0060] In embodiments, the pH-selective antibody is an anti-CTLA-4 antibody comprising heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a heavy chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ IS NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto, and light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a light chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 18. [0061] In embodiments, the pH-selective antibody exhibits attenuated antibody-mediated effects at pH 7.4 in comparison to its antibody-mediated effects in the reduced pH of a cancer microenvironment. In embodiments, the antibody-mediated effects comprise target binding, antibody-dependent cellular phagocytosis (ADCP), and/or antibody-dependent cellular cytotoxicity (ADCC). [0062] In embodiments, the pH-selective antibody exhibits an increased level of activity at a pH less than about 7.0 in comparison to its activity at a pH greater than about 7.0. In embodiments, the pH- selective antibody exhibits an increased level of activity at a pH of about 6.5 in comparison to its activity at a pH of about 7.4. [0063] In embodiments, the pH-selective antibody exhibits a reduced level of activity at a pH greater than about 7.0 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. In embodiments, the pH-selective antibody exhibits a reduced level of activity at a pH of about 7.4 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. DB1/ 133359610.3 11 Attorney Docket No.: SYN-061PC/112492-5061 [0064] In embodiments, the pH-selective antibody exhibits an improved safety profile in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. In embodiments, the pH-selective antibody reduces or eliminates one or more side effects of Table 3. [0065] In embodiments, the cancer is one or more of a solid tumor or a blood-based cancer. In embodiments, the cancer is one or more of a carcinoma, sarcoma, myeloma, leukemia, lymphoma, mixed type cancer, and/or metastatic cancer. In embodiments, the cancer is selected from hormone receptor- positive/HER2-negative breast cancer, triple negative breast cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), Esophageal Diffuse large B-cell lymphoma, metastatic melanoma, hepatocellular carcinoma, metastatic castration-resistant prostate cancer, triple-negative breast cancer, locally advanced or metastatic HER2-expressing cancers, non-small-cell lung cancer (NSCLC), ovarian cancer, PD-1/L1 failure patients with ROR-2 expression in recurrent or metastatic squamous cell carcinoma of the head and neck, melanoma, Merkel cell carcinoma, nonsquamous NSCLC. [0066] In embodiments, the subject has experienced one or more side effects of checkpoint inhibitor therapy. [0067] In embodiments, there is provided a method of reducing or preventing one or more side effects of checkpoint inhibitor therapy that functions, in part, by ADCC, by increasing or expanding the therapeutic window of the checkpoint inhibitor. [0068] In embodiments, the present disclosure provides methods for increasing a cancer patient’s likelihood of receiving checkpoint inhibitor maintenance therapy. In embodiments, the present disclosure provides methods for increasing a cancer patient’s likelihood of receiving a complete regime of the checkpoint inhibitor. In embodiments, the present disclosure provides methods for increasing a cancer patient’s likelihood of receiving a complete regimen or more than a complete regimen of the checkpoint inhibitor. In embodiments, the present disclosure provides methods for increasing a cancer patient’s likelihood of receiving a complete dose of a checkpoint inhibitor. In embodiments, the present disclosure provides methods for increasing the dose or length of administration of a checkpoint inhibitor. [0069] In embodiments, the present disclosure provides methods that allow for a cancer patient to avoid dose delay. [0070] In embodiments, the present disclosure provides methods that allow a patient to be administered a full regimen without having to cease treatment because of, for example, side effects. DB1/ 133359610.3 12 Attorney Docket No.: SYN-061PC/112492-5061 [0071] In embodiments, the present disclosure provides methods that increase an ability of a cancer patient to receive a combination therapy with another anti-cancer agent (e.g., an additional therapeutic agent as described herein). DESCRIPTION OF THE DRAWINGS [0072] Fig. 1 depicts a non-limiting exemplary diagrammatic representation of the acidic tumor microenvironment. Normal tissue, muscle, blood, etc., is maintained at a physiological pH of about 7.4 (left), whereas the tumor extracellular pH reaches about 5.8-6.5, or approximately 50-fold higher [H+]. [0073] Fig.2A-C depicts a non-limiting exemplary diagrammatic representation of the structural interface between the Fc and FcȖRIIIa. Fig.2A depicts a ribbon diagram of the crystallographic structure of the human Fc complexed with FcȖRIIIa (PDB: 3SGL). The two Fc homodimer chains are shown (chain A and chain B), with FcȖRIIIa bound at the top and Fc glycosylation shown as sticks. FcȖRIIIa residues H134 and H135 are shown as spheres. The Fc residues from Table 1 are shown as spheres on chain A, with the corresponding backbone shown in chain B. Fig.2B depicts a close-up view of H134-H135 of FcȖRIIIa at the Fc interface which form hydrogen bonding with the Fc D265. Fig.2C depicts a close-up view the Fc residues that are substituted as described in Table 1. [0074] Figs.3A-3D depict graphical representations of chromatograms for purification of anti-CTLA- 4 antibodies. Fig.3A depicts purification of ipilimumab with wild-type Fc (e.g., heavy chain SEQ ID NO: 17 and light chain SEQ ID NO: 18). Fig.3B depicts purification of ipilimumab with pH-selective Fc mutations (e.g., heavy chain SEQ ID NO: 22 and light chain SEQ ID NO: 18). Fig.3C depicts purification of mouse-variant ipilimumab (e.g., 4F10, heavy chain SEQ ID NO: 17, with the VH swapped for SEQ ID NO: 29 and light chain SEQ ID NO: 18 with the VL swapped with SEQ ID NO: 30). Fig.3D depicts purification of pH-selective mouse-variant ipilimumab (e.g., 4F10, heavy chain SEQ ID NO: 22, with the VH swapped for SEQ ID NO: 29 and light chain SEQ ID NO: 18 with the VL swapped with SEQ ID NO: 30). [0075] Fig.4 depicts a diagrammatic representation of a polyacrylamide gel electrophoresis (PAGE) of the samples taken from the chromatograms of Figs.3A-3D. NR = non-reduced; R = reduced. [0076] Figs.5A-5B depict graphical representations of flow cytometry binding kinetics of wild-type WT Fc domains in comparison to pH-sensitive Fc (“Acid-Fc”). Human and mouse Ipilimumab (Ipi) variants exhibited binding with Expi-CHO cells transiently transfected with mouse and human CTLA-4. Fig.5A depicts flow cytometry used to determine the binding of serially diluted mouse and human ipilimumab variants with CTLA-4, and the geometric mean fluorescence intensity (GMFI) plotted as a function of varying concentrations of antibodies (mouse on top; human on bottom). Fig.5B depicts binding of isotype DB1/ 133359610.3 13 Attorney Docket No.: SYN-061PC/112492-5061 control and ipilimumab variants were monitored and the shift in binding was recorded (mouse on right, human on left). Fitting performed using a One Site-Total Non-Linear Fit (NS=0) function used to determine the effective binding affinity (e.g., as summarized in Table 4). [0077] Figs.6A-6B depict a graphical representation of biolayer interferometry (BLI) results of wild- type WT Fc domain binding in comparison to pH-sensitive Fc (“Acid-Fc”) with FcȖRIIIa. Fig.6A depicts biolayer interferometry traces conducted using FAB2G biosensor tips to determine the association and disassociation of WT Fc (top) and Acid-Fc (bottom) with FcȖRIIIa, with kinetic responses for each phase were fit to a 1:1 Fc:FcȖRIIIa binding model. Fig.6B depicts steady state kinetics of the equilibrium responses fit using a Langmuir isotherm equation to calculate the equilibrium Kd (e.g., as described in Table 5). DETAILED DESCRIPTION Engineering pH-Selectivity for the Tumor Microenvironment [0078] In aspects, the present disclosure provides pH-selective antibodies comprising an Fc domain with an amino acid sequence comprising a substitution of one or more residues at positions 233-235, 267-268, 296, and 298, or equivalent positions corresponding thereto, relative to a wild-type human IgG1 Fc antibody domain (SEQ ID NO: 1), and an antigen-binding portion that binds a checkpoint inhibitor (CPI) target, the target being a checkpoint inhibitor target that functions, in part, by antibody-dependent cell-mediated cytotoxicity (ADCC). [0079] The target, in embodiments, is or comprises one or more of CTLA-4, VISTA, TIGIT, LAG-3, TIM-3, B7-H3, CD73, PD-1, PD-L1, PD-L2, GITR, 4-1BB, CD36, CD25, CCR4, CCR5, CCR8, CCR10, CXCR3, TGF-ȕR, ICOS, CD27, OX40, or CD15. [0080] Fc variants described herein, in embodiments, are engineered for reduced affinity against non- cancerous cells with enhanced affinity in the pH range of the tumor microenvironment (e.g., as illustrated in Fig.1). Normal tissue, muscle, blood, etc., is maintained at a physiological pH of about 7.4 (see e.g., Fig.1 left), whereas the tumor extracellular pH reaches about 5.8-6.5, or approximately a 50-fold higher [H+] (see e.g., Fig.1 right). Without wishing to be bound by theory, this phenomenon is generally due to the Warburg Effect and the tendency of malignant cells to preferential metabolize glucose into pyruvate via glycolysis, and then convert pyruvate into lactate via lactate dehydrogenase. Without wishing to be bound by theory, export of the lactate metabolic waste results in an acidic microenvironment surrounding the tumor. Without wishing to be bound by theory, the acidic environment, particularly in the solid tumor microenvironment, represents a considerable hurdle in targeting malignant cells, and the pH-selective antibodies described herein address this issue by maintaining affinity and/or ADCC activity in the low pH DB1/ 133359610.3 14 Attorney Docket No.: SYN-061PC/112492-5061 tumor microenvironment while diminishing affinity and ADCC activity at physiologic pH. The diminished potency at physiologic pH, in embodiments, provides for less activity against, and toxicity to, healthy (non- cancerous) cells and tissues. In embodiments, the target is T regulatory cells (Tregs), which suppress an immune response. In embodiments, pH-selective Treg targeting results in less autoimmune toxicity directed at healthy tissues. [0081] The “activity,” or “level of activity,” as used in reference to antibodies herein, in embodiments, refers to any measure of in vitro or in vivo antibody function, e.g., pH selectivity or binding ratios, absorbance from antigen binding assay, binding kinetics, in vivo half-life, EC50, percent lysis, or max lysis (e.g., for T cell-mediated cytotoxicity assays), tissue infiltration (e.g., as measured by tumor-infiltrating lymphocytes (TILs)), ADCC, ADCP, tumor volume reduction, degree of metastasis, among other antibody-mediated effects including pharmacokinetics, pharmacodynamics, and treatment-related effects. In embodiments, the activity of pH selective antibodies herein is relative to an antibody or antibody-based construct with a wild-type Fc domain (e.g., wild-type human IgG1), or relative to the function compared under two different conditions (e.g., acidic pH versus physiological pH). [0082] CPIs, in embodiments, function in part via ADCC. For example and without limitation, in embodiments, CPIs bind a target cell surface marker and inhibit one or more checkpoint signaling pathways while initiating cell-mediated cytotoxicity against the bound cell. The pH-selective antibodies described herein, in embodiments, target a Treg cell surface marker for targeted depletion of Tregs via ADCC and/or ADCP. [0083] The checkpoint inhibitor target, in embodiments, is V-domain immunoglobin suppressor of T cell activation (VISTA). Without wishing to be bound by theory, VISTA is rich in histidine residues and suppresses immune responses by binding P-selectin glycoprotein ligand-1 to trigger immune-inhibitory signals only at low pH. [0084] The checkpoint inhibitor target, in embodiments, is CTLA-4. In embodiments, the CTLA-4 is human (hCTLA-4) or murine (mCTLA-4). CTLA-4 (also known as CD152) is a protein receptor that mediates immune checkpoint function and downregulates immune responses. [0085] The pH-selective antibody antigen-binding portion, in embodiments, includes at least a portion of an amino acid sequence of a heavy chain complementarity determining region (CDR) and/or an amino acid sequence of a light chain CDR of ipilimumab (Ipi). Ipi is a fully human IgG1 monoclonal antibody that binds CTLA-4, blocking the inhibitory signal, and facilitating the killing of tumor cells by cytotoxic T lymphocytes. In embodiments, the antigen-binding portion includes 1 or more, 2 or more, or all 3 heavy chain CDR amino acid sequences of Ipi (e.g., as shown in Table 1). In embodiments, the antigen-binding DB1/ 133359610.3 15 Attorney Docket No.: SYN-061PC/112492-5061 portion includes 1 or more, 2 or more, or all 3 light chain CDR amino acid sequences of Ipi (e.g., as shown in Table 1). [0086] The pH-selective antibody antigen-binding portion, in embodiments, comprises an immunoglobulin heavy chain variable region comprising a CDRH1 comprising an amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 5, or SEQ ID NO: 23, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 6, or SEQ ID NO: 24, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 7, or SEQ ID NO: 25, and comprises an immunoglobulin light chain variable region comprising a CDRL1 comprising an amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO: 26, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 27, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 28. [0087] In embodiments, the antigen-binding portion includes the heavy chain variable region (VH) and/or the light chain variable region (VL) amino acid sequences of Ipi (e.g., as shown in Table 1). In embodiments, the pH-selective antibody includes about or at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity or more to the VH amino acid sequence of SEQ ID NO: 15 and/or VL amino acid sequence of SEQ ID NO: 16. In embodiments, the antigen-binding portion includes the heavy chain variable domain CDRs of SEQ ID NOs: 23-25 while having at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity to the remaining amino acid sequence (e.g., framework regions) of SEQ ID NO: 15, outside of the CDRs. In embodiments, the antigen-binding portion includes the heavy chain variable domain CDRs of SEQ ID NOs: 26-28 while having at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity to the remaining amino acid sequence (e.g., framework regions) of SEQ ID NO: 16, outside of the CDRs. Persons skilled in the art are able to determine the portions outside of the antigen-binding residues (CDRs) and are able to determine which residues are mutable (e.g., based on homology modeling between species, etc.). [0088] In embodiments, the antigen-binding portion includes a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 15, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 16, and a human IgG1 Fc domain amino acid sequence having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 1 (e.g., outside of the pH-selectivity residues indicated herein). Such sequence variations in the Fc domain DB1/ 133359610.3 16 Attorney Docket No.: SYN-061PC/112492-5061 corresponds to, in embodiments, differences in immunogenicity engineering, differences between species, substitutions made for manufacturing purposes, and/or differences between IgG subclasses (i.e., IgG1, IgG2, IgG3, IgG4), for example in the hinges and CH2 domains. [0089] The pH-selective antibody, in embodiments, includes the heavy chain (HC) and/or light chain (LC) of Ipi (e.g., as shown in Table 1), where the HC includes one or more Fc substitutions, as described herein. In embodiments, the pH-selective antibody includes a HC amino acid sequence of SEQ ID NO: 17 with an Fc domain having an amino acid sequence including a substitution of one or more residues at positions 233-235, 267-268, 296, and 298, or equivalent positions corresponding thereto, and a LC amino acid sequence of SEQ ID NO: 18. In embodiments, the HC amino acid sequence of SEQ ID NO: 17 additionally includes Fc substitutions at positions S240, A331, and/or I333, or positions corresponding thereto. In embodiments, the substitution is S240D, A331L, I333E, or any combination thereof. [0090] In embodiments, the pH-selective antibody includes a heavy chain having about or at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity or more to SEQ ID NO: 17 and/or a light chain having about or at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity or more to SEQ ID NO: 18, where the Fc amino acid sequence of the heavy chain includes substitutions of S240D, A331L, and/or I333E, or positions corresponding thereto, and the Fc amino acid sequence of the heavy chain includes a substitution of one or more Fc domain residues at one or more of position 233-235, 267- 268, 296, and 298, or positions corresponding thereto. In embodiments, the variations in percent identity relate to the portions of the amino acid sequences of SEQ ID NOs: 17 and 18 (the heavy chaing and light chain, respectively) outside of the antigen-binding CDR residues of SEQ ID NOs: 23-25 and 26-28 for the VH and VL, respectively. In embodiments, this applies to all antibodies presented herein. [0091] The pH-selective antibody, in embodiments, includes at least a portion of an amino acid sequence of a heavy chain complementarity determining region (CDR) and/or an amino acid sequence of a light chain CDR of zalifrelimab. Zalifrelimab is a fully human IgG1 monoclonal antibody that binds CTLA-4. The pH-selective antibody, in embodiments, includes the HC and/or LC of zalifrelimab (e.g., as shown in Table 1), where the HC includes one or more Fc substitutions, as described herein. In embodiments, the pH-selective antibody includes a HC amino acid sequence of SEQ ID NO: 19 with an Fc domain with an amino acid sequence having a substitution of one or more residues at positions 233- 235, 267-268, 296, and 298, or equivalent positions corresponding thereto, and a LC amino acid sequence of SEQ ID NO: 20. In embodiments, the HC amino acid sequence of SEQ ID NO: 19 DB1/ 133359610.3 17 Attorney Docket No.: SYN-061PC/112492-5061 additionally includes Fc substitutions at positions S240, A331, and/or I333, or positions corresponding thereto. In embodiments, the substitution is S240D/A331L/I333E. [0092] In embodiments, the pH-selective antibody includes a heavy chain having about or at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity or more to SEQ ID NO: 19 and/or a light chain having about or at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity or more to SEQ ID NO: 20, where the Fc amino acid sequence of the heavy chain includes substitutions of S240D, A331L, and/or I333E, or positions corresponding thereto, and the Fc amino acid sequence of the heavy chain comprises a substitution of one or more Fc domain residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [0093] In embodiments, the pH-selective antibody includes a heavy chain having about or at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity or more to SEQ ID NO: 21 and/or a light chain having about or at least about 95% sequence identity, about or at least about 96% sequence identity, about or at least about 97% sequence identity, about or at least about 98% sequence identity, about or at least about 99% sequence identity or more to SEQ ID NO: 20, where the Fc amino acid sequence of the heavy chain includes a substitution of one or more Fc domain residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [0094] In embodiments, the pH-selective antibody is a monoclonal anti-CTLA-4 antibody (e.g., ipilimumab) comprising a heavy variable domain CDRs having the amino acid sequences SEQ ID NOs: 23-25 and a light variable domain CDRs having the amino acid sequences SEQ ID NOs: 26-28 and comprising a human IgG1 Fc domain having variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto. [0095] In embodiments, the pH-selective antibody is a monoclonal anti-CTLA-4 antibody (e.g., ipilimumab) comprising a heavy variable domain CDRs having the amino acid sequences SEQ ID NOs: 23-25 and a variable heavy domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity, outside of the CDR regions, to the amino acid sequence of SEQ ID NO: 15, and a light variable domain CDRs having the amino acid sequences SEQ ID NOs: 26-28 and a variable light domain having at least about 95%, at least about 97%, at least about 98%, or at least DB1/ 133359610.3 18 Attorney Docket No.: SYN-061PC/112492-5061 about 99% sequence identity, outside of the CDR regions, to the amino acid sequence of SEQ ID NO: 16 and comprising a human IgG1 Fc domain having variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto. [0096] In embodiments, the pH-selective antibody is a monoclonal anti-CTLA-4 antibody (e.g., ipilimumab) comprising a heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences SEQ ID NOs: 23-25 and a heavy chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity, outside of the CDR regions, to the amino acid sequence of SEQ ID NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto, and a light variable domain CDRs having the amino acid sequences SEQ ID NOs: 26-28 and at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity, outside of the CDR regions, to the amino acid sequence of SEQ ID NO: 16. [0097] The pH-selective antibody, in embodiments, includes one or more Fc substitutions that improves the therapeutic index and/or reduces the toxicities of zalifrelimab, as described herein. Table 1: Exemplary WT human IgG1 Fc, pH-selective Fc, and pH-selective antigen-binding domain amino acid sequences. The heavy chain CDRs (HCDRs) denoted as SEQ ID NOs: 2-4, the light chain CDRs (LCDRs) denoted as SEQ ID NOs: 8-10, the VH and VL denoted as SEQ ID NOs: 15 and 16, and the HC and LC denoted as SEQ ID NOs: 17 and 18, respectively, are the amino acid sequences of the fully human, anti-CTLA-4 monoclonal IgG1 antibody, ipilimumab (Ipi). The HCDRs denoted as SEQ ID NOs: 5-7 and LCDRs denoted as SEQ ID NOs: 11-14 represent CDR amino acid sequences which are pH- selective. The HC and LC denoted as SEQ ID NOs: 19 and 20, respectively, are the amino acid V P P D DB1/ 133359610.3 19 Attorney Docket No.: SYN-061PC/112492-5061 HCDR2 TFISYDGNNK [SEQ ID NO: 3] HCDR3 ARTGWLGPFDY [SEQ ID NO: 4] G T D G E DB1/ 133359610.3 20 Attorney Docket No.: SYN-061PC/112492-5061 NYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK [SEQ ID NO: 17] Q S V T S G G T V TI Y Q P D K I W A S N P P S G S DB1/ 133359610.3 21 Attorney Docket No.: SYN-061PC/112492-5061 GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVEDEDPEVKFNW E P Y [0098] Underlined amino acids (e.g., as indicated in Table 1), in embodiments, correspond to amino acid positions that are subject to one or more substitutions, as described herein, regardless of numbering convention. Persons skilled in the art, with the benefit of this disclosure in its entirety, will appreciate the spectrum of antibody amino acid numbering conventions (e.g., Kabat, Chothia, IMGT, etc.), and the differences in position numbering among the amino acids indicated herein for substitution. DB1/ 133359610.3 22 Attorney Docket No.: SYN-061PC/112492-5061 [0099] Fc variants described herein, in embodiments, are human IgG1 Fc variants engineered for pH- selectivity, where the Fc variants exhibit substantially equivalent antibody-mediated effects within the tumor environment in comparison to a wild-type human IgG1 Fc domain, but the antibody-mediated effects are otherwise attenuated outside of the tumor environment. These antibody-mediated effects, in embodiments, include ADCC, ADCP, among other antibody functions as described herein. The pH- selective antibody, in embodiments, includes any combination of the amino acid variants summarized in Table 2. Compositions herein include, in embodiments, one or more pH-selective antibody variants selected from Table 2. Table 2: Exemplary antibody Fc domain amino acid variants relative to wild-type human IgG1 Fc residues (SEQ ID NO: 1). Position 233 denoted in Table 2 relates to position 116 in SEQ ID NO: 1, as this sequence is the Fc domain portion. Residue # 233 234 235 267 268 296 298 Wild-T e E L L S H Y S [00100] Wild-type IgG1 Fc residues L234, L235, G236, G237, S267, and A327 are within < 6.5 Å of FcȖRIIIa H134 and H135 (e.g., as shown in Fig.2A-C) and, in embodiments, are substituted with acidic residues (i.e., negatively charged), while residues E233, Y296, and S298 are < 5 Å of polar FcȖRIIIa residues and, in embodiments, are substituted with histidine. Without wishing to be bound by theory, in embodiments, under acidic conditions Fc S267E forms electrostatic interactions with protonated H134 on FcȖRIIIa, while at both pH values, binding strength is tuned by a salt bridge formed between Fc H268D and K131 on FcȖRIIIa and Fc Y296H disruption of interactions with K128 on FcȖRIIIa. [00101] The pH-selective antibody, in embodiments, includes a substitution of the residue at position 233 (E233), or the position corresponding thereto (e.g., in an Ig Fc domain), that is negatively charged. In embodiments, the negatively charged residue is the wild-type glutamic acid (e.g., E233 of IgG1 SEQ ID NO: 1) or the wild-type glutamic acid is substituted by an aspartic acid (E233D). DB1/ 133359610.3 23 Attorney Docket No.: SYN-061PC/112492-5061 [00102] The pH-selective antibody, in embodiments, includes a substitution of the residue at position 234 (L234), or the position corresponding thereto (e.g., in an Ig Fc domain), that is aliphatic. The aliphatic residue, in embodiments, is the wild-type leucine (e.g., L234 of IgG1 SEQ ID NO: 1) or the wild-type leucine is substituted by an aliphatic residue selected from glycine, alanine, valine, proline, or isoleucine. In embodiments, the aliphatic substitution at position 234 is a valine (L234V). [00103] The pH-selective antibody, in embodiments, includes a substitution of the residue at position 235 (L235), or the position corresponding thereto (e.g., in an Ig Fc domain), that is aliphatic or negatively charged. The aliphatic residue, in embodiments, is the wild-type leucine (e.g., L235 of IgG1 SEQ ID NO: 1), or the wild-type leucine is substituted by an aliphatic residue selected from glycine, alanine, valine, proline, or isoleucine. The negatively charged residue, in embodiments, is an aspartic acid or glutamic acid. In embodiments, the aliphatic substitution at position 235 is a valine (L235V). In embodiments, the negatively charged substitution at position 235 is an aspartic acid (L235D). [00104] The pH-selective antibody, in embodiments, includes a substitution of the residue at position 267 (S267), or the position corresponding thereto (e.g., in an Ig Fc domain), that is aliphatic or negatively charged. In embodiments, the wild-type serine (e.g., S267 of IgG1 SEQ ID NO: 1) is substituted by an aliphatic residue selected from glycine, alanine, valine, proline, leucine, or isoleucine In embodiments, the wild-type serine (e.g., S267 of IgG1 SEQ ID NO: 1) is substituted by a negatively charged residue selected from aspartic acid or glutamic acid. In embodiments, the aliphatic substitution at position 267 is a glycine (S267G). In embodiments, the negatively charged substitution at position 267 is an aspartic acid (S267D). In embodiments, the negatively charged substitution at position 267 is an glutamic acid (S267E). [00105] The pH-selective antibody, in embodiments, includes a substitution of the residue at position 268 (H268), or the position corresponding thereto (e.g., in an Ig Fc domain), that is negatively charged. In embodiments, the wild-type histidine (e.g., H268 of IgG1 SEQ ID NO: 1) is substituted by a negatively charged residue selected from aspartic acid or glutamic acid. In embodiments, the aliphatic substitution at position 268 is an aspartic acid (H268D). [00106] The pH-selective antibody, in embodiments, includes a substitution of the residue at position 296 (Y296), or the position corresponding thereto (e.g., in an Ig Fc domain), that is positively charged. In embodiments, the wild-type tyrosine (e.g., Y296 of IgG1 SEQ ID NO: 1) is substituted by a positively charged residue selected from histidine, lysine, or arginine. In embodiments, the positively charged substitution at position 296 is a histidine (Y296H). DB1/ 133359610.3 24 Attorney Docket No.: SYN-061PC/112492-5061 [00107] The pH-selective antibody, in embodiments, includes a substitution of the residue at position 298 (S298), or the position corresponding thereto (e.g., in an Ig Fc domain), that is positively charged. In embodiments, the wild-type serine (e.g., S298 of IgG1 SEQ ID NO: 1) is substituted by a positively charged residue selected from histidine, lysine, or arginine. In embodiments, the positively charged substitution at position 298 is a arginine (S298R). [00108] In embodiments, the pH-selective antibody includes a series of Fc amino acid sequence substitutions of E233D, L234V, L235V, S267E, H268D, and Y296H. In embodiments, the pH-selective antibody includes a series of Fc amino acid sequence substitutions of E233D, L234V, L235V, S267E, H268D, and S298R. In embodiments, the pH-selective antibody includes a series of Fc amino acid sequence substitutions of E233D, L234V, L235D, S267G, H268D, and Y296H. In embodiments, the pH- selective antibody includes a series of Fc amino acid sequence substitutions of E233D, L234V, L235D, S267E, H268D, and Y296H. In embodiments, the pH-selective antibody includes a series of Fc amino acid sequence substitutions of S267E, H268D, and Y296H. In embodiments, the pH-selective antibody includes a series of Fc amino acid sequence substitutions of S267D, H268D, and S298R. In embodiments, the pH-selective antibody includes a series of Fc amino acid sequence substitutions of S267G, H268D, and Y296H. [00109] The pH-selective antibody, in embodiments, includes an Fc amino acid sequence with S267E and H268D substitutions, or substitutions at equivalent positions corresponding thereto. The pH-selective antibody, in embodiments, includes an Fc amino acid sequence with S267E, H268D, and Y296H substitutions, or substitutions at equivalent positions corresponding thereto. The pH-selective antibody Fc substitutions of S267E, H268D, and Y296H are not in close contact (< 5 Å) with the FcRn or the ȕ2- microglobulin (ȕ2m) residues in crystallographic structures, and as such changes at these locations have not been previously reported to impact FcRn binding. [00110] Provided herein in exemplary, non-limiting embodiments are IgG1 Fc variants for pH- selectivity. Persons skilled in the art, upon review of this disclosure in its entirety, will understand that the Fc variants disclosed herein for pH-selectivity can be transferred between subclasses of IgG Fc domains (i.e., IgG1, IgG2, IgG3, or IgG4) by making substitutions corresponding to equivalent positions. For example and without limitation, pH-selective substitutions are made in equivalent positions in other IgG subclasses, such as cemiplimab, which is an anti-PD-1 human IgG4 monoclonal antibody. In embodiments, Fc variants disclosed herein can be transferred between Ig classes, for example and without limitation, the corresponding substituted residues are introduced into an IgM, IgA, IgD, or IgE Fc domain, which confer pH-selectivity, among other features described herein. DB1/ 133359610.3 25 Attorney Docket No.: SYN-061PC/112492-5061 [00111] The biological, biochemical, and biophysical Fc characteristics for pH-selective antibodies described herein, in embodiments, are preserved (e.g., target-binding, serum half-life, etc.), enhanced (e.g., Fc receptor affinity at pH < 7.0, intratumoral activity, safety profile, etc.), and/or diminished (e.g., Fc receptor affinity at pH > 7.0, off-target binding, etc.). [00112] The affinity (e.g., as measured by Kd) of pH-selective antibodies herein, in embodiments, is greater for an antibody Fc receptor at a pH less than about 7.0 in comparison to its affinity at a pH greater than about 7.0, i.e., where greater affinity would be represented by a lower value of Kd. [00113] In embodiments, the pH-selective antibody has a higher affinity for an antibody Fc receptor at about or at least about pH 7.0 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.9 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.8 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.7 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.6 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.5 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.4 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.3 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.2 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.1 relative to its affinity at about or at least about pH 7.4, about or at least about pH 6.0 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.9 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.8 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.7 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.6 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.5 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.4 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.3 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.2 relative to its affinity at about or at least about pH 7.4, about or at least about pH 5.1 relative to its affinity at about or at least about pH 7.4, or about or at least about pH 5.0 relative to its affinity at about or at least about pH 7.4. [00114] The affinity of the pH-selective antibody, in embodiments, is greater for an antibody Fc receptor at a pH range that corresponds to the extracellular environment of malignant cells (a pH of about 6.5) in comparison to its affinity at a pH of about 7.4. In embodiments, the pH-selective antibody Fc domain contains residues changes that reduce the affinity at pH 7.4 due to faster dissociation rates, where the reduction is by about or at least about 0.5-fold, about or at least about 1-fold, about or at least about 1.5- fold, about or at least about 2-fold, or about or at least about 2.5-fold or more. DB1/ 133359610.3 26 Attorney Docket No.: SYN-061PC/112492-5061 [00115] In embodiments, the pH-selective antibody exhibits about or at least about a 1-fold increase in affinity, about or at least about a 1.5-fold increase in affinity, about or at least about a 2-fold increase in affinity, about or at least about a 2.5-fold increase in affinity, about or at least about a 3-fold increase in affinity, about or at least about a 3.5-fold increase in affinity, about or at least about a 4-fold increase in affinity, about or at least about a 4.5-fold increase in affinity, about or at least about a 5-fold increase in affinity for an antibody Fc receptor at a pH of about 6.5 compared to its affinity for an antibody Fc receptor at pH 7.4. [00116] The selectivity of the pH-selective antibody, in embodiments, is greater for an antibody Fc receptor at a pH of less than about 7.0 in comparison to a pH of greater than about 7.0 relative to an antibody with a cognate wild-type Fc domain. Selectivity, in embodiments, is determined as a ratio of antibody-mediated effect (e.g., as measured by an EC50 value of ADCC, affinity (Kd) of FcRn binding, steady-state constant, etc.) between two conditions (e.g., pH > 7.0 versus pH < 7.0). [00117] In embodiments, selectivity is calculated as a ratio of antibody affinity (e.g., Kd) at a pH of about 7.4 versus at a pH of about 6.5, where a selectivity greater than 1 would indicate preference for binding at pH 6.5 over pH 7.4. In such a case, the pH-selective antibody exhibits, in embodiments, a selectivity of about or at least about 1.1, about or at least about 1.2, about or at least about 1.3, about or at least about 1.4, about or at least about 1.5, about or at least about 1.6, about or at least about 1.7, about or at least about 1.8, about or at least about 1.9, about or at least about 2.0, about or at least about 2.1, about or at least about 2.2, about or at least about 2.2, about or at least about 2.3, about or at least about 2.4, about or at least about 2.5, about or at least about 2.6, about or at least about 2.7, about or at least about 2.8, about or at least about 2.9, about or at least about 3.0, about or at least about 3.1, about or at least about 3.2, about or at least about 3.3, about or at least about 3.4, about or at least about 3.5, about or at least about 3.6, about or at least about 3.8, or about or at least about 4.0 or more. [00118] The antibody Fc receptor as used herein, in embodiments, is one or more of an Fc gamma- receptor (FcȖR), FcRn, FcȖRI (CD64), FcȖRII (CD32), and FcȖRIII (CD16). [00119] In embodiments, the pH-selective antibody exhibits a dissociation constant (^_^^^) at pH 7.4 that is about or at least about 0.2-fold greater, about or at least about 0.4-fold greater, about or at least about 0.6-fold greater, about or at least about 0.8-fold greater, about or at least about 1.0-fold greater, about or at least about 1.5-fold greater, about or at least about 2-fold, about or at least about 2.5-fold greater, or about or at least about 3-fold greater than that of the wild-type human IgG1 Fc, e.g., with respect to FcȖRIIIa binding. DB1/ 133359610.3 27 Attorney Docket No.: SYN-061PC/112492-5061 [00120] In embodiments, the pH-selective antibody exhibits an equilibrium constant (Kd) at pH 7.4 that is about or at least about 0.2-fold greater, about or at least about 0.4-fold greater, about or at least about 0.6-fold greater, about or at least about 0.8-fold greater, about or at least about 1.0-fold greater, about or at least about 1.5-fold greater, about or at least about 2-fold, about or at least about 2.5-fold greater, or about or at least about 3-fold greater than that of the wild-type human IgG1 Fc, e.g., with respect to FcȖRIIIa binding. [00121] In embodiments, the pH-selective antibody exhibits a steady-state constant (K_d,SS) at pH 7.4 that is about or at least about 0.2-fold greater, about or at least about 0.4-fold greater, about or at least about 0.6-fold greater, about or at least about 0.8-fold greater, about or at least about 1.0-fold greater, about or at least about 1.5-fold greater, about or at least about 2-fold, about or at least about 2.5-fold greater, or about or at least about 3-fold greater than that of the wild-type human IgG1 Fc, e.g., with respect to FcȖRIIIa binding. [00122] The pH-selective antibody, in embodiments, exhibits increased selectivity of binding for the Fc receptor and/or the checkpoint inhibitor target in an acidic environment in comparison to an environment at a pH greater than about 7.0. In embodiments, the pH-selective antibody exhibits a degree of Fc receptor binding and/or checkpoint inhibitor target biding that is equivalent to a wild-type IgG Fc receptor at pH less than about 7 (e.g., at pH 6.5). In embodiments, the pH-selective antibody exhibits a degree of Fc receptor binding and/or checkpoint inhibitor target biding that is diminished relative to a wild-type IgG Fc receptor at pH greater than about 7 (e.g., at pH 7.4). [00123] In embodiments, the pH-selective antibody comprises a variable heavy chain amino acid sequence and a variable light chain amino acid sequence of ipilimumab (e.g., SEQ ID NOs: 15 and 16, respectively), wherein the variable heavy chain amino acid sequence has one or more substitutions in a CDR amino acid sequence and/or the variable light chain amino acid sequence has one or more substitutions in a CDR amino acid sequence. In embodiments, the variable heavy chain amino acid sequence (SEQ ID NO: 15) possesses substitutions of one or more of S31H, N55H, and T95H, e.g., as shown in Table 1 in SEQ ID NOs: 5-7. In embodiments, the variable light chain amino acid sequence (SEQ ID NO: 16) possesses substitutions of one or more of S27E, S30D or S30E, and Y32E, e.g., as shown in Table 1 in SEQ ID NOs: 11-14, respectively. These variable chain substitutions, in embodiments, are located in one of more CDRs of Ipi and confer pH-selective CTLA-4 binding, specifically with enhanced binding under conditions of pH < 7.0. [00124] In embodiments, the pH-selective antibody comprises an antigen-binding portion that binds CTLA-4 and comprises an immunoglobulin heavy chain variable region comprising a CDRH1 comprising DB1/ 133359610.3 28 Attorney Docket No.: SYN-061PC/112492-5061 an amino acid sequence of SEQ ID NO: 5, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 6, and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 7, and comprises an immunoglobulin light chain variable region comprising a CDRL1 comprising an amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 9, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 10, where the pH-selective antibody exhibits increased CTLA-4 binding in an acidic environment in comparison to at a pH of about 7.4. [00125] Without wishing to be bound by theory, in embodiments, the combination of the anti-CTLA-4 CDRs of SEQ ID NO: 5 (CDRH1), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), one of SEQ ID NOs: 11-13 (CDRL1), SEQ ID NO: 9 (CDRL2), and SEQ ID NO: 10 (CDRL3), and the Fc substitution of residues 233-235, 267-268, 296, and 298, or positions corresponding thereto, relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1, results in anti-CTLA-4 with about or at least about 30-fold, about or at least about 40-fold, about or at least about 50-fold, about or at least about 60-fold, about or at least about 70-fold, about or at least about 80-fold, about or at least about 90-fold, or about or at least about 100-fold or more enhanced level of activity at about a pH of 6.0 compared to at about a pH of 7.4 (e.g. in comparison to ipilimumab). [00126] The pH-selective antibody, in embodiments, exhibits increased binding for the checkpoint inhibitor target on T cells within a tumor microenvironment in comparison to T cells outside of the tumor microenvironment. In embodiments, the pH-selective antibody exhibits increased binding for the checkpoint inhibitor target on cancer cells within a tumor microenvironment in comparison to cells outside of the tumor microenvironment. In embodiments, the pH-selective antibody preferably binds CTLA-4 on T regulatory cells (T regs) within a tumor microenvironment in comparison to T regs outside the tumor microenvironment. [00127] The key biological activities of pH-selective antibodies, in embodiments, are retained and/or enhanced. In embodiments, the pH-selective antibody exhibits greater antibody-dependent cellular phagocytosis (ADCP) and/or antibody-dependent cellular cytotoxicity (ADCC) at a pH less than about 7.0 in comparison to a pH greater than about 7.0. [00128] The pH-selective antibody, in embodiments, exhibits increased ADCC at acidic pH ranges (e.g., ~pH 5.8-6.5) relative to its own level of ADCC at physiological pH (e.g., ~pH 7.4). In embodiments, the pH-selective antibody exhibits about or at least about a 0.5-fold increase in ADCC, about or at least about a 1-fold increase in ADCC, about or at least about a 1.5-fold increase in ADCC, about or at least about a 2-fold increase in ADCC, about or at least about a 2.5-fold increase in ADCC, about or at least about a 3-fold increase in ADCC, about or at least about a 3.5-fold increase in ADCC, about or at least DB1/ 133359610.3 29 Attorney Docket No.: SYN-061PC/112492-5061 about a 4-fold increase in ADCC, about or at least about a 4.5-fold increase in ADCC, about or at least about a 5-fold increase in ADCC, about or at least about a 10-fold increase in ADCC, about or at least about a 20-fold increase in ADCC, or about or at least about a 30-fold increase in ADCC at about pH 6.5 compared to its level of ADCC at about pH 7.4. [00129] The pH-selective antibody, in embodiments, exhibits reduced ADCC at physiological pH ranges (e.g., pH ~7.4) relative to the level of ADCC for a wild-type antibody Fc receptor at physiological pH. In embodiments, the pH-selective antibody exhibits about or at least about a 0.5-fold decrease in ADCC, about or at least about a 1-fold decrease in ADCC, about or at least about a 1.5-fold decrease in ADCC, about or at least about a 2-fold decrease in ADCC, about or at least about a 2.5-fold decrease in ADCC, about or at least about a 3-fold decrease in ADCC, about or at least about a 3.5-fold decrease in ADCC, about or at least about a 4-fold decrease in ADCC, about or at least about a 4.5-fold decrease in ADCC, about or at least about a 5-fold decrease in ADCC, about or at least about a 10-fold decrease in ADCC, about or at least about a 20-fold decrease in ADCC, or about or at least about a 30-fold decrease in ADCC at about pH 7.4 compared to a level of ADCC for a wild-type antibody Fc receptor at about pH 7.4. [00130] In embodiments, selectivity of the pH-selective antibody is calculated as a ratio of ADCC (e.g., EC₅₀) at a pH of about 7.4 versus at a pH of about 6.5, where a selectivity greater than 1 would indicate preference for ADCC at pH 6.5 over pH 7.4 (e.g., as described in Table 4). In such a case, the pH- selective antibody exhibits, in embodiments, a selectivity of about or at least about 2.0, about or at least about 3.0, about or at least about 4.0, about or at least about 5.0, about or at least about 6.0, about or at least about 7.0, about or at least about 8.0, about or at least about 9.0, about or at least about 10.0, about or at least about 11.0, about or at least about 12.0, about or at least about 13.0, about or at least about 14.0, about or at least about 15.0, about or at least about 16.0, about or at least about 17.0, about or at least about 18.0, about or at least about 19.0, about or at least about 20.0, about or at least about 21.0, about or at least about 22.0, about or at least about 23.0, about or at least about 24.0, about or at least about 25.0, about or at least about 26.0, about or at least about 27.0, about or at least about 28.0, about or at least about 29.0, or about or at least about 30.0 or more. [00131] The pH-selective antibody, in embodiments, exhibits greatly improved pH-selective ADCC compared to the improvement in pH-selective FcR binding. Without wishing to be bound by theory, this is due to ADCC being a higher order activity than FcR binding, where ADCC function requires clustering of antibody-bound FcRs. DB1/ 133359610.3 30 Attorney Docket No.: SYN-061PC/112492-5061 [00132] In embodiments, the pH-selective antibody includes one or more additional Fc substitutions that further improve ADCC, ADCP, Treg depletion, and/or checkpoint inhibition which do not necessarily confer an improvement in pH-selectivity. For example and with without limitation, in embodiments, the pH-selective antibody contains one or more additional Fc substitutions which improve Fc receptor binding, but do not significantly alter the pH-selectivity. [00133] The pH-selective antibody, in embodiments, exhibits an increased level of activity at a pH less than about 7.0 in comparison to its activity at a pH greater than about 7.0. The level of activity, in embodiments, refers to any measure of antibody function, e.g., pH selectivity or binding ratios, absorbance from Fc receptor binding assay, binding kinetics for Fc receptor and/or target, in vivo half- life, EC₅₀ (e.g., ADCC), phagocytosis score (e.g., ADCP), percent lysis (e.g., ADCC), max lysis (e.g., ADCC), among other antibody-mediated effects such as a degree of ADCP and/or ADCC. [00134] In embodiments, the pH-selective antibody exhibits an increased level of activity at a pH of about 6.5 in comparison to its activity at a pH of about 7.4. [00135] In embodiments, the pH-selective antibody exhibits a reduced level of activity at a pH greater than about 7.0 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [00136] In embodiments, the pH-selective antibody exhibits a reduced level of activity at a pH of about 7.4 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [00137] The pH-selective antibody, in embodiments, exhibits an improved safety profile in comparison to an antibody with a wild-type Fc domain and/or a Fc domain lacking substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or equivalent positions corresponding thereto. Safety profile, in embodiments, relates to binding of CPI targets outside of the solid tumor, tumor microenvironment, metastasis, or other location which leads to immunotoxicities and off-target antibody- mediated effects. In embodiments, improved safety profile refers to reduced or eliminated adverse events and/or symptoms, for example and without limitation, as described in Table 3 below. [00138] Antibody in vivo half-life is, in part, determined by pH-selective binding between the Fc domain and the Fc receptor. The pH-selective antibody, in embodiments, exhibits an in vivo half-life that is at least as long as an in vivo half-life of an antibody with a wild-type Fc domain and/or a Fc domain lacking substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or DB1/ 133359610.3 31 Attorney Docket No.: SYN-061PC/112492-5061 equivalent positions corresponding thereto. Without wishing to be bound by theory, in embodiments, diminished peripheral binding improves in vivo half-life and/or increases tumor bioavailability of the pH- selective antibody by reducing the likelihood of antibody sequestration outside of the tumor environment. [00139] In vivo half-life extension strategies, in embodiments, are employed to extend the half-life of pH-selective anitbodies described herein. In embodiments, the pH-selective antibody has one or more amino acids substitutions in the Fc domain at residues outside of positions 233-235, 267-268, 296, and 298, or equivalent positions corresponding thereto, relative to a wild-type human IgG1 Fc antibody domain of SEQ ID NO: 1. In embodiments, the one or more amino acids substitutions in the Fc domain is at residues 252, 254, or 256, or positions corresponding thereto, relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. For example and without limitation, in embodiments, the pH-selective antibody comprises M252Y, S254T, and T256E (YTE) substitutions, or positions corresponding thereto, in the Fc domain relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. [00140] In embodiments, the pH-selective antibody exhibits an in vivo half-life that is greater by about or at least about 0.5-fold, about or at least about 1-fold, about or at least about 1.5-fold, about or at least about 2-fold, about or at least about 2.5-fold, or about or at least about 3-fold or more than the half-life of an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution at positions 233- 235, 267-268, 296, and 298, or positions corresponding thereto. [00141] The pH-selective antibodies disclosed herein, in embodiments, are humanized or fully human. In embodiments, the Fc variants in pH-selective antibodies disclosed herein can be transferred to antibodies of other species, such as murine, cynomolgus, etc., as well as to chimeric antibodies or antibodies altered for reduced immunogenicity. For example and without limitation, in embodiments, pH- selective antibodies with Ipi sequences are human antibodies. [00142] Without wishing to be bound by theory, the Fc substitutions introduced into antibodies for pH- selectivity described herein do not substantially increase the immunogenicity of the antibodies when administered to a subject. [00143] The pH-selective antibodies disclosed herein, in embodiments, have one or more post- translational modifications (PTMs). PTMs, in embodiments, include typical PTMs that alter or decorate antibody amino acids, including glycans, glycosylation, fucosylation, phosphorylation, carbamylation, deamidation, N-terminal pyroglutamate, among others depending on the system used for antibody production. Alternatively, in embodiments, the pH-selective antibodies disclosed herein lack one or more PTMs. For example and without limitation, in embodiments, the pH-selective antibody is non-fucosylated. DB1/ 133359610.3 32 Attorney Docket No.: SYN-061PC/112492-5061 Additionally, in embodiments, and as illustrated in Fig.2A, the variant Fc chains exhibit glycosylation that does not interfere with pH-selectivity. [00144] Antibody-drug conjugates (ADCs) have proven effective in treating a variety of cancers. In embodiments, the pH-selective antibody is configured to be conjugated to one or more linkers and/or drugs on residues outside of the pH-selective Fc substitutions. Without wishing to be bound by theory, the pH-selective antibodies disclosed herein are suitable for use as ADCs and as fusion proteins with improved safety profile by exhibiting pH-selectivity, such as a reduced level of activity outside of an acidic environment, such as a tumor microenvironment. [00145] The pH-selective antibodies described herein, in embodiments, can be contemplated to be used in contexts where antibody release from FcRn is preferred, for example and without limitation, to release from the Fc receptor after internalization within endosome acidification. [00146] In embodiments, the pH-selective antibody is bispecific and/or chimeric. Methods of Treating Cancer Using pH-Selective Antibodies [00147] In aspects, provided herein are methods of treating cancer by administering a pH-selective antibody, as described herein. The pH-selective antibody represents next-generation embodiments of checkpoint inhibitors (CPIs) that exhibit improved safety profile and therapeutic index over currently available FDA-approved, antibody-based CPIs. The pH-selective antibodies described herein, in embodiments, possess Fc domain modifications that reduce the capacity for off-target binding. In embodiments, the pH-selectivity results in a reduction in immunotoxicities, including immune-related adverse events (IRAEs) and immune-related adverse reactions (IMARs). [00148] Methods of treating cancer herein, in embodiments, include administering pH-selective antibodies that bind a checkpoint inhibitor target, the target being a checkpoint inhibitor that functions, in part, by antibody-dependent cell-mediated cytotoxicity (ADCC). The target, in embodiments, is or comprises one or more of CTLA-4, VISTA, TIGIT, LAG-3, TIM-3, B7-H3, CD73, PD-1, PD-L1, PD-L2, GITR, 4-1BB, CD36, CD25, CCR4, CCR5, CCR8, CCR10, CXCR3, TGF-ȕR, ICOS, CD27, OX40, or CD15. The CPI target, in embodiments, is VISTA. [00149] Without wishing to be bound by theory, methods of treatment herein, in embodiments, represent a treatment strategy for targeting cancer cells in the acidic environment, particularly in the solid tumor microenvironment, by specifically depleting T regulatory cells (Tregs) within the tumor microenvironment. Methods of treatment herein, in embodiments, include administering pH-selective antibodies, as described herein, which maintain affinity and ADCC/ADCP activity in the low pH tumor microenvironment while diminishing affinity and ADCC activity at physiological pH. The diminished DB1/ 133359610.3 33 Attorney Docket No.: SYN-061PC/112492-5061 potency at physiological pH, in embodiments, provides for less activity against, and toxicity to, healthy (non-cancerous) cells and tissues. In embodiments, the target is Tregs, which suppress an immune response. In embodiments, pH-selective Treg targeting results in less autoimmune toxicity directed at healthy tissues. Without wishing to be bound by theory, the pH-selective FcR binding confers a profound increase in pH-selective ADCC, which is a higher-order binding function that relies on numerous individual FcR binding events. [00150] The CPI target, in embodiments, is CTLA-4. CTLA-4 generally functions as an important regulator of T cell priming and activation. Its expression requires co-stimulation mediated by the interaction of CD28 on T cells and CD80 and/or CD86 on antigen-presenting cells, typically occurring in lymph nodes. CTLA-4 outcompetes CD28 for CD80 and/or CD86 binding and thus reduces the pool of activated, antigen-specific T cells that are primed to carry out cell-mediated immunity. [00151] Methods of treatment targeting CTLA-4 include, in embodiments, administration of a pH- selective antibody comprising a heavy chain variable region comprising an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 15, and a light chain variable region comprising an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 16. [00152] In embodiments, methods include administering a pH-selective antibody that binds CTLA-4 (anti-CTLA-4) and comprises heavy variable domain CDRs having the amino acid sequences of SEQ ID NOs: 23-25 and a variable heavy domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 15, light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a variable light domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 16, and a human IgG1 Fc domain having variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto. [00153] In embodiments, methods include administering a pH-selective antibody that binds CTLA-4 (anti-CTLA-4) and comprises heavy variable domain CDRs having the amino acid sequences of SEQ ID NOs: 23-25 and a heavy chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity (outside of the CDRs) to the amino acid sequence of SEQ IS NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto, and light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a light chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity (outside of the CDRs) to the amino acid sequence of SEQ ID NO: 18. DB1/ 133359610.3 34 Attorney Docket No.: SYN-061PC/112492-5061 [00154] Methods of treatment herein, in embodiments, mitigate the toxicities associated with CPIs. Within the context of treating cancer by checkpoint inhibition, CPIs have broad toxicities due to their capacity for systemic, off-target effects. There is evidence that infiltration of tissues with activated T cells is a hallmark of IRAEs caused by CPIs. For example and without limitation, expansion of clonal T cells in inflamed tissue has been observed in cases of fatal myocarditis where T cell clones were observed to be shared between the tumor and the myocardial tissue obtained at the time of necropsy, where T cell- inflamed tissue is also associated with myocarditis, hepatitis, pneumonitis, and colitis. [00155] CTLA-4 function – either through gene knockout in animal models or through pharmacological inhibition with a mAb in animals and humans – is associated with broad autoimmunity and autoinflammatory side effects across many tissues. In patients, the toxicity of IPI is dose dependent, and the incidence and severity of high-grade (Common Terminology Criteria for Adverse Events (CTCAE), grades 3+) side effects range from 25% to 50% in patients with melanoma directly proportional to dose (i.e., toxicities at 3 mgkg^í1 are less than at 10 mgkg^í1) and clinical setting (i.e., fewer side effects in the metastatic setting than in the adjuvant setting). CTLA-4 blockade appears to expand existing T cell clones in a nonspecific manner, suppresses Treg cells, and promotes B cell activity. Its clinical efficacy is associated with reduced clonotype loss and maintenance of high-frequency peripheral blood clonotypes from the initiation of treatment, another side-effect due to off-target binding. [00156] Methods of treatment herein, in embodiments, include administering a pH-selective antibody that binds CTLA-4, where the pH-selective antibody will preferentially bind CTLA-4 on Tregs in the acidic tumor microenvironment and selectivity eliminate these cells as a function of their co-localization within this environment. This pH-selectivity, in embodiments, favors binding in the tumor in comparison to binding in peripheral, healthy tissues. Diminished FcR binding at physiological pH, in embodiments, reduces off-target autoimmunity from treatment. In embodiments, off-target autoimmunity that is diminished includes expansion of existing autoantibodies by B cells, disinhibition of T cells targeting normal tissue, secretion of cytokines by T cells, binding of CPI antibodies to healthy tissue, and complement fixation. [00157] Methods of treatment herein, in embodiments, include administering a pH-selective antibody that binds CTLA-4, resulting in selectively increasing the T effector (Teff) to Treg cell ratio within the tumor. In embodiments, the pH-selective antibody enables increases in the absolute number of Teff and Treg cells in the lymph nodes and of Teff cells in the tumor, while selectively reducing the absolute number of Treg cells in the tumor. DB1/ 133359610.3 35 Attorney Docket No.: SYN-061PC/112492-5061 [00158] Methods of treatment herein, in embodiments, include administering a pH-selective antibody that reduces or eliminates one or more toxicities, side-effects, and/or symptoms as described in Table 3. Table 3: Exemplary toxicities and symptoms associated with CPIs (e.g., ipilimumab). Illustrative Toxicity Illustrative Symptoms E h l l h DB1/ 133359610.3 36 Attorney Docket No.: SYN-061PC/112492-5061 Hypotension Mental status changes [ ] e o s o reamen escr e eren, n em o mens, ncu e a mnserng a p -seective antibody where the pH-selectivity is engineered into one or more existing CPI antibodies that suffer from toxicity drawbacks. For example and in non-limiting embodiments, pH-selectivity is engineered into an anti-PD-1 antibody (e.g., pembrolizumab, nivolumab, or cemiplimab) or anti-PD-L1 antibody (e.g., atezolizumab, dostarlimab, durvalumab, or avelumab) to improve the therapeutic index. In embodiments, treatments utilizing pH-selective antibodies exhibit an improved safety profile in comparison to an antibody with a wild-type Fc domain and/or a Fc domain lacking substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. [00160] In embodiments, methods herein include administering a pH-selective antibody that exhibits improved antibody-mediated effects in the acidic pH of a cancer microenvironment compared to at pH 7.4. The antibody-mediated effects include, in embodiments, target binding, antibody-dependent cellular phagocytosis (ADCP), and/or antibody-dependent cellular cytotoxicity (ADCC). [00161] Methods herein, in embodiments, include administering a pH-selective antibody that maintains an increased level of activity at a pH less than about 7.0 in comparison to its activity at a pH greater than about 7.0. In embodiments, the pH-selective antibody exhibits an increased level of activity at a pH of about 6.5 in comparison to its activity at a pH of about 7.4. DB1/ 133359610.3 37 Attorney Docket No.: SYN-061PC/112492-5061 [00162] Methods herein, in embodiments, include administering a pH-selective antibody that exhibits a reduced level of activity at a pH greater than about 7.0 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution at positions 233-235, 267-268, 296, and 298, or positions corresponding thereto. In embodiments, the pH-selective antibody exhibits a reduced level of activity at a pH of about 7.4 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution at positions 233-235, 267-268, 296, and 298, or positions corresponding thereto. [00163] Methods of treating cancer include, in embodiments, one or more of a solid tumor or blood- based cancer. In embodiments, the cancer is one or more of a carcinoma, sarcoma, myeloma, leukemia, lymphoma, mixed type cancer, and/or metastatic cancer. [00164] In embodiments, the cancer is selected from hormone receptor-positive/HER2-negative breast cancer, triple negative breast cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), Esophageal Diffuse large B-cell lymphoma, metastatic melanoma, hepatocellular carcinoma, metastatic castration- resistant prostate cancer, triple-negative breast cancer, locally advanced or metastatic HER2-expressing cancers, non-small-cell lung cancer (NSCLC), ovarian cancer, PD-1/L1 failure patients with ROR-2 expression in recurrent or metastatic squamous cell carcinoma of the head and neck, melanoma, Merkel cell carcinoma, and nonsquamous NSCLC. [00165] Methods herein, in embodiments, include any cancer that is treatable with a CPI. In embodiments, methods of treating cancer herein include any cancer that can be treated with a CPI that functions through ADCC of Tregs. [00166] Methods of treating cancer herein include, in embodiments, reducing and/or preventing one or more side effects of checkpoint inhibitor therapy that functions, in part, by ADCC, by increasing or expanding the therapeutic window of the checkpoint inhibitor. [00167] Increasing the therapeutic window includes, in embodiments, increasing a cancer patient’s likelihood of receiving checkpoint inhibitor maintenance therapy, for example, where toxicity considerations would otherwise preclude treatment. Increasing the therapeutic window includes, in embodiments, increasing a cancer patient’s likelihood of receiving a complete regime of the checkpoint inhibitor. Increasing the therapeutic window includes, in embodiments, increasing a cancer patient’s likelihood of receiving a complete regimen or more than a complete regimen of the checkpoint inhibitor. Increasing the therapeutic window includes, in embodiments, increasing a cancer patient’s likelihood of receiving a complete dose of a checkpoint inhibitor. Increasing the therapeutic window includes, in embodiments, increasing the dose or length of administration of a checkpoint inhibitor. DB1/ 133359610.3 38 Attorney Docket No.: SYN-061PC/112492-5061 [00168] In embodiments, the present disclosure provides methods that allow for a cancer patient to avoid dose delay. In embodiments, the present disclosure provides methods that allow a patient to be administered a full regimen without having to cease treatment because of, for example, side effects. [00169] In embodiments, the present disclosure provides methods that increase an ability of a cancer patient to receive a combination therapy with another anti-cancer agent (e.g., an additional therapeutic agent, as described herein). [00170] Methods of treatment herein, in embodiments, reduce the need for or eliminate the need for agents used for treatment of immune-related adverse events (IRAEs) and/or immune-related adverse reactions (IMARs) associated with CPIs. In embodiments, methods of treatment include co-administration of one or more agents used to treat IRAEs/IMARs. Agents used to treat IRAEs/IMARs include, in embodiments, glucocorticoids (e.g., used to induce general and broad immunosuppression, such as budesonide), Infliximab (anti-TNF), mycophenolic acid (e.g., depletes nucleotides leading to decreased proliferation of B and T cells), antithymocyte globulin (e.g., T cell depletion, modulation of leukocyte– endothelial interactions, B cell lineage apoptosis, impairs DC function, induction of regulatory T cell), Tocilizumab (anti-IL-6), Vedolizumab (e.g., Į4ȕ7 integrin inhibition; inhibition of T cell trafficking), intravenous immunoglobulin (e.g., broad and non-specific immunomodulation), Rituximab (anti-CD20; depletion of B cells), and Tacrolimus (e.g., calcineurin inhibitor). Treatments for IRAEs/IMARs generally counter the effects of CPIs, and thus the diminished use of these modalities from the use of pH-selective antibodies herein, in embodiments, improve CPI-mediated anticancer effects. [00171] In embodiments, administration of pH-selective antibodies in methods of treatment herein improve patient CTCAE in comparison to cognate treatments that lack pH-selectivity. CTCAE is a descriptive terminology which can be utilized for reporting adverse events and symptoms. The CTCAE is based on a severity grading scale of 1 (mild) to 5 (death/imminent mortality). In embodiments, improvement of CTCAE grading includes reduction from about 5 to about 4, about 4 to about 3, about 3 to about 2, about 2 to about 1, or about 1 to no adverse events. Dosing and Administration [00172] The dosage of any pH-selective antibodies disclosed herein as well as the dosing schedule can depend on various parameters and factors, including, but not limited to, the specific marker-targeted pH-selective antibody, the severity of the condition, the subject’s age, weight, general health, and the administering physician’s discretion. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages are adjusted somewhat DB1/ 133359610.3 39 Attorney Docket No.: SYN-061PC/112492-5061 depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the cancer being treated, the severity of the cancer, and the anatomical location of the cancer. Some variations in the dosage can be expected. [00173] Methods of treatment using pH-selective antibodies described herein, in embodiments, include dosage ranges in concentration of pH-selective antibodies per kilogram (kg) subject body weight. Suitable dosage ranges for methods of treatment described herein can include about 5 ng/mL to about 500 mg/mL, or weight/subject body weight in the range of at least about 1 ng/kg to at least about 10 mg/kg. [00174] Methods of treatment using pH-selective antibodies described herein, in embodiments, include intravenous, intramuscular, or parenteral administration, i.e., pH-selective antibodies are infused into a subject via infusion or injection into the subject’s blood or tissues. [00175] In embodiments, pH-selective antibodies disclosed herein are administered by a controlled- release or a sustained-release means or by delivery of a device that is well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, microspheres, or a combination thereof, to provide the desired release profile in varying proportions. Controlled-or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds. [00176] In embodiments, a controlled-release system is placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol.2, pp.115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533 may be used. [00177] In embodiments, the methods using pH-selective antibodies include applying pH-selective antibodies to a surface of a device (e.g., a catheter) or contained within a pump, patch, or other drug delivery device. The excipient or carrier can be selected based on the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical DB1/ 133359610.3 40 Attorney Docket No.: SYN-061PC/112492-5061 formulations, are described in Remington’s Pharmaceutical Sciences (E. W. Martin), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary). [00178] The dosage regimen utilizing any pH-selective antibodies disclosed herein can be selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific composition of the invention employed. Any pH-selective antibodies disclosed herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three, or four times daily. Furthermore, any pH-selective antibodies disclosed herein can be administered continuously rather than intermittently throughout the dosage regimen. [00179] In embodiments, pH-selective antibodies are administered in consecutive doses about every 24 hours, about every 2 days, about every 4 days, about every 7 days, about every 2 weeks, about every 4 weeks, about every month, about every 2 months, about every 6 months, or about every year. [00180] In embodiments, a combined remission or clinical remission of the cancer, improvement of symptoms, reduction of primary tumor volume, and/or reduction in the number of tumors or metastasis is achieved within about 2 years, about 1 year, about 6 months, about 24 weeks, about 18 weeks, about 12 weeks, about 8 weeks, about 6 weeks, about 4 weeks, about 2 weeks, or about 1 week from administration of the composition and methods with such compositions. Nucleic Acid Constructs and Host Cells for pH-Selective Antibodies [00181] In aspects, the present disclosure relates to nucleic acid constructs encoding a pH-selective IgG1 Fc antibody domain comprising a substitution of one or more residues at positions 233-235, 267- 268, 296, and 298, or positions corresponding thereto, relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. Nucleic acid constructs, in embodiments, encode antibodies or antibody constructs, Fc fusion proteins, among other proteins containing at least a part of the pH-selective Fc antibody domain as described herein. [00182] In embodiments, the nucleic acid construct is DNA or RNA. The RNA, in embodiments is an mRNA or a modified mRNA (e.g., circular mRNA). [00183] In aspects, the present disclosure relates to host cells that comprise one or more nucleic acid constructs encoding a pH-selective antibody and/or can express and secrete a pH-selective antibody, as described herein. Within the context of methods of treatment, host cells, in embodiments, function as delivery vehicles to delivery pH-selective antibodies to one or more locations within a patient to be treated. DB1/ 133359610.3 41 Attorney Docket No.: SYN-061PC/112492-5061 Compositions [00184] In aspects, the present disclosure relates to compositions for the treatment of cancer comprising a pH-selective antibody. In embodiments, compositions include pH-selective antibodies. In embodiments, compositions include a pH-selective antibody and at least one additional anticancer therapy. In embodiments, compositions include one or more nucleic acids encoding a pH-selective antibody or Fc construct. In embodiments, compositions include one or more host cells configured to express and/or secrete a pH-selective antibody. [00185] In embodiments, the pH-selective antibodies are present in the composition at a concentration of about 10³ antibodies/mL to about 10¹⁴ antibodies/mL. Alternatively, in embodiments, pH-selective antibody compositions are present in compositions as weight/volume in the range of about 1 ng/mL to about 500 mg/mL. Pharmaceutical Compositions and Formulations [00186] In aspects, the composition is a pharmaceutical composition. In embodiments, the pharmaceutical compositions of the present invention are formulated to provide a therapeutically effective amount of pH-selective antibodies as the active ingredient. In embodiments, the pharmaceutical compositions of the present invention are formulated to provide a therapeutically effective amount of one or more checkpoint inhibitors as the pH-selective antibody and as the active ingredient. Typically, the pharmaceutical compositions also comprise one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. [00187] Pharmaceutical excipients can be liquids, such as water, oils, and polyols, including those of petroleum, animal, vegetable, or synthetic origin. The pharmaceutical excipients can be, for example, saline, bacteriostatic water, gelatin, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. Pharmaceutically acceptable excipients are generally sterile when administered to a subject. Water is a useful excipient when any agent disclosed herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. Any composition disclosed herein, if desired, can also formulated with wetting or emulsifying agents, or pH buffering agents. Other examples of suitable pharmaceutical excipients are described in DB1/ 133359610.3 42 Attorney Docket No.: SYN-061PC/112492-5061 Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19^th ed.1995), incorporated herein by reference. [00188] In embodiments, the composition comprises an excipient or carrier. In embodiments, the diluent is a pharmaceutically acceptable excipient or carrier. [00189] In embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable diluent. Non-limiting example of diluents include liquid diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, and inert solid diluents such as calcium carbonate, calcium phosphate or kaolin. In embodiments, the diluent comprises one or more of saline, phosphate buffered saline, Dulbecco’s Modified Eagle Medium (DMEM), alpha modified Minimal Essential Medium (alpha MEM), Roswell Park Memorial Institute Media 1640 (RPMI Media 1640), HBSS, human albumin, Ringer’s solution, and the like, or any combination thereof. [00190] In embodiments, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, tablet, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. In embodiments, the compositions can be in the form of elixirs, suspensions, emulsions, solutions, syrups, gels, soft and hard gelatin capsules, suppositories, and sterile injectable solutions. As is known in the art, the type of diluent can vary depending upon the intended route of administration. In embodiments, the resulting compositions can include additional agents, such as preservatives, cryopreservatives (e.g., DMSO), and/or lyoprotectants (e.g., polyols, salts). In embodiments, the carrier can be, or can include a lipid- based or polymer-based colloid. In embodiments, the carrier material can be a colloid formulated as a liposome, a hydrogel, a microparticle, a nanoparticle, or a block copolymer micelle. In embodiments, the carrier material can form a capsule, and that material may be a polymer-based colloid. [00191] In embodiments, the pharmaceutical compositions comprising the pH-selective antibodies include a solubilizing agent. In embodiments, the pharmaceutical compositions comprising the pH- selective antibodies include a cryoprotective agent or an agent to improve thermal stability, such as DMSO or glycerol. The pharmaceutical compositions, in embodiments, can be delivered with a suitable vehicle or delivery device as known in the art. [00192] In embodiments, the compositions can be prepared in any manner well known in the pharmaceutical arts, and can be administered by a variety of routes (e.g., subcutaneous, intravenous, parenteral, etc.) depending upon whether local or systemic treatment is desired and upon the area to be treated. In embodiments, administration can be topical (including ophthalmic and to mucous membranes DB1/ 133359610.3 43 Attorney Docket No.: SYN-061PC/112492-5061 including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral, or parenteral. In embodiments, methods can include ocular delivery, topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. In embodiments, parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. In embodiments, parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. [00193] In embodiments, the pharmaceutical compositions contain, as the active ingredient, nucleic acids and vectors described herein in combination with one or more pharmaceutically acceptable carriers. In embodiments, the terms “pharmaceutically acceptable” (or “pharmacologically acceptable”) refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction, when administered to an animal or a human, as appropriate. The methods and compositions disclosed herein can be applied to a wide range of species, e.g., humans, non-human primates (e.g., monkeys), horses or other livestock, dogs, cats, ferrets or other mammals kept as pets, rats, mice, or other laboratory animals. In embodiments, the term “pharmaceutically acceptable carrier,” includes any and all solvents, dispersion media, coatings, anti-infective, isotonic and absorption delaying agents, buffers, excipients, binders, lubricants, gels, surfactants and the like, that may be used as media for a pharmaceutically acceptable substance. [00194] In embodiments, the compositions can be applied to a surface of a device (e.g., a catheter) or contained within a syringe, pump, or other drug delivery device. In embodiments, the compositions can be administered alone, or in a mixture, in the presence of a pharmaceutically acceptable excipient or carrier (e.g., physiological saline). The excipient or carrier is selected based on the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington’s Pharmaceutical Sciences (E. W. Martin), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary). [00195] In embodiments, the compositions, e.g., pharmaceutical compositions, disclosed herein are suspended in a saline buffer (including, without limitation, TBS, PBS, and the like). [00196] The present technology includes the disclosed pH-selective antibodies in various formulations of pharmaceutical compositions. The pH-selective antibodies disclosed herein, in embodiments, can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing DB1/ 133359610.3 44 Attorney Docket No.: SYN-061PC/112492-5061 liquids, powders, sustained-release formulations, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. [00197] Pharmaceutical compositions comprising the pH-selective antibodies described herein may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the pharmaceutical compositions are prepared by uniformly and intimately bringing therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art). [00198] In embodiments, any pH-selective antibodies disclosed herein are formulated in accordance with routine procedures as a pharmaceutical composition adapted for a mode of administration disclosed herein. Additional Therapeutic Agents [00199] In embodiments, the compositions or methods described herein further comprise a therapeutically effective amount of one or more additional therapeutic agents. In embodiments, the one or more additional therapeutic agents is a CPI or anticancer agent. [00200] In embodiments, the present compositions or methods contemplate other additional therapeutic agents, for example, an analgesic, to aid in treating inflammation or pain at the site of the administration, or an anti-infective agent to prevent infection of the site of treatment with the composition. Non-limiting examples of additional therapeutic agents include analgesics, such as nonsteroidal anti- inflammatory drugs, opiate agonists and salicylates; anti-infective agents, such as anthelmintics, antianaerobics, antibiotics, aminoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, miscellaneous B-lactam antibiotics, penicillin antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, antimycobacterials, antituberculosis antimycobacterials, antiprotozoals, antimalarial antiprotozoals, antiviral agents, anti-retroviral agents, scabicides, anti- inflammatory agents, corticosteroid anti-inflammatory agents, antipruritics/local anesthetics, topical anti- infectives, antifungal topical anti-infectives, antiviral topical anti-infectives; electrolytic and renal agents, such as acidifying agents, alkalinizing agents, diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics, osmotic diuretics, potassium-sparing diuretics, thiazide diuretics, electrolyte replacements, and uricosuric agents; enzymes, such as pancreatic enzymes and thrombolytic enzymes; gastrointestinal agents, such as antidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents, salicylate DB1/ 133359610.3 45 Attorney Docket No.: SYN-061PC/112492-5061 gastrointestinal anti-inflammatory agents, antacid anti-ulcer agents, gastric acid-pump inhibitor anti-ulcer agents, gastric mucosal anti-ulcer agents, H2-blocker anti-ulcer agents, cholelitholytic agents, digestants, emetics, laxatives and stool softeners, and prokinetic agents; general anesthetics, such as inhalation anesthetics, halogenated inhalation anesthetics, intravenous anesthetics, barbiturate intravenous anesthetics, benzodiazepine intravenous anesthetics, and opiate agonist intravenous anesthetics; hormones and hormone modifiers, such as abortifacients, adrenal agents, corticosteroid adrenal agents, androgens, anti-androgens, immunobiological agents, such as immunoglobulins, immunosuppressives, toxoids, and vaccines; local anesthetics, such as amide local anesthetics and ester local anesthetics; musculoskeletal agents, such as anti-gout anti-inflammatory agents, corticosteroid anti-inflammatory agents, gold compound anti-inflammatory agents, immunosuppressive anti-inflammatory agents, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylate anti-inflammatory agents, minerals; vitamins, such as vitamin A , vitamin B , vitamin C, vitamin D, vitamin E, and vitamin K; and radionuclides such as Yttrium-90, Iodine-131, Samarium-153, Lutetium-177, Astatine-211, Lead-212/bismuth-212, Radium- 223, Actinium-225, and Thorium-227. [00201] Additional non-limiting examples of useful therapeutic agents from the above categories include: (1) analgesics in general, such as lidocaine or derivatives thereof, and nonsteroidal anti- inflammatory drugs (NSAIDs) analgesics, including diclofenac, ibuprofen, ketoprofen, and naproxen; (2) opiate agonist analgesics, such as codeine, fentanyl, hydromorphone, and morphine; (3) salicylate analgesics, such as aspirin (ASA) (enteric coated ASA); (4) H1-blocker antihistamines, such as clemastine and terfenadine; (5) anti-infective agents, such as mupirocin; (6) antianaerobic anti-infectives, such as chloramphenicol and clindamycin; (7) antifungal antibiotic anti-infectives, such as amphotericin b, clotrimazole, fluconazole, and ketoconazole; (8) macrolide antibiotic anti-infectives, such as azithromycin and erythromycin; (9) miscellaneous B-lactam antibiotic anti-infectives, such as aztreonam and imipenem; (10) penicillin antibiotic anti-infectives, such a s nafcillin, oxacillin, penicillin G, and penicillin V; (11) quinolone antibiotic anti-infectives, such as ciprofloxacin and norfloxacin; (12) tetracycline antibiotic anti-infectives, such as doxycycline, minocycline, and tetracycline; (13) antituberculosis antimycobacterial anti-infectives such as isoniazid (INH), and rifampin; (14) antiprotozoal anti-infectives, such as atovaquone and dapsone; (15) antimalarial antiprotozoal anti-infectives, such as chloroquine and pyrimethamine; (16) anti-retroviral anti-infectives, such as ritonavir and zidovudine; (17) antiviral anti-infective agents, such as acyclovir, ganciclovir, interferon alfa, remdesivir, and rimantadine; (18) antifungal topical anti-infectives, such as amphotericin B, clotrimazole, miconazole, and nystatin; (19) antiviral topical anti-infectives, such as acyclovir; (20) electrolytic and renal agents, such as lactulose; (21) loop diuretics, such as furosemide; (22) potassium-sparing diuretics, such as triamterene; (23) DB1/ 133359610.3 46 Attorney Docket No.: SYN-061PC/112492-5061 thiazide diuretics, such as hydrochlorothiazide (HCTZ); (24) uricosuric agents, such as probenecid; (25) enzymes such as Rnase and DNase; (26) antiemetics, such as prochlorperazine; (27) salicylate gastrointestinal anti-inflammatory agents, such as sulfasalazine; (28) gastric acid-pump inhibitor anti- ulcer agents, such as omeprazole; (29) H2-blocker anti-ulcer agents, such as cimetidine, famotidine, nizatidine, and ranitidine; (30) digestants, such as pancrelipase; (31) prokinetic agents, such as erythromycin; (32) ester local anesthetics, such as benzocaine and procaine; (33) musculoskeletal corticosteroid anti-inflammatory agents, such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, and prednisone; (34) musculoskeletal anti-inflammatory immunosuppressives, such as azathioprine, cyclophosphamide, and methotrexate; (35) musculoskeletal nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorlac, and naproxen; (36) minerals, such as iron, calcium, and magnesium; (37) vitamin B compounds, such as cyanocobalamin (vitamin B12) and niacin (vitamin B3); (38) vitamin C compounds, such as ascorbic acid; and (39) vitamin D compounds, such as calcitriol. [00202] In embodiments, the one or more additional therapeutic agents is an anticancer agent, for example and without limitation, Abecma, Abemaciclib, Abiraterone Acetate, Abraxane, ABVD, 47BOVE, 47 BOVE-PC, AC, Acalabrutinib, AC-T, Actemra, Adcetris, ADE, Ado-Trastuzumab Emtansine, Adriamycin, Afatinib Dimaleate, Afinitor, Akynzeo, Aldara, Aldesleukin, Alecensa, Alectinib, Alemtuzumab, Alimta, Aliqopa, Alkeran for Injection, Alkeran Tablets, Aloxi, Alpelisib, Alunbrig, Ameluz, Amifostine, Aminolevulinic Acid Hydrochloride, Amivantamab-vmjw, Anastrozole, Apalutamide, Aprepitant, Aranesp, Aredia, Arimidex, Aromasin, Arranon, Arsenic Trioxide, Arzerra, Asciminib Hydrochloride, Asparaginase Erwinia Chrysanthemi, Asparlas, Atezolizumab, Avapritinib, Avastin, Avelumab, Axicabtagene Ciloleucel, Axitinib, Ayvakit, Azacitidine, Azedra, Balversa, Bavencio, BEACOPP, Belantamab Mafodotin-blmf, Beleodaq, Belinostat, Belzutifan, Bendamustine Hydrochloride, Bendeka, BEP, Besponsa, Besremi, Bevacizumab, Bexarotene, Bicalutamide, BiCNU, Binimetinib, Blenrep, Bleomycin Sulfate, Blinatumomab, Blincyto, Bortezomib, Bosulif, Bosutinib, Braftovi, Brentuximab Vedotin, Brexucabtagene Autoleucel, Breyanzi, Brigatinib, Brukinsa, BuMel, Busulfan, Busulfex, Cabazitaxel, Cablivi, Cabometyx, Cabozantinib-S-Malate, CAF, Calaspargase Pegol-mknl, Calquence, Campath, Camptosar, Capecitabine, Caplacizumab-yhdp, Capmatinib Hydrochloride, CAPOX, Carac, Carboplatin, CARBOPLATIN-TAXOL, Carfilzomib, Carmustine, Carmustine Implant, Casodex, CEM, Cemiplimab-rwlc, Ceritinib, Cerubidine, Cervarix (Recombinant HPV Bivalent Vaccine), Cetuximab, CEV, Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Cladribine, Clofarabine, Clolar, CMF, Cobimetinib Fumarate, Cometriq, Copanlisib Hydrochloride, COPDAC, Copiktra, COPP, COPP-ABV, Cosmegen, Cotellic, Crizotinib, CVP, Cyclophosphamide, Cyramza, DB1/ 133359610.3 47 Attorney Docket No.: SYN-061PC/112492-5061 Cytarabine, Dabrafenib Mesylate, Dacarbazine, Dacogen, Dacomitinib, Dactinomycin, Danyelza, Daratumumab, Daratumumab and Hyaluronidase-fihj, Darbepoetin Alfa, Darolutamide, Darzalex, Darzalex Faspro, Dasatinib, Daunorubicin Hydrochloride, Daunorubicin Hydrochloride and Cytarabine Liposome, Daurismo, Decitabine, Decitabine and Cedazuridine, Defibrotide Sodium, Defitelio, Degarelix, Denileukin Diftitox, Denosumab, Dexamethasone, Dexrazoxane Hydrochloride, Dinutuximab, Docetaxel, Dostarlimab-gxly, Doxil, Doxorubicin Hydrochloride, Doxorubicin Hydrochloride Liposome, Durvalumab, Duvelisib, Efudex, Eligard, Elitek, Ellence, Elotuzumab, Eloxatin, Eltrombopag Olamine, Elzonris, Emapalumab-lzsg, Emend, Empliciti, Enasidenib Mesylate, Encorafenib, Enfortumab Vedotin-ejfv, Enhertu, Entrectinib, Enzalutamide, Epirubicin Hydrochloride, EPOCH, Epoetin Alfa, Epogen, Erbitux, Erdafitinib, Eribulin Mesylate, Erivedge, Erleada, Erlotinib Hydrochloride, Erwinaze, Ethyol, Etopophos, Etoposide, Etoposide Phosphate, Everolimus, Evista, Evomela, Exemestane, Exkivity, 5-FU, 5-FU, Fam- Trastuzumab Deruxtecan-nxki, Fareston, Faslodex, FEC, Fedratinib Hydrochloride, Femara, Filgrastim, Firmagon, Fludarabine Phosphate, Fluoroplex, Fluorouracil Injection, Fluorouracil-Topical, Flutamide, FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, Folotyn, Fostamatinib Disodium, Fotivda, Fulphila, FU-LV, Fulvestrant, Fyarro, Gamifant, Gardasil (Recombinant HPV Quadrivalent Vaccine), Gardasil 9 (Recombinant HPV Nonavalent Vaccine), Gavreto, Gazyva, Gefitinib, Gemcitabine Hydrochloride, GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, Gemtuzumab Ozogamicin, Gemzar, Gilotrif, Gilteritinib Fumarate, Glasdegib Maleate, Gleevec, Gliadel Wafer, Glucarpidase, Goserelin Acetate, Granisetron, Granisetron Hydrochloride, Granix, Halaven, Hemangeol, Herceptin Hylecta, Herceptin, HPV Bivalent Vaccine, Recombinant, HPV Nonavalent Vaccine, Recombinant, HPV Quadrivalent Vaccine, Recombinant, Hycamtin, Hydrea, Hydroxyurea, Hyper-CVAD, Ibrance, Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig, Idamycin PFS, Idarubicin Hydrochloride, Idecabtagene Vicleucel, Idelalisib, Idhifa, Ifex, Ifosfamide, Interleukin-2 (recombinant), Imatinib Mesylate, Imbruvica, Imfinzi, Imiquimod, Imlygic, Infigratinib Phosphate, Infugem, Inlyta, Inotuzumab Ozogamicin, Inqovi, Inrebic, Interferon Alfa-2b, Intron A, Iobenguane I131, Ipilimumab, Iressa, Irinotecan Hydrochloride, Isatuximab-irfc, Istodax, Ivosidenib, Ixabepilone, Ixazomib Citrate, Ixempra, Jakafi, JEB, Jelmyto, Jemperli, Jevtana, Kadcyla, Kepivance, Keytruda, Kimmtrak, Kisqali, Koselugo, Kymriah, Kyprolis, Lanreotide Acetate, Lapatinib Ditosylate, Larotrectinib Sulfate, Lenalidomide, Lenvatinib Mesylate, Lenvima, Letrozole, Leucovorin Calcium, Leukeran, Leuprolide Acetate, Levulan Kerastik, Libtayo, Lisocabtagene Maraleucel, Lomustine, Loncastuximab Tesirine-lpyl, Lonsurf, Lorbrena, Lorlatinib, Lumakras, Lumoxiti, Lupron Depot, Lurbinectedin, Luspatercept-aamt, Lutathera, Lutetium (Lu 177-Dotatate), Lynparza, Margenza, Margetuximab-cmkb, Marqibo, Matulane, Mechlorethamine Hydrochloride, Megestrol Acetate, Mekinist, Mektovi, Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, Mesnex, Methotrexate Sodium, Methylnaltrexone Bromide, DB1/ 133359610.3 48 Attorney Docket No.: SYN-061PC/112492-5061 Midostaurin, Mitomycin, Mitoxantrone Hydrochloride, Mobocertinib Succinate, Mogamulizumab-kpkc, Monjuvi, MOPP, Moxetumomab Pasudotox-tdfk, Mozobil, MVAC, Mvasi, Myleran, Mylotarg, Nanoparticle Paclitaxel, Naxitamab-gqgk, Necitumumab, Nelarabine, Neratinib Maleate, Nerlynx, Netupitant, Neulasta, Neupogen, Nexavar, Nilandron, Nilotinib, Nilutamide, Ninlaro, Niraparib Tosylate Monohydrate, Nivestym, Nivolumab, Nplate, Nubeqa, Nyvepria, Obinutuzumab, Odomzo, OEPA, Ofatumumab, OFF, Olaparib, Omacetaxine Mepesuccinate, Oncaspar, Ondansetron Hydrochloride, Onivyde, Ontak, Onureg, Opdivo, OPPA, Orgovyx, Osimertinib Mesylate, Oxaliplatin, Paclitaxel, Paclitaxel Albumin- stabilized Nanoparticle Formulation, PAD, Padcev, Palbociclib, Palifermin, Palonosetron Hydrochloride, Pamidronate Disodium, Panitumumab, Paraplatin, Pazopanib Hydrochloride, PCV, PEB, Pegaspargase, Pegfilgrastim, Peginterferon Alfa-2b, PEG-Intron, Pemazyre, Pembrolizumab, Pemetrexed Disodium, Pemigatinib, Perjeta, Pertuzumab, Pexidartinib Hydrochloride, Phesgo, Piqray, Plerixafor, Polatuzumab Vedotin-piiq, Polivy, Pomalidomide, Pomalyst, Ponatinib Hydrochloride, Portrazza, Poteligeo, Pralatrexate, Pralsetinib, Prednisone, Procarbazine Hydrochloride, Procrit, Proleukin, Prolia, Promacta, Propranolol Hydrochloride, Provenge, Purinethol, Purixan, Qinlock, Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, Ravulizumab-cwvz, Reblozyl, R-CHOP, R-CVP, Recombinant Human Papillomavirus (HPV) Bivalent Vaccine, Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, Relistor, Relugolix, R-EPOCH, Retacrit, Retevmo, Revlimid, Ribociclib, R-ICE, Ripretinib, Rituxan, Rituxan Hycela, Rituximab, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Ropeginterferon Alfa-2b-njft, Rozlytrek, Rubidomycin, Rubraca, Rucaparib Camsylate, Ruxolitinib Phosphate, Rybrevant, Rydapt, Rylaze, Sacituzumab Govitecan-hziy, Sancuso, Sarclisa, Sclerosol Intrapleural Aerosol, Selinexor, Selpercatinib, Selumetinib Sulfate, Scemblix, Siltuximab, Sipuleucel-T, Sirolimus Protein-Bound Particles, Soltamox, Somatuline Depot, Sonidegib, Sorafenib Tosylate, Sotorasib, Sprycel, STANFORD V, Sterile Talc Powder, Steritalc, Stivarga, Sunitinib Malate, Sustol, Sutent, Sylatron, Sylvant, Synribo, Tabloid, Tabrecta, TAC, Tafasitamab-cxix, Tafinlar, Tagraxofusp-erzs, Tagrisso, Talazoparib Tosylate, Talimogene Laherparepvec, Talzenna, Tamoxifen Citrate, Tarceva, Targretin, Tasigna, Tavalisse, Taxotere, Tazemetostat Hydrobromide, Tazverik, Tebentafusp-tebn, Tecartus, Tecentriq, Temodar, Temozolomide, Temsirolimus, Tepadina, Tepmetko, Tepotinib Hydrochloride, Thalidomide, Thalomid, Thioguanine, Thiotepa, Tibsovo, Tisagenlecleucel, Tisotumab Vedotin-tftv, Tivdak, Tivozanib Hydrochloride, Tocilizumab, Tolak, Topotecan Hydrochloride, Toremifene, Torisel, Totect, TPF, Trabectedin, Trametinib Dimethyl Sulfoxide, Trastuzumab, Trastuzumab and Hyaluronidase-oysk, Treanda, Trexall, Trifluridine and Tipiracil Hydrochloride, Trisenox, Trodelvy, Truseltiq, Truxima, Tucatinib, Tukysa, Turalio, Tykerb, Ukoniq, Ultomiris, Umbralisib Tosylate, Undencyca, Unituxin, Uridine Triacetate, VAC, Valrubicin, Valstar, Vandetanib, VAMP, Varubi, DB1/ 133359610.3 49 Attorney Docket No.: SYN-061PC/112492-5061 Vectibix, VeIP, Velcade, Vemurafenib, Venclexta, Venetoclax, Verzenio, Vidaza, Vinblastine Sulfate, Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, VIP, Vismodegib, Vistogard, Vitrakvi, Vizimpro, Voraxaze, Vorinostat, Votrient, Vyxeos, Welireg, Xalkori, Xatmep, Xeloda, XELIRI, XELOX, Xgeva, Xofigo, Xospata, Xpovio, Xtandi, Yervoy, Yescarta, Yondelis, Yonsa, Zaltrap, Zanubrutinib, Zarxio, Zejula, Zelboraf, Zepzelca, Zevalin, Ziextenzo, Zinecard, Zirabev (Bevcizumab), Ziv-Aflibercept, Zofran, Zoladex, Zoledronic Acid, Zolinza, Zometa, Zyclara, Zydelig, Zykadia, Zynlonta, and Zytiga. [00203] The additional therapeutic agent, in embodiments, is an anticancer agent, including in non- limiting examples, a checkpoint inhibitor, e.g., pembrolizumab, nivolumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, or avelumab, radiation therapy (XRT), oncolytic virus, chemotherapeutic, etc. In embodiments, the method of treatment includes co-administration of a pH-sensitive ipilimumab, as described herein, and nivolumab. Subjects and/or Animals [00204] In embodiments, the subject and/or animal is a mammal, e.g., a human, primate, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate. In embodiments, the subject and/or animal is a transgenic animal comprising a fluorescent cell, such as, for example, an RPE cell and/or an immune cell with GFP. In embodiments, the subject and/or animal is a human. In embodiments, the human is a pediatric human, human adult, geriatric human, an infant or child. In other embodiments, the human is referred to as a subject, or a patient. [00205] In embodiments, the method of treatment includes administering to a human who has an age in a range of from about 0 months to about 6 months old, from about 6 months to about 12 months old, from about 12 months to about 18 months old, from about 18 months to about 36 months old, from about 1 year to about 5 years old, from about 5 years to about 10 years old, from about 10 years to about 15 years old, from about 15 years to about 20 years old, from about 20 years to about 25 years old, from about 25 years to about 30 years old, from about 30 years to about 35 years old, from about 35 years to about 40 years old, from about 40 years to about 45 years old, from about 45 years to about 50 years old, from about 50 years to about 55 years old, from about 55 years to about 60 years old, from about 60 years to about 65 years old, from about 65 years to about 70 years old, from about 70 years to about 75 years old, from about 75 years to about 80 years old, from about 80 years to about 85 years old, from about 85 years to about 90 years old, from about 90 years to about 95 years old or from about 95 years to about 100 years old. DB1/ 133359610.3 50 Attorney Docket No.: SYN-061PC/112492-5061 [00206] In embodiments, the subject is a non-human animal, and therefore the invention pertains to veterinary use. In embodiments, the non-human animal is a household pet, a livestock animal, or a laboratory animal. [00207] In embodiments, sera and/or immune cells are evaluated and/or effected. In embodiments, immune cells include cells of a subject’s and/or animal’s innate immune system. In embodiments, such cells include, but are not limited to, NK cell, monocyte, DC, B cell, macrophage, CD4+ T cell, and CD8+ T cell. In various embodiments, the invention provides for detecting a presence, detecting an absence, or measuring an amount of cancer cells, or tumor cDNA or RNA in a sample originating from a subject. Definitions [00208] The following definitions are used in connection with the invention disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this invention belongs. [00209] An “effective amount,” or “therapeutically effective amount,” is an amount that is effective for treating, preventing, or ameliorating cancer or a symptom thereof, such as those described herein, or an amount that is intended to reduce the number of cancer cells, reduce a tumor volume, and/or reduce the number of tumors and/or metastasis. [00210] As used herein, “a,” “an,” or “the” can mean one or more than one. [00211] As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features. [00212] Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, and may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.” [00213] The term “antibody,” and its equivalents as used herein, in embodiments, refers to any antibody or antibody format that includes an Fc domain, including immunoglobulins of various families subclasses, such as IgG1, IgG2, IgG3, IgG4, etc., and types (IgA, IgM, IgE, etc.) This includes, in embodiments, Fc-fusion proteins, antibody-drug conjugates (ADCs), and various Fc constructs. DB1/ 133359610.3 51 Attorney Docket No.: SYN-061PC/112492-5061 [00214] The term “pH-selective,” and its equivalents as used herein in relation to an antibody, in embodiments, refer to the ability of an antibody to exhibit changes in functionality as a function of pH ([H+]). The antibody functionality, in embodiments, is binding affinity (e.g., antigen binding capacity and/or Fc receptor binding capacity), in vivo half-life, ADCC, ADCP, among other antibody functionality. The pH- selectivity, in embodiments, relates to the range from approximately pH 5.0 to approximately pH 7.4. [00215] The term “Fc receptor,” or “FcR,” as used herein, in embodiments, refers to all receptors that bind an antibody Fc domain. In embodiments, an Fc receptor includes Fc gamma-receptor (FcȖR), FcRn, FcȖRI (CD64), FcȖRII (CD32), and FcȖRIII (CD16), as well as homologs and orthologs thereof. EXAMPLES Example 1: In vitro Evaluation of pH-Selective Antibody-Based Checkpoint Inhibition in CTLA-4+ Cells [00216] Anti-CTLA-4 human IgG1 monoclonal antibody (e.g., ipilimumab) functions by blocking CTLA- 4 interactions and initiating ADCC. ADCC-mediated Treg deletion in tumors is highly correlated with efficacy while Treg depletion in the periphery results in toxicities and autoimmune diseases, such as colitis. The Fc domain of Ipilimumab (Ipi) is modified to contain the pH-selective Fc amino acid substitutions, as described herein, and is used to treat human NK cells (NK92 cells) and/or CTLA-4 positive cells (e.g., activated T cells from PBMCs) to analyze the effectiveness of the pH-selective antibody form of Ipi. The in vitro assays include data describing pH-selective ADCC, Treg lysis, effector T cell activation, and cytokine release. Example 2: In vivo Evaluation of pH-Selective Antibody-Based Checkpoint Inhibition in Cancer Treatment [00217] The Fc domain of Ipilimumab (Ipi) is modified to contain the pH-selective Fc amino acid substitutions, as described herein, and is used to evaluate the effectiveness of pH-selective checkpoint inhibition in two mouse models: 1) a B16/F10 melanoma mouse and 2) an MC38 colon cancer model (huCD16A mice x huCTLA4 mice). The first mouse model has humanized Fc receptors, wherein Ipi is designed to bind to mouse CTLA4. The second mouse model has a fully humanized immune system due to reconstitution with human CD34+ hematopoietic stem cells. In the second model, Ipi binds human CTLA4. Additionally, the second mouse model involves stem cell engraftment and human immune reconstitution that can include supplementation with the appropriate cytokines (e.g., IL-15) to ensure adequate reconstitution with NK cells, which mediate much of the ADCC function. [00218] Five treatment groups are used: 1) null LALAPG Fc, WT Fc, acid-Fc (pH-selective variant), enhanced Fc, isotype (n = 10 each group). Antibodies are administered to treat subcutaneously- established tumors and lung metastasis. An optional follow-up study utilizes a bicarbonate-supplemented diet to neutralize tumor against treatment. Outcomes focus on tumor size and number, body weight, DB1/ 133359610.3 52 Attorney Docket No.: SYN-061PC/112492-5061 presence of tumor infiltrating lymphocytes, cytokine panel, and number of FoxP3-positive cells in tumor and spleen periphery. [00219] Mouse Feasibility Studies [00220] The growth of F16-B10 mouse melanoma cells in humanized Fc mice is assessed from a subcutaneous flank tumor, as well as from lung metastasis. Toxicity testing includes administering about or at least about 1 mg/kg antibody to about or at least about 15 mg/kg dosages, harvesting blood at about or at least about 1 hrs. to about or at least about 72 hrs. after administration, and measuring cytokine levels. Toxicity is compared to antibodies lacking pH-selective Fc variants. Cells isolated from the spleen, as well as isolated T cells (e.g., NK cells), will be evaluated for ex vivo ADCC in the presence of Ipi, for example at pH 6.5 and pH 7.4. Additionally, dose escalation studies, involving increasing doses of the test antibodies will be used to determine an LD50, verifying if lethality is caused by immune activation. The pH-selective test antibody is expected to exhibit lower immune activation and therefore exhibit a higher LD50. The effect may be amplified by alkalinizing the mice via bicarbonate in the water supply. [00221] Treatment Studies [00222] High dose anti-CTLA-4 antibodies (e.g., Ipi) are tested for the effect of pH-selectivity on efficacy and toxicity. Antibody efficacy is assessed as a function of tumor pH. Tumor pH is measured in mice inoculated with MC38 cells (e.g., 1 x 10⁶ cells; human CTLA-4 knock-in mice bearing MC38 tumors) grown to a tumor volume of about 100–400 mm³ and then measured with an optical pH sensor probe. Treatment groups include an isotype control (i.e., non-specific Fab and WT Fc treatment arms), anti- mouse CTLA-4 with WT Fc, anti-mouse CTLA-4 with pH-selective Fc, and anti-mouse CTLA-4 with SDALIE Fc (i.e., high affinity human CD16a variant, expected to increase efficacy and toxicity). Dosing follows about or at least about 1-15 mg/kg biweekly for 3 weeks. Efficacy is monitored using tumor volume measurement, cytokine release measurement from tumor-infiltrating lymphocytes (TIL), Treg depletion in tumors, and intratumoral T eff/T reg ratios and absolute counts. Toxicity is monitored by measuring peripheral Treg activation and cytokine levels, where Treg levels decreasing to a greater extent in the tumor than in the periphery indicating pH-selectivity. Example 3: YERVOY-like antibodies with wild-type or acid-Fc bind human CTLA-4 [00223] Antibodies were generated that bind human CTLA-4 (YERVOY, or Ipilimumab) or mouse CTLA-4 (4F10, SEQ ID NOs: 22-23) using standard cloning and protein expression methods with protein A purification.4F10 was cloned as a chimeric antibody comprising the mouse variable regions and human IgG1 and kappa constant domains. DB1/ 133359610.3 53 Attorney Docket No.: SYN-061PC/112492-5061 [00224] Chromatographic and polyacrylamide gel electrophoresis (PAGE) analyses (under reducing and non-reducing conditions) was performed to determine if the mutations to the Fc domain (e.g., S267E, H268D, and Y296H) adversely affected protein production and/or the secondary or tertiary structure of the antibody. As shown in Figs. 3A-3D, retention volumes of elution from chromatography-based purification revealed no difference between wild-type Fc constructs and pH-selective Fc constructs (Acid- Fc) for both human and mouse anti-CTLA-4 antibodies. As shown in Fig. 4, PAGE analyses demonstrated that the purified antibodies were the anticipated molecular weight under non-reducing conditions, with both heavy and light variable domains intact and making the appropriate disulfide bridges. [00225] Flow cytometry was used to detect antibody binding to Chinese Hamster Ovary (CHO) cells that were transiently transfected to express human or mouse CTLA-4 on the cell surface. 2.5 ^g of plasmid encoding either a FLAG-tagged human or mouse CTLA-4 construct were transfected into 2.5x10^⁶ CHO cells using EXPIFECTAMINE CHO transfection kit (ThermoFisher). Two days after transfection, cells were harvested and washed twice with flow buffer containing 10% fetal bovine serum (FBS) in phosphate buffered saline (PBS). Cells were subsequently incubated for 1 hour at ambient temperature (approx.22°C) in serially diluted human and mouse ipilimumab variants (having “Acid-Fc” variants S267E, H268D, and Y296H, as described in Table 2). Next, cells were washed twice with flow buffer and anti-PE RPE antibody (AGILENT) was added at a 1:500 ratio and incubated for 1 hour at ambient temperature. Cells were then washed twice with flow buffer and incubated at a ratio of 1:1000 in ALEXAFLUOR 647-conjugated Goat anti-human Fc antibody (ImmunoResearch Laboratories) for 1 hour at ambient temperature. Samples were washed, resuspended in flow buffer, and the binding was detected by flow cytometry using BD ACCURI flow cytometer. The flow cytometry data were analyzed in FLOWJO v10.10.0 data analysis software. Live cells that were positive for both FLAG and ALEXAFLUOR 647 were used to determine the mean fluorescence intensity (MFI). As summarized in Figs.5A and 5B, MFI, in replicates, were plotted against varying concentration of antibodies, with the data fit using a One Site- Total Non-Linear Fit (NS=0) function to determine the effective binding affinity. Both biological and technical replicates were used in this experiment, and the effective Kd were similar in both cases. The binding curves and effective Kd obtained from the analysis are shown in Figs.5A and 5B, where WT refers to the wild-type Fc sequences of both the 4F10 (mouse variant of Ipimumab) and Ipimumab in comparison to the Acid-Fc variants (having S267E, H268D, and Y296H, as described in Table 2). Overall, the data demonstrated that the pH-selective mutations did not adversely affect antigen binding. Table 4: Calculated in vitro cell-based CTLA-4 affinities of wild-type (WT) and pH-selective (Acid-F) human and mouse Ipilimumab variants with human or mouse CTLA-4. Ipi-WT = heavy chain SEQ ID NO: 17 and light chain SEQ ID NO: 18; Ipi-Acid-Fc = heavy chain SEQ ID NO: 22 and light chain SEQ ID NO: DB1/ 133359610.3 54 Attorney Docket No.: SYN-061PC/112492-5061 18; 4F10-WT = heavy chain SEQ ID NO: 17 with the VH domain swapped for SEQ ID NO: 29 and light chain SEQ ID NO: 18 with the VL domain swapped with SEQ ID NO: 30; 4F10-Acid-Fc = heavy chain SEQ ID NO: 22, with the VH domain swapped for SEQ ID NO: 29, and light chain SEQ ID NO: 18 with the VL domain swapped with SEQ ID NO: 30. Ligand Species Ipimumab Variants Binding Affinity (Kd) 95% CI Ipi-WT 3.191 2.030-5.029 8 4 6 [00226] The binding of Ipilimumab Fc variants with Fc RIIIa was analyzed at physiological pH (e.g., pH 7.4) and an acidic environment representing a tumor microenvironment (e.g., pH 6.5) using biolayer interferometry (BLI). OCTET FAB2G Biosensor tips were prewetted in BLI running buffer (0.1% bovine serum albumin (BSA) in TWEEN 20 phosphate buffered saline (PBST)) for 10 min and dipped into wells containing 10 ^g/mL of either WT or Acid-Fc variant of Ipilimumab until a shift of > 3 nm was detected. The sensors were then baselined for 180 s into running buffer at pH 7.4 or pH 6.5. After baselining, the biosensor tips were dipped into serially diluted FcȖRIIIa (2 ^M to 62.5 ^M concentrations) for 180 s to determine the association signal. For determining the disassociation signal, the sensors were dipped into wells containing the running buffer for 60 s. After association and disassociation constants were obtained, a 1:1 concentration ratio of Fc:FcȖRIIIa association and disassociation model was fit using the full association step and the first 5 s of the disassociation period (e.g., as shown in Fig.6A) with a Langmuir isotherm equation (R_eq = R_maxכC/(K_d + C)) used to calculate the equilibrium Kd (e.g., as shown in Fig. 6B). Table 5: Calculated in vitro FcȖRIIIa affinities of wild-type (WT) and pH-selective (Acid-F) ipilimumab variants with human CTLA-4. Ipi-WT = heavy chain SEQ ID NO: 17 and light chain SEQ ID NO: 18; Ipi- Acid-Fc = heavy chain SEQ ID NO: 22 and light chain SEQ ID NO: 18. Antibody Variant Kd, pH 7.4 95% CI Kd, pH 6.5 95% CI Ratio pH 7.4/pH 6.5 [00227] Overall, the data demonstrated that the pH-selective Fc domain (Acid-Fc) exhibited an increase in selectivity (e.g., ratio pH 7.4/pH 6.5) for binding at acidic pH (pH 6.5) relative to physiological DB1/ 133359610.3 55 Attorney Docket No.: SYN-061PC/112492-5061 pH (pH 7.4) in comparison to the ipilimumab Fc domain. The mutations in the Acid-Fc domain granted the anti-CTLA-4 antibody with a statistically significant decrease in the ability to engage with the FcȖRIIIa receptor at physiological pH (e.g., pH 7.4), while maintaining binding at acidic pH (e.g., pH 6.5). EQUIVALENTS [00228] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. [00229] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections. DB1/ 133359610.3 56

Claims

Attorney Docket No.: SYN-061PC/112492-5061 CLAIMS What is claimed is: 1. A composition comprising a pH-selective antibody comprising: a) an Fc amino acid sequence comprising a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto, relative to a wild-type human IgG1 Fc antibody domain of SEQ ID NO: 1; and b) an antigen-binding portion that binds a checkpoint inhibitor target, the target being a checkpoint inhibitor that functions, in part, by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP). 2. The composition of claim 1, wherein the checkpoint inhibitor target is or comprises one or more of CTLA-4, VISTA, TIGIT, LAG-3, TIM-3, B7-H3, CD73, PD-1, PD-L1, PD-L2, GITR, 4-1BB, CD36, CD25, CCR4, CCR5, CCR8, CCR10, CXCR3, TGF-ȕR, ICOS, CD27, OX40, or CD15. 3. The composition of claim 2, wherein the checkpoint inhibitor target is CTLA-4, optionally wherein the CTLA-4 is human (hCTLA-4) or murine (mCTLA-4). 4. The composition of any one of the preceding claims, wherein the antigen-binding portion comprises an immunoglobulin heavy chain variable region comprising: a CDRH1 comprising an amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 5, or SEQ ID NO: 23; a CDRH2 comprising an amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 6, or SEQ ID NO: 24; and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 7, or SEQ ID NO: 25; and comprises an immunoglobulin light chain variable region comprising: a CDRL1 comprising an amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, or SEQ ID NO: 26; a CDRL2 comprising an amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 27; and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 28. 5. The composition of claim 4, wherein the antigen-binding portion binds CTLA-4 and comprises: a heavy chain variable region comprising a HCDR1 of SEQ ID NO: 23, a HCDR2 of SEQ ID NO: 24, and a HCDR3 of SEQ ID NO: 25 and an amino acid sequence having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 15; and DB1/ 133359610.3 57 Attorney Docket No.: SYN-061PC/112492-5061 a light chain variable region comprising a LCDR1 of SEQ ID NO: 26, a LCDR2 of SEQ ID NO: 27, and a LCDR3 of SEQ ID NO: 28 and an amino acid sequence having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 16. 6. The composition of claim 5, wherein the pH-selective antibody binds CTLA-4 and comprises: a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 15; a light chain variable region comprising an amino acid sequence of SEQ ID NO: 16; and a human IgG1 Fc domain amino acid sequence having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to SEQ ID NO: 1 and having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 7. The composition of any one of claims 4-6, wherein the pH-selective antibody binds CTLA-4 and comprises: a heavy chain comprising a HCDR1 of SEQ ID NO: 23, a HCDR2 of SEQ ID NO: 24, and a HCDR3 of SEQ ID NO: 25 and an amino acid sequence of at least about 95%, at least about 98%, or at least about 99% to SEQ ID NO: 17, with a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto; and a light chain comprising a LCDR1 of SEQ ID NO: 26, a LCDR2 of SEQ ID NO: 27, and a LCDR3 of SEQ ID NO: 28 and an amino acid sequence of at least about 95%, at least about 98%, or at least about 99% to SEQ ID NO: 18. 8. The composition of any one of the preceding claims, wherein the substitution of the residue at position 233, or the position corresponding thereto, is a negatively charged amino acid. 9. The composition of claim 8, wherein the negatively charged amino acid is selected from aspartic acid or glutamic acid. 10. The composition of any one of the preceding claims, wherein the substitution of the residue at position 234, or the position corresponding thereto, is an aliphatic amino acid. 11. The composition of claim 10, wherein the aliphatic amino acid is selected from glycine, alanine, valine, proline, and isoleucine. 12. The composition of claim 10, wherein the aliphatic residue is valine. 13. The composition of any one of the preceding claims, wherein the substitution of the residue at DB1/ 133359610.3 58 Attorney Docket No.: SYN-061PC/112492-5061 position 235, or the position corresponding thereto, is an aliphatic or a negatively charged amino acid. 14. The composition of claim 13, wherein the aliphatic amino acid is selected from glycine, alanine, valine, proline, or isoleucine. 15. The composition of claim 13, wherein the negatively charged amino acid is selected from aspartic acid and glutamic acid. 16. The composition of any one of the preceding claims, wherein the substitution of the residue at position 267, or the position corresponding thereto, is an aliphatic or a negatively charged amino acid. 17. The composition of claim 16, wherein the aliphatic amino acid is selected from glycine, alanine, valine, proline, isoleucine, and leucine. 18. The composition of claim 16, wherein the negatively charged amino acid is selected from aspartic acid and glutamic acid. 19. The composition of any one of the preceding claims, wherein the substitution of the residue at position 268, or the position corresponding thereto, is a negatively charged amino acid. 20. The composition of claim 19, wherein the negatively charged amino acid is selected from aspartic acid and glutamic acid. 21. The composition of any one of the preceding claims, wherein the substitution of the residue at position 296, or the position corresponding thereto, is a positively charged amino acid. 22. The composition of claim 21, wherein the positively charged amino acid is selected from histidine, lysine, and arginine. 23. The composition of any one of the preceding claims, wherein the substitution of the residue at position 298, or the position corresponding thereto, is a positively charged amino acid. 24. The composition of claim 23, wherein the positively charged amino acid is selected from histidine, lysine, and arginine. 25. The composition of any one of the preceding claims, wherein the Fc amino acid sequence comprises one or more of: 1) E233D, L234V, L235V, S267E, H268D, and Y296H; 2) E233D, L234V, L235V, S267E, H268D, and S298R; 3) E233D, L234V, L235D, S267G, H268D, and Y296H; DB1/ 133359610.3 59 Attorney Docket No.: SYN-061PC/112492-5061 4) E233D, L234V, L235D, S267E, H268D, and Y296H; 5) S267E, H268D, and Y296H; 6) S267D, H268D, and S298R; or 7) S267G, H268D, and Y296H, or positions corresponding thereto. 26. The composition of claim 25, wherein the Fc amino acid sequence comprises the substitutions S267E and H268D, or positions corresponding thereto. 27. The composition of claim 25, wherein the Fc amino acid sequence comprises the substitutions S267E, H268D, and Y296H, or positions corresponding thereto. 28. The composition of any one of the preceding claims, wherein the pH-selective antibody comprises one or more additional Fc amino acid sequence substitutions at one or more positions of S240, A331, and/or I333, or positions corresponding thereto. 29. The composition of claim 28, wherein the pH-selective antibody comprises the additional Fc amino acid sequence substitutions S240D, A331L, and/or I333E, or positions corresponding thereto; or S240D/A331L/I333E, or positions corresponding thereto. 30. The composition of any one of claims 27-29, wherein the pH-selective antibody comprises: 1) a heavy chain comprising an amino acid sequence of SEQ ID NO: 19 further comprising the Fc amino acid substitutions of S240D, A331L, and/or I333E, or positions corresponding thereto, and a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto; and a light chain comprising an amino acid sequence of SEQ ID NO: 20; or 2) a heavy chain amino acid sequence comprising at least 95% sequence identity to SEQ ID NO: 21 further comprising a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto; and a light chain comprising at least 95% sequence identity to SEQ ID NO: 20. 31. The composition of claim 27, wherein the pH-selective antibody comprises a heavy chain amino acid sequence comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto; and a light chain comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 18. 32. The composition of any one of the preceding claims, wherein the pH-selective antibody is an DB1/ 133359610.3 60 Attorney Docket No.: SYN-061PC/112492-5061 IgG1 antibody. 33. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits greater affinity for an antibody Fc receptor at a pH less than about 7.0 in comparison to its affinity at a pH greater than about 7.0. 34. The composition of any one of the preceding claims, wherein the pH-selective antibody has higher affinity for an antibody Fc receptor at: about or at least about pH 7.0 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.9 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.8 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.7 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.6 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.5 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.4 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.3 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.2 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.1 relative to its affinity at about or at least about pH 7.4; about or at least about pH 6.0 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.9 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.8 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.7 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.6 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.5 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.4 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.3 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.2 relative to its affinity at about or at least about pH 7.4; about or at least about pH 5.1 relative to its affinity at about or at least about pH 7.4; or about or at least about pH 5.0 relative to its affinity at about or at least about pH 7.4. 35. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits greater affinity for an antibody Fc receptor at a pH of about 6.5 in comparison to its affinity at a pH of about 7.4. 36. The composition of claim 35, wherein the pH-selective antibody exhibits about or at least about a 1-fold increase in affinity, about or at least about a 1.5-fold increase in affinity, about or at least DB1/ 133359610.3 61 Attorney Docket No.: SYN-061PC/112492-5061 about a 2-fold increase in affinity, about or at least about a 2.5-fold increase in affinity, about or at least about a 3-fold increase in affinity, about or at least about a 3.5-fold increase in affinity, about or at least about a 4-fold increase in affinity, about or at least about a 4.5-fold increase in affinity, about or at least about a 5-fold increase in affinity for an antibody Fc receptor at a pH of about 6.5 compared to its affinity for an antibody Fc receptor at pH 7.4. 37. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits greater selectivity for binding an antibody Fc receptor at a pH less than about 7.0 in comparison to a pH greater than about 7.0 relative to an antibody with a wild-type Fc domain. 38. The composition of claim 37, wherein the pH-selective antibody exhibits a selectivity for binding at a pH of about 6.5 versus at a pH of about 7.4 of about or at least about 1.1, about or at least about 1.2, about or at least about 1.3, about or at least about 1.4, about or at least about 1.5, about or at least about 1.6, about or at least about 1.7, about or at least about 1.8, about or at least about 1.9, about or at least about 2.0, about or at least about 2.1, about or at least about 2.2, about or at least about 2.2, about or at least about 2.3, about or at least about 2.4, about or at least about 2.5, about or at least about 2.6, about or at least about 2.7, about or at least about 2.8, about or at least about 2.9, about or at least about 3.0, about or at least about 3.1, about or at least about 3.2, about or at least about 3.3, about or at least about 3.4, about or at least about 3.5, about or at least about 3.6, about or at least about 3.8, or about or at least about 4.0. 39. The composition of any one of claims 33-38, wherein the antibody Fc receptor is one or more of an Fc gamma-receptor (FcȖR), FcRn, FcȖRI (CD64), FcȖRII (CD32), and FcȖRIII (CD16). 40. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits pH-selective FcȖRIIIa binding. 41. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits increased binding for the checkpoint inhibitor target in an acidic environment in comparison to an environment at a pH greater than about 7.0. 42. The composition of any one of the preceding claims, wherein the pH-selective antibody comprises an antigen-binding portion that binds CTLA-4 and comprises an immunoglobulin heavy chain variable region comprising: a CDRH1 comprising an amino acid sequence of SEQ ID NO: 5; a CDRH2 comprising an amino acid sequence of SEQ ID NO: 6; and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 7; and comprises an immunoglobulin light chain variable region comprising: DB1/ 133359610.3 62 Attorney Docket No.: SYN-061PC/112492-5061 a CDRL1 comprising an amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13; a CDRL2 comprising an amino acid sequence of SEQ ID NO: 9; and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 10, wherein the pH-selective antibody exhibits an increased level of CTLA-4 binding in an acidic environment in comparison to at a pH of about 7.4. 43. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits increased binding for the checkpoint inhibitor target on T cells within a tumor microenvironment in comparison to T cells outside of the tumor microenvironment. 44. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits increased binding for the checkpoint inhibitor target on cancer cells within a tumor microenvironment in comparison to cells outside of the tumor microenvironment. 45. The composition of any one of the preceding claims, wherein the pH-selective antibody preferably binds CTLA-4 on T regulatory cells (T regs) within a tumor microenvironment in comparison to T regs outside the tumor microenvironment. 46. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits greater antibody-dependent cellular phagocytosis (ADCP) and/or antibody-dependent cellular cytotoxicity (ADCC) at a pH less than about 7.0 in comparison to a pH greater than about 7.0. 47. The composition of claim 46, wherein the pH-selective antibody exhibits about or at least about a 0.5-fold increase in ADCC, about or at least about a 1-fold increase in ADCC, about or at least about a 1.5-fold increase in ADCC, about or at least about a 2-fold increase in ADCC, about or at least about a 2.5-fold increase in ADCC, about or at least about a 3-fold increase in ADCC, about or at least about a 3.5-fold increase in ADCC, about or at least about a 4-fold increase in ADCC, about or at least about a 4.5-fold increase in ADCC, about or at least about a 5-fold increase in ADCC, about or at least about a 10-fold increase in ADCC, about or at least about a 20-fold increase in ADCC, or about or at least about a 30-fold increase in ADCC at about pH 6.5 compared to its level of ADCC at about pH 7.4. 48. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits about or at least about a 1-fold decrease in ADCC, about or at least about a 1.5-fold decrease in ADCC, about or at least about a 2-fold decrease in ADCC, about or at least about a 2.5-fold decrease in ADCC, about or at least about a 3-fold decrease in ADCC, about or at least about a 3.5-fold decrease in ADCC, about or at least about a 4-fold decrease in ADCC, about or at least DB1/ 133359610.3 63 Attorney Docket No.: SYN-061PC/112492-5061 about a 4.5-fold decrease in ADCC, about or at least about a 5-fold decrease in ADCC, about or at least about a 10-fold decrease in ADCC, about or at least about a 20-fold decrease in ADCC, or about or at least about a 30-fold decrease in ADCC at about pH 7.4 compared to a level of ADCC for a wild-type antibody Fc receptor at about pH 7.4. 49. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits greater selectivity for ADCC at a pH less than about 7.0 in comparison to a pH greater than about 7.0 relative to an antibody with a wild-type Fc domain. 50. The composition of claim 49, wherein the pH-selective antibody exhibits a selectivity for ADCC at a pH of about 6.5 versus at a pH of about 7.4 of about or at least about 2.0, about or at least about 3.0, about or at least about 4.0, about or at least about 5.0, about or at least about 6.0, about or at least about 7.0, about or at least about 8.0, about or at least about 9.0, about or at least about 10.0, about or at least about 11.0, about or at least about 12.0, about or at least about 13.0, about or at least about 14.0, about or at least about 15.0, about or at least about 16.0, about or at least about 17.0, about or at least about 18.0, about or at least about 19.0, about or at least about 20.0, about or at least about 21.0, about or at least about 22.0, about or at least about 23.0, about or at least about 24.0, about or at least about 25.0, about or at least about 26.0, about or at least about 27.0, about or at least about 28.0, about or at least about 29.0, or about or at least about 30.0. 51. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits an increased level of activity at a pH less than about 7.0 in comparison to its activity at a pH greater than about 7.0. 52. The composition of claim 49, wherein the pH-selective antibody exhibits an increased level of activity at a pH of about 6.5 in comparison to its activity at a pH of about 7.4. 53. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits a reduced level of activity at a pH greater than about 7.0 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 54. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits a reduced level of activity at a pH of about 7.4 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 55. The composition of any one of the preceding claims, wherein the pH-selective antibody exhibits DB1/ 133359610.3 64 Attorney Docket No.: SYN-061PC/112492-5061 an improved safety profile in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 56. The composition of any one of the preceding claims, wherein the pH-selective antibody has an in vivo half-life that is at least as long as or is greater than an in vivo half-life of an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 57. The composition of claim 56, wherein the pH-selective antibody exhibits an in vivo half-life that is about or at least about 0.5-fold, about or at least about 1-fold, about or at least about 1.5-fold, about or at least about 2-fold, about or at least about 2.5-fold, or about or at least about 3-fold longer than a half-life of an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 58. The composition of any one of the preceding claims, wherein the pH-selective antibody further comprises one or more amino acid substitutions in the Fc domain that increase the half-life, optionally wherein the Fc domain comprises one or more amino acids substitutions at residues 252, 254, or 256, or positions corresponding thereto, relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. 59. The composition of claim 58, wherein the pH-selective antibody further comprises M252Y, S254T, and T256E (YTE) substitutions, or positions corresponding thereto, in the Fc domain relative to a wild-type IgG1 Fc antibody domain of SEQ ID NO: 1. 60. The composition of any one of the preceding claims, wherein the pH-selective antibody is humanized or fully human. 61. The composition of any one of the preceding claims, wherein the pH-selective antibody has one or more post-translational modifications (PTMs). 62. The composition of any one of claims 1-61, wherein the pH-selective antibody lacks one or more post-translational modifications (PTMs). 63. The composition of claims 61 or 62, wherein the one or more PTMs is a glycan, glycosylation, fucosylation, phosphorylation, carbamylation, deamidation, and/or N-terminal pyroglutamate. 64. The composition of any one of claims 1-60, wherein the pH-selective antibody is non-fucosylated. 65. The composition of any one of the preceding claims, wherein the pH-selective antibody is DB1/ 133359610.3 65 Attorney Docket No.: SYN-061PC/112492-5061 conjugated to one or more linkers and/or drugs. 66. The composition of any one of the preceding claims, wherein the pH-selective antibody is bispecific and/or chimeric. 67. A composition comprising an anti-CTLA-4 pH-selective antibody comprising: heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25; light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28; and a human IgG1 Fc domain comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 1 and having variants S267E, H268D, and Y296H, or equivalent positions corresponding thereto. 68. A composition comprising an anti-CTLA-4 pH-selective antibody comprising: heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a variable heavy domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 15; light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a variable light domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 16; and a human IgG1 Fc domain comprising at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 1 and having variants S267E, H268D, and Y296H, or equivalent positions corresponding thereto. 69. A composition comprising an anti-CTLA-4 pH-selective antibody comprising: heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a heavy chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ IS NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto; and light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a light DB1/ 133359610.3 66 Attorney Docket No.: SYN-061PC/112492-5061 chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 18. 70. A nucleic acid construct encoding a pH-selective antibody of any one or claims 1-69. 71. The nucleic acid construct of claim 70, wherein the nucleic acid construct is DNA or RNA. 72. The nucleic acid construct of claim 68, wherein the RNA is an mRNA or a modified mRNA. 73. A host cell comprising the nucleic acid construct of claim 72. 74. A method of treating cancer comprising administering a pH-selective antibody of any one of claims 1-69, a nucleic acid of claim 70-72, or a host cell of claim 73 to a subject in need thereof. 75. The method of claim 74, wherein the pH-selective antibody binds a checkpoint inhibitor target, the target being a checkpoint inhibitor that functions, in part, by antibody-dependent cell- mediated cytotoxicity (ADCC). 76. The method of claim 74 or 75, wherein checkpoint inhibitor target is or comprises one or more of CTLA-4, VISTA, TIGIT, LAG-3, TIM-3, B7-H3, CD73, PD-1, PD-L1, PD-L2, GITR, 4-1BB, CD36, CD25, CCR4, CCR5, CCR8, CCR10, CXCR3, TGF-ȕR, ICOS, CD27, OX40, or CD15. 77. The method of any one of claims 74-76, wherein the pH-selective antibody comprises: a heavy chain variable region comprising an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 15; and a light chain variable region comprising an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 16. 78. The method of claim 77, wherein the pH-selective antibody binds CTLA-4 (anti-CTLA-4) and comprises: heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a variable heavy domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 15; light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a variable light domain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 16; and a human IgG1 Fc domain having variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto. DB1/ 133359610.3 67 Attorney Docket No.: SYN-061PC/112492-5061 79. The method of any one of claims 74-77, wherein the pH-selective antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 17 with a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto; and a light chain comprising an amino acid sequence of SEQ ID NO: 18. 80. The method of any one of claims 77-79, wherein the pH-selective antibody binds CTLA-4 (anti- CTLA-4) and comprises: heavy variable domain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 23-25 and a heavy chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ IS NO: 22 and having human IgG1 Fc domain variants S267E, H268D, and Y296H relative to SEQ ID NO: 1, or equivalent positions corresponding thereto; and light variable domain CDRs having the amino acid sequences of SEQ ID NOs: 26-28 and a light chain having at least about 95%, at least about 97%, at least about 98%, or at least about 99% sequence identity to the amino acid sequence of SEQ ID NO: 18. 81. The method of any one of claims 74-80, wherein the pH-selective antibody exhibits attenuated antibody-mediated effects at pH 7.4 in comparison to its antibody-mediated effects in the reduced pH of a cancer microenvironment. 82. The method of claim 81, wherein the antibody-mediated effects comprise target binding, antibody-dependent cellular phagocytosis (ADCP), and/or antibody-dependent cellular cytotoxicity (ADCC). 83. The method of any one of claims 74-82, wherein the pH-selective antibody exhibits an increased level of activity at a pH less than about 7.0 in comparison to its activity at a pH greater than about 7.0. 84. The pH-selective antibody of claim 83, wherein the pH-selective antibody exhibits an increased level of activity at a pH of about 6.5 in comparison to its activity at a pH of about 7.4. 85. The method of any one of claims 74-84, wherein the pH-selective antibody exhibits a reduced level of activity at a pH greater than about 7.0 in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 86. The pH-selective antibody of claim 85, wherein the pH-selective antibody exhibits a reduced level of activity at a pH of about 7.4 in comparison to an antibody with a wild-type Fc domain and/or a DB1/ 133359610.3 68 Attorney Docket No.: SYN-061PC/112492-5061 Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 87. The method of any one of claims 74-86, wherein the pH-selective antibody exhibits an improved safety profile in comparison to an antibody with a wild-type Fc domain and/or a Fc domain not having a substitution of one or more residues at one or more of position 233-235, 267-268, 296, and 298, or positions corresponding thereto. 88. The method of any one of claims 74-87, wherein the pH-selective antibody reduces or eliminates one or more side effects of Table 3. 89. The method of any one of claims 74-88, wherein the cancer is one or more of a solid tumor or blood-based cancer. 90. The method of any one of claims 74-89, wherein the cancer is one or more of a carcinoma, sarcoma, myeloma, leukemia, lymphoma, mixed type cancer, and/or metastatic cancer. 91. The method of claim 90, wherein the cancer is selected from hormone receptor-positive/HER2- negative breast cancer, triple negative breast cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), Esophageal Diffuse large B-cell lymphoma, metastatic melanoma, hepatocellular carcinoma, metastatic castration-resistant prostate cancer, triple-negative breast cancer, locally advanced or metastatic HER2-expressing cancers, non-small-cell lung cancer (NSCLC), ovarian cancer, PD-1/L1 failure patients with ROR-2 expression in recurrent or metastatic squamous cell carcinoma of the head and neck, melanoma, Merkel cell carcinoma, and nonsquamous NSCLC. 92. The method of any one of claims 74-91, wherein the subject has experienced one or more side effects of checkpoint inhibitor therapy. DB1/ 133359610.3 69